MXPA06004522A - Method of therapy - Google Patents

Abstract

Numerous diseases have been linked to the production of regulator cells. The present invention relates to the observation that the immune system is cycling in these diseases. Based on these observations, the present invention provides methods for treating diseases such as cancer and a HIV infection. The present invention also relates to methods of determining when a therapy to treat a disease characterized by the production of regulator cells should be administered to a patient.

Description

METHOD OF THERAPY FIELD OF THE INVENTION Numerous diseases have been linked to the production of regulatory cells. The present invention relates to the observation that the immune system cyclizes in these diseases. Based on these observations, the present invention provides methods for treating diseases such as cancer and HIV infection. The present invention also relates to methods for determining when a therapy should be administered to a patient to treat a disease characterized by the production of regulatory cells.

BACKGROUND OF THE INVENTION In the past, attempts have been made to induce the immune system to present an efficient response against malignant cells. Despite significant promising advances, such a response has not yet been fully achieved and many immunology-based therapies have proven to be discouraging. Numerous studies using in vitro cellular tests show that cytotoxic lymphocytes have the ability to kill tumor cells. Why this destruction based on immune response does not effectively control tumor growth in vitro is a riddle. The cancer patient also has an increased concentration of immune complexes in circulation, which indicates that the immune system is active, in particular against certain tumor antigens. The level of these immune complexes can increase with the progression of the disease (Horvath et al, 1982, Aziz et al, 1998). Regulatory cells (also known in the art as suppressor cells) have been implicated in the immune response of an individual against cancer (North and Awwad, 1990; WO 03/068257). Because most cancer antigens are actually produced by the patient these are considered "proper" by the immune system. Based on the presence and / or increased amount of tumor antigen, the immune system of the hosts presents a response characterized by the production of effector cells that target the cells that produce the tumor antigen. However, in many cases, these effector cells are recognized by the immune system as those that target the host cells themselves, and therefore a population of regulatory cells is produced to downregulate the effector cell population . Therefore, the production of these regulatory cells limits the ability of the immune system to effectively kill cancer cells. More recently, it has been shown that regulatory cells are involved in the immune response of individuals towards a viral infection. WO 02/13828 describes the production of regulatory cells during retroviral infection, and methods for treating said infections by down regulating the population of regulatory cells while maintaining the population of effector cells. Likewise, Peterson et al (2002) observed that a population of CD4 + regulatory cells suppresses the ability of CD8 + effector cells to control infections of Friend murine retroviruses in mice. Measurements of some plasma concentrations of acute phase protein can be of diagnostic or prognostic value under specific clinical conditions. The best known acute phase protein is reactive protein C (CRP). CRP is a plasma protein that increases in the blood with inflammation from certain conditions. The level of CRP in blood plasma can be raised as high as 1000 times with inflammation. Conditions that commonly lead to marked changes in CRP include bacterial and viral infection, trauma, surgery, burns, inflammatory conditions, heart disease and vascular diseases, and advanced cancer. Most acute phase proteins are synthesized by hepatocytes, some are produced by other cell types, including monocytes, endothelial cells, fibroblasts and adipocytes. Acute phase proteins include serum amyloid A (SAA), CRP and P component of serum amyloid (SAP). The immediate response capacity of CRP and SAA towards stimuli, along with its wide range of concentration and automated measurement facility, has led to the use of plasma levels of CRP and SAA to accurately monitor the severity of inflammation and the efficacy of disease management during certain pathological conditions. WO 103/070270 describes the use of acute phase inflammatory markers in regimens for the effective treatment of HIV. These methods are based on at least partially "restarting" the immune system by a treatment such as HAART followed by the analysis of acute phase inflammatory proteins as markers for the expansion of effector / regulatory cells. The appearance of acute phase inflammatory proteins seems to be linked to the expansion of effector cells, which occurs before the expansion of regulatory cells, and therefore the patient can be treated with an appropriate agent that allows the population of effector cells it is maintained while being destroyed, the production of, or the activity of, regulatory cells is prevented. In essence, after suspension of the HAART treatment it is considered that the patient's immune system can treat the HIV -emergent particles as a new infection, and therefore a new population of effector cells can be produced. In a similar manner to WO 03/070 270, WO 03/068 257 refers to at least partially restarting the immune system, however, in this case in the context of cancer treatment. Again, the treatment focuses on the initial pre-emergence of effector cells after a reduction in tumor burden through techniques such as surgery or administration of anti-proliferative drugs. None of the documents WO 02/138 28, WO 03/070270 or WO 03/068257 appreciate that the immune response has cycles in patients with cancer or HIV without taking into account the administration of the treatment for these diseases. The present invention is based on the observation of this cyclization, and therefore provides methods for treatment of diseases related to the production or activity of regulatory cells.

SUMMARY OF THE INVENTION The inventor of the present invention has surprisingly discovered that the immune system cyclizes during pathological conditions characterized by the presence of regulatory cells. This cycle occurs on a regular basis of approximately 14 to 15 days in humans. Although not wishing to be limited to the theory, it seems that the expansion of effector cells against a target antigen is followed by the expansion of the regulatory cells directed against the effectors. After the regulatory cells control the effector cells, the number and / or activity of both cell types is reduced, which in turn is followed by the same cycle due to the continuous presence or the incomplete removal of antigen which gives as It results in an oscillating, persistent but ineffective immune response against, for example, the tumor or the virus. The knowledge of this cycle can be used to treat diseases in which it is known that the emergence of regulatory cells is detrimental to the patient. Examples of such diseases include cancer and persistent infections such as by the human immunodeficiency virus. More specifically, the treatment of a patient can be synchronized in such a manner that the numbers of effector cells against a cellular or viral antigen are maximized while at the same time reducing or eliminating the numbers of regulatory cells. In fact, the inventor of the present invention has observed that the treatment of a wide variety of cancers with anti-cancer drugs results in, on average, a complete response rate in the range of 6.5 to 7%. This range of 6.5 to 7% is consistent with a cycle of approximately 14 to 15 days of effector cell expansion followed by regulatory cell expansion. More specifically, when the cyclization of the effector and regulatory cells is not considered, in a medical practitioner it has an approximate probability of 1 in 14.5 (6.8%) of administering an anti-proliferative drug at a time when the numbers of effector cells are high but the numbers of regulatory cells barely begin to expand and are therefore vulnerable to treatments that target dividing cells. This leaves high numbers of effector cells that target cancer cells, resulting in a complete response to therapy. Accordingly, in a first aspect, the present invention provides a method for determining at what time an agent should be administered to a patient suffering from a disease characterized by the production of regulatory cells, the method comprises monitoring the patient, or the samples obtained therefrom, with respect to at least one of: a) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or b) a marker of the immune system. In another aspect, the present invention provides a method for treating a disease characterized by the production of regulatory cells, the method comprising: i) monitoring a patient suffering from the disease with respect to at least one of: a) numbers and / or or regulatory cell activity, b) numbers and / or effector cell activity, c) a molecule associated with the disease, and / or d) a marker of the immune system, and ii) exposing the patient to an agent to treat the disease, wherein the timing of administration of the agent is selected such that the activity of the effector cells is not significantly reduced.

Preferably, the disease characterized by the production of regulatory cells is selected from, but is not limited to, cancer and an infection. The infection can be caused by any type of infectious agent such as, but not limited to, a virus, bacteria, protozoa, nematode, prion, or fungus. Preferably, the infectious agent causes persistent chronic infection characterized in that the patient's immune system can not eliminate the infectious agent. Examples of infectious agents that cause chronic persistent infection are viruses such as HIV, hepatitis B virus and hepatitis C virus. Although not wishing to be limited to the theory, it seems that as the antigen load increases, for example, from increased tumor growth or viral replication, after regulatory cell activity, the patient's immune system responds in a manner similar to a first exposure to the antigen. This immune response includes the production of: acute phase inflammatory markers such as serum amyloid A and reactive protein C. An appropriate time to administer to the agent is between the time when the acute phase inflammatory marker levels have reached a maximum and before the marker starts to rise in the next cycle.

Accordingly, a particularly preferred immune system marker is an acute phase inflammatory marker. More preferably, the acute phase inflammatory marker is selected from, but not limited to, the group consisting of serum amyloid A, serum amyloid P, and reactive protein C. Preferably, the immune system marker reflects the number and / or activity of the regulatory cells, and / or the number and / or activity of the effector cells. In one embodiment, the patient is monitored for an increase in the number and / or activity of regulatory cells by the analysis of CD4 + CD8 + T cell levels. With respect to this embodiment, it is preferred that the agent is administered at approximately the time when CD4 + CD8 + T cells are detected. In another embodiment, the patient is monitored for an increase in the number and / or activity of effector cells by the analysis of CD8 + CD4 + T cell levels. With respect to this embodiment, it is preferred that the agent be administered at approximately the time when the CD8 + CD4 + T cell numbers have reached a maximum. In another embodiment, the molecule associated with the disease is an antigen produced by a cancer cell or an infectious agent. In this embodiment, the agent is administered approximately when the levels of the molecule associated with the disease begin to decrease. In a further embodiment, the disease is cancer and the patient is monitored for fluctuations in antigen levels or tumor antigens. With respect to this embodiment, it is preferred that the agent be administered approximately at the time when tumor antigen levels begin to decrease. Even in a further embodiment, the disease is caused by an infectious agent and the patient is monitored for fluctuations in antigen levels or antigens produced by the infectious agent.

With respect to this modality, it is preferred that the agent be administered approximately at the time when antigen levels begin to decrease, or organisms or viruses (viral load) infectious. In another modality, the marker of the immune system is body temperature. With respect to this embodiment, it is preferred that the agent be administered when the body temperature reaches a maximum and before the body temperature begins to rise in the next cycle. As indicated in the present invention, the inventor of the present has observed that fluctuations in numerous factors indicate that the immune system is having cycles in patients suffering from a disease characterized by the production of regulatory cells. These factors include acute phase inflammatory markers, viral antigens, cancer antigens and body temperature. These factors are linked, directly or indirectly, to the general state of the immune system including, but not necessarily limited to, effector cell production and / or activity, production and / or regulatory cell activity, and / or production and / or activity of cell B. The person skilled in the art will appreciate that diseases such as cancer and AIDS have a complex effect on the patient. Likewise, the natural variations between individuals linked to factors such as their genotype, nutrition, physical condition, previous and current pathological condition, all influence the way in which an individual responds to a pathological state. Therefore, although in most cases the cycle is approximately 14 to 15 days, in some individuals it may be slightly shorter or longer. In addition, like the menstrual cycle, the length of the cycle may vary slightly within an individual due to natural variation and / or environmental factors. Therefore, the individual variation can be found at least with respect to, for example, i) the length of the cycle, ii) the absolute numbers of effector or regulatory cells during the cycle, or iii) the levels of inflammatory markers of acute phase during the cycle. Such variation may be exaggerated in patients with cancer or advanced infection, in which the patient's immune system has been challenged for a considerable length of time. As a result, it is very likely that it is most desired to monitor the patient for a sufficient length of time to ensure that the dynamics of the immune system cycles are understood within a particular patient. Preferably, the patient is monitored for a period of at least 7 days, more preferred for at least 14 days, more preferred for at least 21 days, more preferred for at least 28 days, more preferred for at least 35 days, more preferred for at least 42 days, and even more preferred for at least 49 days. Another complicating factor is that it has been discovered that at least the levels of some acute phase inflammatory markers complete a cycle approximately every 7 days (approximately half the length of a "complete" cycle of the immune system). Therefore, it seems that relying on these types of markers can improve the probability of successful treatment from approximately 6.8% (based on the random administration of the agent) to approximately 50% (based on the choice of the correct administration time). randomly choosing which peaks are linked with the appropriate time to choose the regulatory cells as targets). Although this is an improvement in current techniques, it is preferred that said markers be monitored in conjunction with other factors (e.g., a molecule associated with the disease, regulatory cells and / or effector cells) to optimize the probability of selecting the appropriate time. to administer the agent. Therefore, in another modality, the patient is monitored for an acute phase inflammatory marker, and a molecule associated with the disease. With respect to this modality, the agent is administered between the time when the acute phase inflammatory marker levels have reached a maximum and before the marker begins to rise in the next cycle, and at the moment in which the levels of the molecule associated with the disease begins to decrease or has been predicted to begin to decrease based on previous analyzes of the molecule. In general, it is preferred that numerous factors be monitored at the same time. This is because, due to the factors described above, it is unlikely that each factor will have a perfect cycle profile within a period of 14/15 days, particularly over a number of cycles, to routinely provide a clear indication of the appropriate time to administer the agent. Although the analysis of numerous factors of a prolonged period can be expensive, and may present at least some inconvenience to the patient, diseases such as cancer and AIDS are life threatening. Therefore, it is worthwhile to understand as much as possible regarding the cycles of the immune system in a given patient before the patient is treated. In addition, although analyzes of the different factor cycles in some patients may result in complex profiles, given the guidelines provided in the present invention, it is within the ability of the medical practitioner to analyze the monitoring data to determine the optimum time to administer. the agent. In the present invention an example of careful multi-factor analysis is provided to determine the appropriate time to effectively treat a disease characterized by the production of regulatory cells. An additional complicating factor may be if the patient has recently acquired a disease or trauma unrelated to what is being treated. For example, a patient who is being treated for an HIV infection can also get the common flu virus. The presence of the influenza virus can result, for example, in an increase in inflammatory markers of acute phase independent of the cyclization of these markers which occurs due to HIV infection. Other diseases that can cause complications in the monitoring of effector / regulator cell cycling for use in the methods of the present invention include, rheumatoid arthritis, ulcers and chronic gum disease. Accordingly, it would be desirable to monitor the patient regarding any factors that may result in high levels of, for example, acute phase inflammatory markers to ensure that the factor being monitored actually reflects the effector / regulatory cell cyclization that results from the disease that is being treated. Also, it is preferred that the patient be monitored as frequently as possible to ensure that the cyclization of the immune system within a given patient is appropriately characterized. Of course, this can ensure that the agent is administered at the appropriate time and that any small variations in, for example, numbers or effector / regulatory cell activity, or markers thereof, are not misinterpreted. Preferably, the patient is monitored at least every 3 days, more preferred at least every 2 days, and more preferred at least every day. Monitoring may occur more frequently, for example every 12 hours, when cyclization reaches a stage at which synchronization is likely to be appropriate for administering the agent. Preferably, the agent inhibits the production of, limits the function of, and / or destroys, the regulatory cells. More preferably, the agent is selected from the group consisting of anti-cancer drugs such as anti-proliferative drugs, radiation, dsRNA and antibodies that inhibit the production and / or activity of regulatory cells. Preferably, the anti-proliferative drug is selected from the group consisting of, but not limited to, taxol, vincristine, vinblastine and anhydro vinblastine. With respect to cancer, in contrast to the typical anti-cancer drug therapy which is administered to target tumor cells, the treatment method described in the present invention actually targets the regulatory cells as target. This leaves appropriate numbers of effector cells to produce the desired therapeutic effect.

Examples of preferred antibodies include, but are not limited to, anti-CD4 +, anti-CTLA-4 (antigen 4 associated with cytotoxic lymphocyte), anti-GITR (tumor necrosis factor receptor induced by glucocorticoid), anti-CD28 and anti-CD25. Preferably, the patient has not been exposed to a treatment for the disease for at least 14 days, more preferred for at least 21 days, and even more preferred for at least 28 days. The inventor of the present invention has also determined that treatment for a disease characterized by the production of regulatory cells can be improved (or opportunities for successful treatment can be increased) when the vaccine is administered at the appropriate time. In these cases, the vaccine reinforces the innate immune response against the disease. This can probably be a result of increased numbers and / or activity of the effector cells. Although theoretically the regulatory cells are eventually produced, the reinforcement of the immune system allows the patient to appropriately control the disease before the emergence of the regulatory cells. This scenario may explain why previous studies have shown that anti-HIV and anti-tumor vaccines are only successful in a small number of patients. More specifically, there is only a small chance that the vaccine will be administered at the same time as the innate immune response to the disease is occurring. Other administration times in the prior art occur when there are numbers and / or high activity of regulatory cells, or at times in which the natural cyclization of the immune system is decoupled. Therefore, in another aspect, the present invention provides a method for determining the time at which a vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells, the method comprising monitoring the patient, or the samples obtained therefrom, with respect to at least one of: a) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or ) a marker of the immune system. In a further aspect, the present invention provides a method for treating a disease characterized by the production of regulatory cells, the method comprising: i) monitoring a patient suffering from the disease with respect to at least one of: a) the number and / or activity of regulatory cells, b) number and / or activity of effector cells, c) a molecule associated with the disease, and / or d) a marker of the immune system, and ii) exposing the patient to a vaccine to treat the disease, in which the timing of administration of the vaccine is selected such that the activity of the effector cells is not significantly reduced. In one embodiment, the vaccine is administered approximately at the time when effector cell levels are increased. In another embodiment, the vaccine is administered approximately at the time when the levels of a molecule associated with the disease begin to decrease. In a further embodiment, the vaccine is administered at about the time when the levels of an acute phase inflammatory marker begin to increase. As noted above, it has been found that at least some acute phase inflammatory markers complete a cycle around approximately a 7-day period in which only every second peak of acute phase inflammatory marker levels is associated with the numbers effector cell Therefore, in this embodiment, it is very likely that the monitoring needs to be combined with the analysis of other factors described in the present invention. The observation that the immune system has cycles during disease states characterized by the presence of regulatory cells can also be used as an indicator of the presence of said disease. These diagnostic procedures may be particularly useful for analyzing a patient regarding the recurrence of the pathological condition (such as a tumor) after treatment, or to analyze a patient diagnosed as susceptible to the disease (such as in cases in which the individual has been previously identified as having a cancer susceptibility gene) for the onset of the disease. Therefore, in a further aspect the present invention provides a method for diagnosing a disease characterized by the production of regulatory cells, the method comprising monitoring the patient, or samples obtained therefrom, with respect to at least one of: a ) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or b) a marker of the immune system, in which the cyclization of either a) ad) indicates that the disease may be present. Of course, as indicated above, it will be necessary to analyze the patient in relation to other pathological conditions, such as minor infections such as influenza, etc., to ensure that any observed cyclization (especially when analyzing acute phase inflammatory markers) is directly linked. with a disease characterized by the production of regulatory cells. Although monitoring should ideally continue indefinitely, it is very likely that this will not be practical in most situations. Therefore, the diagnostic procedure can be performed on an intermittent basis based on an assessed risk of the emerging or re-emerging pathological condition. As will be appreciated by the person skilled in the art from the discussions in the present invention, the term "intermittent basis" means that the method may require that an appropriate number of samples be analyzed over a time interval to determine whether the cyclization of the immune system is being presented (for example samples obtained at least every 3 days for a period of approximately 14 days), however, if the test is negative it might not be necessary to repeat this procedure (for example) for another year . In another aspect, the present invention provides the use of a test that detects a marker of the immune system to determine at what time an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells. Preferably, the marker is an acute phase inflammatory marker. More preferred, the marker is a positive acute phase inflammatory marker. Even more preferred, the marker is selected from the group consisting of, but not limited to, serum amyloid A and reactive protein C. In another aspect, the present invention provides the use of a test that detects numbers and / or effector cell activity to determine the time at which an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells. Preferably the test detects the number of CD8 + CD4 + T cells. In another aspect, the present invention provides the use of a test that detects numbers and / or regulatory cell activity to determine at what time an agent or vaccine should be administered to a patient suffering from a disease characterized by cell production. regulators. Preferably, the test detects the number of CD4 + CD8 + T cells. In another aspect, the present invention provides the use of a test that detects a molecule associated with a disease characterized by the production of regulatory cells to determine at what point an agent or vaccine should be administered to treat the disease. Preferably, the test detects an antigen produced by a cancer cell or an infectious agent. Preferably, the patient has not been exposed to a treatment for the disease for at least 14 days, more preferred for at least 21 days, and even more preferred for at least 28 days. In a further aspect, the present invention provides the use of an agent for the manufacture of a medicament for administering to a patient suffering from a disease characterized by the production of regulatory cells., in which the agent is administered at a time that is selected such that the activity of effector cells is not significantly reduced, and in which the patient has not been exposed to a treatment for the disease for at least 14 days. Preferably, the agent inhibits the production of, limits the function of, and / or destroys, the regulatory cells. As will be readily appreciated by those skilled in the art, the methods of the present invention may be repeated to provide a more complete treatment. Preferably, the patient is a mammal. More preferred, the mammal is a human. In a further aspect, the present invention provides a kit for determining the time at which an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells, the kit comprising at least one reagent for monitoring the patient, or samples obtained therefrom, with respect to at least one of: a) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or d) a marker of the immune system. Preferably, the kit comprises written instructions for effecting a method of the invention that includes reference to the preferred numbers of samples to be analyzed, and the time between sample analyzes. As will be apparent, preferred features and features of one aspect of the invention can be applied to many other aspects of the invention. Throughout this description, it should be understood that the word "comprise", or variations such as, "comprises" or "comprising", implies the inclusion of an element, integer or step, or group of elements, integers or steps mentioned, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The invention is described hereinafter by the following non-limiting examples and with reference to the appended figures.

BRIEF DESCRIPTION OF THE FIGURES Figure 1. A) Levels of C reactive protein and CA125 tumor marker over a period of 14 days in a patient with ovarian cancer. B) Levels of serum amyloid A in the same patient over the same period (the levels of C-reactive protein come from A) doubled). Figure 2. Reactive protein C levels in response to removing a first human HIV patient from the HAART treatment. Figure 3. Viral load and fluctuations of CRP in a second patient with HIV after completing HAART. Figure 4. The fluctuations of CRP and C4 in Mrs OM over 32 days show a different periodicity with a repetition oscillation of approximately 7/14 days. The measurements are taken every Monday, Wednesday and Friday. In this case the oscillation of C4 is more regular. Note the upward trend in both parameters throughout the 32-day period. Figure 5. Fluctuations of C4 and C3 of serum complement factors in Mrs OM over 32 days show an almost synchronous and regular periodicity of approximately 7/14 days. Note the upward trend in both parameters over the 32-day period. Figure 6. C4 fluctuations of serum complement factor and elevation of CA125 levels with progressive disease in Mrs OM. Note the upward trend in both parameters over the 32-day period. Figure 7. Reactive protein C versus time in Mrs OM, (days) monitoring and therapeutic events, May 28, 2004 (day l) -9 August 2004 (day 74). CRP monitoring begins on May 28 (day 1) and increases steadily with the progression of the disease. The oscillation of the immune response of approximately 14 days is obtained from the combined interpretation of the data collected from serum CRP, C4 and CA125 (see also figure 4). Caption: A = Radiation therapy begins, day 38, = July 5, 2004.

B = Predicted CRP peak, day 46, 47 and 48, = 13, 14, July 15, 2004. C = Synchronization of the first application of chemotherapy, day 49, July 16, 2004. D = Predicted peak of CRP , day 63 and 64, = 28, July 29, 2004. Radiation therapy is stopped. E = Synchronization of the second application of chemotherapy, day 65, = July 30, 2004. F = Fever, day 66, = July 31, 2004, hemorrhage from the tumor, day 67, = August 1, 2004. G = CRP falls to 62.7 mg / l, day 69, = August 4, 2004. H = Endoscopy does not report evidence of the tumor, day 74, = August 9, 2004. Figure 8. Reactive protein C and amyloid A serum against time in Mrs FO. Figure 9. Serum amyloid C A and IL-2 against time in Mrs FO. Figure 10. Serum amyloid A and cancer marker CA125 against time in Mrs FO. Figure 11. Reactive protein C and C3 against time in Mrs FO. Figure 12. Reactive protein C against time in Mr GA.

DETAILED DESCRIPTION OF THE INVENTION Definitions As used in the present invention the terms "to treat", "treat" or "treatment" includes administering a therapeutically effective amount of an agent sufficient to reduce or eliminate at least one symptom of the disease. As used in the present invention, the term "tumor burden" usually refers to the number of cancer cells in an individual at any given time. The measurement of the level of tumor antigen in the individual can be considered as an indication of tumor burden. As used in the present invention, the term "viral load" in general refers to the number of viral particles in an individual at any given time. The measurement of the level of viral antigen in the individual can be considered as an indication of the viral load. "Regulatory cells" include, but are not necessarily limited to, a sub-population of T cells CD4 +. Such cells are also known in the art as "suppressor cells". Regulatory cells can either act directly on the effector cells or can reaffirm their effects on effector cells through other mechanisms. CD4 + cells express the marker known in the art as CD4. Typically, the term "CD4 + T cells" as used in the present invention does not refer to cells that also express CD8. However, this term may include T cells that also express other antigenic markers such as CD25. "Effector cells" includes, but is not necessarily limited to, the population of T cells known as CD8 + cells. As used in the present invention, the term "limits the function of, and / or destroys" when referring to the exposure of "regulatory cells" to the agent means that the number, and / or activity, of the regulatory cells it is regulated in a negative way by the agent. Most preferably, the number, and / or activity, of the regulatory cells is completely eradicated by the agent. As used in the present invention, "disease characterized by the production of regulatory cells" refers to any condition in which the number or activity of regulatory cells plays a role in prolonging the disease state. Examples of said disease include, but are not limited to, cancer and infections. The term "immune system marker" refers in general terms to any molecule or factor that provides an indication of the state and / or activity of the immune system. These markers may be directly linked to the activity and / or production of regulatory and / or effector cells, and / or may provide a more general indication of the total response of the immune system to an antigen. Examples of a suitable immune system marker include acute phase inflammatory markers such as reactive protein C and serum amyloid A. Another example of a marker of the immune system are indicators of cell destruction such as, but not limited to, cholesterol and beta-2-microglobulin in serum. Cholesterol and beta-2-microglobulin are integral components of cell membranes. In particular, beta-2-microglobulin is the accessory molecule for the class I receptor of the major histocompatibility complex or MHC-I receptor. Accordingly, with the cyclization of the immune response against the disease together with the destruction of the target cell, serum levels of these two molecules are often elevated in cancer patients. Therefore, oscillations in the indicators of cell destruction, such as cholesterol and beta-2-microglobulin, may also prove to be useful in determining the beginning or end of the immune response cycle. Of course, after the present discovery of the cyclization of the immune system in a disease characterized by the production of regulatory cells, one skilled in the art can easily identify additional markers useful in the methods of the invention. As used in the present invention, the term "a molecule associated with the disease" refers to any molecule that is linked to the pathological state. In a preferred embodiment, the label is a protein. Said protein markers are well known in the art. Examples of appropriate tumor antigen markers are described in the present invention. Markers for, if not all, infectious diseases are also well known, for example HIV gag or env proteins. As used in the present invention, the term "chronic persistent infection" refers to the presence of an infectious agent in the patient which is not easily controlled by the patient's immune system or available therapies. Examples include, but are not limited to, infections with Mycobacterium tuberculosis (which causes tuberculosis), HIV, hepatitis B virus or hepatitis C virus. To be classified as a "persistent chronic infection" is he prefers that the patient had the infection for 3 months, more preferred for at least 6 months. For the purposes of this invention, the term "antibody", unless otherwise specified, includes fragments of complete antibodies that retain their binding activity for an objective analyte. Such fragments include the Fv, F (ab ') and F (ab') 2 fragments, as well as the individual chain antibodies (scFv). Also, the antibodies and fragments thereof can be humanized antibodies, for example as described in EP-A-239400. As is known in the art, a cancer is generally considered as uncontrolled growth of cells. The methods of the present invention can be used to treat any cancer including, but not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast tissue cancer, prostate cancer, colon cancer, squamous cell cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, liver cancer, bladder cancer, hepatoma, colorectal cancer, cervical cancer, endometrial carcinoma, salivary gland carcinoma, mesothelioma, kidney cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, skin cancer, melanoma, brain cancer, neuroblastoma, myeloma, various types of cancer of the head and neck, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing's sarcoma and peripheral neuroepithelioma. The "sample" refers to a material suspected of containing regulatory cells, effector cells, markers of the immune system and / or a molecule associated with the disease. The sample may be used as obtained directly from the source or by following at least one (partial) purification step. The sample can be prepared in any convenient medium that does not interfere with the method of the invention. Typically, the sample is an aqueous solution or biological fluid as described in more detail below. The sample can be obtained from any source, such as a physiological fluid, including blood, serum, plasma, saliva, sputum, lens fluid, sweat, feces, urine, milk, ascitic fluid, mucus, synovial fluid, peritoneal fluid , transdermal exudates, pharyngeal exudates, bronchoalveolar lavages, aspirations of the trachea, cerebrospinal fluid, semen, cervical mucus, vaginal or urethral secretions, amniotic fluid, and the like. Preferably, the sample is blood or a fraction thereof. The pre-treatment may involve, for example, preparing plasma from blood, diluting viscous fluids, and the like. The treatment methods may involve filtration, distillation, separation, concentration, inactivation of interfering components, and the addition of reagents. The selection and pre-treatment of biological samples before evaluation are well known in the art and need not be described in greater detail. Unless otherwise indicated, the recombinant DNA and immunological techniques used in the present invention are standard procedures, well known to those skilled in the art. These techniques are described and explained through literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989), TA Brown (ed.), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al (editors), Current Protocols in Molecular Biology, Greene Pub.

Associates and Wiley-Interscience (1988, including all new editions to date), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988), and J.E. Coligan et al (editors) Current Protocols in Immunology, John Wiley & Sons (including all new editions to date), and are incorporated for reference herein.

Inflammatory markers of acute phase Some inflammatory markers of acute phase initially increase during an immune response (known hereinafter as positive acute phase inflammatory markers) while others initially reduce during an immune response (referred to in the present invention hereafter as negative acute phase inflammatory markers). Acute phase inflammatory markers are also known in the art as acute phase reactants or acute phase proteins. Those skilled in the art are aware of the many tests that can be used to monitor acute phase inflammatory markers. Examples of positive acute phase inflammatory markers include, but are not limited to, C reactive protein, serum amyloid A, serum P amyloid component, complement proteins such as C2 inhibitor, C3, C4, C5, C9, B, Cl and C4 binding protein, fibrinogen, von Willebrand factor, al-antitrypsin, al-antichymotrypsin, a2-antiplasmin, heparin cofactor II, plasminogen activator inhibitor I, haptoglobin, hemopexin, ceruloplasmin, manganese superoxide dismutase, Acid glycoprotein, hemoxygenase, mannose binding protein, leukocyte protein I, lipoprotein (a), lipopolysaccharide binding protein, and interleukins such as IL-1, IL-2, IL-6, IL- 10 and receivers for them. Examples of negative acute phase inflammatory markers include, but are not limited to, albumin, pre-albumin, transferrin, apoAI, apoAII, glycoprotein 2 HS, inter-a-trypsin inhibitor, histidine-rich glycoprotein. Serum amyloid A (SAA) was discovered as a component of plasma that shares antigenicity with AA amyloid, the main fibrillar component in reactive AA amyloid deposits. It has been shown that SAA is an acute phase reactant whose blood levels rise up to 1000 times or more as part of the body's responses to various injuries including trauma, infection and inflammation. The levels of SAA can be determined as is known in the art, see for example Weinstein et al (1984), Liuzzo et al (1994), O'Hara et al (2000), Kimura et al (2001) and O'Hanlon. et al (2002). Reactive protein C (CRP) is an important positive acute phase response protein, and its serum concentration can be increased as much as 1000 times during the acute phase response. CRP is a pentamer consisting of five identical subunits, each having a molecular weight of approximately 23,500. C-reactive protein levels can be determined using techniques known in the art, these include, but are not limited to, those described in Senju et al (1983), Weinstein et al (1984), Price et al (1987), Liuzzo et al (1994), Eda et al (1998), Kimura et al (2001) and O'Hanlon et al (2002). Complement proteins are a group of at least 20 immunologically distinct components. These normally circulate in the blood in an inactive form. These can interact sequentially with antigen-antibody complexes, with each other and with cell membranes in a complex but adaptable way to destroy viruses and bacteria and from the pathological point of view, including the host cells themselves. Abnormal serum levels of complement proteins may be due to any of inherited or acquired diseases. At least the circulating levels of C3 and C4 reflect a balance between complement consumption due to immune complex formation and increased synthesis due to the acute phase response. Methods for measuring complement protein levels are well known in the art. The levels of different inter-leucines can also be determined using procedures known in the art such as using the ProteoPlex ™ cytokine test kit (EMD Biosciences Inc., CA USA).

Agents The agent can be any factor or treatment useful for treating a disease characterized by the production of regulatory cells. Preferably, the agent results selectively or non-selectively in the destruction, inhibition of production, or reduction of activity, of the regulatory cells. For example, a CD4 + specific antibody can be used to specifically target CD4 + T cells as target. However, in some cases a non-selective agent, such as an antiproliferative drug or radiation, both of which destroy the dividing cells, can be used. In particular, as with the other cell types, regulatory cells are particularly vulnerable to destruction by anti-mitotic (anti-proliferative) drugs or spindle poisons (for example vinblastine or paclitaxel) when they are divided and specifically in the mitosis. The term "anti-proliferative drug" is a term well understood in the art and refers to any compound that destroys dividing cells or inhibits them from further proliferation. Anti-proliferative drugs include, but are not limited to, mecloretamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, thioguanine, pentostatin, vinblastine, anhydro vinblastine, vincristine, etoposide, teniposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin, L-asparaginase, cisplatin, mitoxantrone, hydroxyurea, procarbazine, mitotane, aminoglutethimide, prednisone, hydroxyprogesterone caproate, acetate of medroprogesterone, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, radioactive isotopes, ricin A chain, taxol, diphtheria toxin, colchicine and pseudomonas exotoxin A. The agents are usually administered in the dosage forms that are readily available to the clinician, and are usually administered in their normally prescribed amounts (such as, for example, the amounts described in Physician's Desk Reference, 55th edition, 2001, or the amounts described in the manufacturer's literature for agent use). In one embodiment, the agent is administered as an individual bolus injection. In another embodiment, the agent is administered by infusion. The infusion period can be, for example, at least 3 hours, at least 12 hours or at least 24 hours. Recent studies suggest that CD4 + CD25 + T cells play an important role in the regulation of immune system cells directed against autoantigens (Salomon et al, 2000, Suri-Payer and Cantor, 2001). It has also been shown that targeting CD4 + CD25 + T cells increases the ability of an animal to control tumor growth (Onizuka et al, 1999, Shimizu et al, 1999, Sutmuller et al, 2001). Accordingly, CD4 + CD25 + T cells can act as regulatory cells as used in the present invention. The activity of CD4 + CD25 + T cells can be regulated in a negative way by anti-GITR, anti-CD28 and / or anti-CTLA-4 (Read et al, 2000, Takahashi et al, 2000, Shimizu et al, 2002) . Therefore, these antibodies may be useful as agents for use in the methods of the present invention. Another example of an agent that can be administered in a method of the invention is dsRNA. The dsRNA is used in RNA interference (RNAi) which is a phenomenon where after introduction into a cell, the mRNA homologous to the dsRNA is specifically degraded in such a way that the synthesis of gene products is suppressed. Examples of such agents that cause RNAi include, but are not limited to, a sequence having at least about 70% homology to the nucleic acid sequence of a target gene or a sequence that can hybridize under astringent conditions, RNA containing a double-stranded portion with a length of at least 10 nucleotides or variants thereof. Examples of target genes include, but are not limited to, a gene necessary for the replication of a regulatory cell, a gene necessary for the survival of a cancer cell, or a gene necessary for the growth and / or replication of an agent infectious. DsRNA that has a length of about 20 bases (e.g., representatively 21 to 23 bases approximately) or less than about 20 bases can be used, which is termed siRNA in the art. The expression of siRNA in cells can suppress the expression of a gene chosen as target by the siRNA. In another embodiment, an agent that can cause RNAi may have a short orifice structure having an adhesive portion at the 3 'end (shRNA); Short orquilla RNA). As used in the present invention, the term "shRNA" refers to a molecule of about 20 or more base pairs in which a single-stranded RNA partially contains a palindromic base sequence and forms a double-stranded structure in the same (that is, a structure in the basket). shRNA can be synthesized chemically in artificial form. Alternatively, shRNA can be produced by ligating sense and antisense strands of a DNA sequence in reverse directions and synthesizing RNA in vi tro with T7 RNA polymerase using the DNA as a template. The length of the double stranded portion is not particularly limited, but about 10 or more nucleotides are preferred, and more preferably about 20 or more nucleotides are preferred. The 3 'end that is projected preferably can be DNA, more preferred DNA of at least two nucleotides in length, and even more preferred DNA of 2-4 nucleotides in length. An agent that can cause RNAi useful for the invention can be synthesized artificially (chemically or biochemically) or be of natural origin. There is substantially no difference interleaved in the terms of the effect of the present invention. A chemically synthesized agent is preferably purified by liquid chromatography or the like. An agent that can cause RNAi used in the present invention can also be produced in vitro. In this synthesis system, the T7 RNA polymerase and the T7 promoter can be used to synthesize antisense and sense RNA molecules from the DNA template. These RNA molecules are fixed and after that they are introduced into a cell. The dsRNA may be delivered to the patient using any means known in the art. Examples of methods for delivering dsRNA to a patient are described in, for example, US 20040180357, US 20040203024 and 20040192629.

Synchronization of the exposure of the individual to the agent For the investigator who randomly applies a single treatment of anti-proliferative chemotherapy to a patient with cancer, there is an approximate probability of 1 in 14, to 1 in 15, of obtaining the correct synchronization. A probability of one in fourteen is equal to a 7% chance of applying the therapy on the correct day, when the regulatory cells are vulnerable to inactivation. If this is done, the tumor must present regression mediated by immune destruction. More specifically, the hypothesis is that once the regulatory cells have been eliminated by therapeutic intervention, the immune response against the tumor or virus can proceed in an unimpeded manner, eventually leading to control of the disease. Although not wishing to be limited to the theory, it is believed that the relative number of effector cells expands in response to an antigen before regulatory cells. Accordingly, as used in the present invention, the term "effector cell activity is not significantly reduced" means that the timing of the administration of the agent is such that the agent exerts a proportionally increasing effect against the regulatory cells that of the effector cells. It is clearly preferred that the agent be administered at a time when the ratio of effect against the regulatory cells to the effect against the effector cells is greatest. As indicated above, the present invention is based on the phenomenon that the immune system completes a cycle over a period of approximately 14 to 15 days in a patient suffering from a disease characterized by the production of regulatory cells. In most cases, the time point at which the agent should be administered should be calculated empirically in individuals at different stages of the disease because the kinetics of their immune response may vary. Other factors such as the general health of the individual and / or the genetic constitution of the individual may also have effects on the time that is appropriate to administer the agent. As will be appreciated by those skilled in the art, conditions such as cancer and persistent chronic infection are serious diseases, which often endanger life. Due to the many factors, the last of which are not natural variations between individuals, it will typically be required for a patient to be monitored for a reasonable length of time to appreciate the nature of the cyclization of the immune system in the individual, and to be monitored. to analyze a number of factors (such as a combination of acute phase markers and disease antigens), to finally determine the most appropriate time to administer to the agent to optimize the probabilities of an effective treatment. Techniques known in the field can be used to monitor the growing population of effector and / or regulatory cells during the "cycle". Serial blood samples can be collected and evaluated quantitatively for all subsets of CD4 + by FACS analysis. It is necessary to maintain this FACS monitoring until the regulatory cells begin to expand in cloned form in response to the pathological state, either produced by the tumor or administered to the individual. Other possible tests to monitor the growing population of regulatory cells include lymphocyte proliferation / activation tests and various cytokine level tests (eg a test for IL-4, IL-6 or IL-10). In addition, serial blood samples can be collected and quantitatively evaluated for all effector cell activity such as, but not limited to CD8 +, CRP, SAA and various cytokines. Said effector cell markers precede the regulatory cell markers. When the disease is cancer, another way to determine the time to administer the agent is to monitor the tumor burden. It is contemplated that the tumor load is reduced due to the activity of the effector cells, however, the subsequent increase in the regulatory cells may negatively regulate the effector cells which results in a slowdown of the tumor burden reduction. Accordingly, the agent can be administered approximately before deceleration of the tumor load reduction. Techniques known in the art can be used, for example RT-PCR or antibody detection, of markers expressed by the tumor, to measure the tumor burden under these circumstances. Examples of appropriate tumor antigen marker tests include, but are not limited to, AFP (marker for hepatocellular carcinoma and germ cell tumors), CA 15-3 (marker for numerous cancers including breast tissue cancer), CA 19-9 (marker for various cancers including pancreatic cancer and bile duct cancers), CA 125 (marker for various cancers including ovarian cancer), calcitonin (marker for various tumors including medullary carcinoma of the thyroid), catecholamines and metabolites ( pheochromocytoma), CEA (marker for various cancers including colorectal cancers and other gastrointestinal cancers), hCG / beta hCG (marker for various cancers including germ cell tumors and choriocarcinomas), 5HIAA in urine (carcinoid syndrome), PSA (prostate cancer), sertonin (carcinoid syndrome) and thyroglobulin (carcinoma of the thyroid).

It may be necessary for onyotry to be very frequent, for example as frequent as every few hours, to ensure that the correct time point is chosen for the administration of the agent. Preferably, monitoring is carried out at least every 48 hours. Most preferably, monitoring is carried out at least every 24 hours. Optimally, monitoring is continued to determine the effect of the agent. Negative negative regulation, re-emergence of regulatory cells or increases in, for example, tumor loading means that the method of the present invention should be repeated. Such repeated cycles of treatment can generate immunological memory. Therefore it is possible that the present invention, used in repetitive mode, can provide a certain prophylactic protective effect.

Vaccines As indicated above, the inventor has observed after a literature investigation that the treatment of a variety of cancers with therapeutic vaccines, on average produces a complete response rate of approximately 10% (see, for example, Trefzer et al. , 2004, Lotem et al., 2004, Smithers et al., 2003, Belli et al., 2002, Berd et al., 2001, Wittig et al., 2001). This implies a window of opportunity for therapeutic application of 1.5 days every 14 days (10%). This is similar and is within the probability ranges of the full response rates of approximately 7% (1 day in 14) observed in cancer chemotherapy reported in the present invention. Therefore, a similar mechanism works in the situation of vaccines in which the inoculation of a cancer vaccine in the patient at the correct time is sufficient to alter the mechanisms / regulatory cells which allows the effectors to annihilate the tumor. which results in a complete response. Of course, the vaccines used in the present invention result in an immune response against a disease characterized by the production of regulatory cells. Said vaccine comprises at least one antigen, or a polynucleotide coding for said antigen. The vaccine may be provided in any manner known in the art, such as, but not limited to, DNA vaccine, the ingestion of a transgenic organism that expresses the antigen, or a composition comprising the antigen. As used in the present invention, an "antigen" is any polypeptide sequence that contains an epitope that is capable of producing an immune response against the disease. Antigens that can create an immune response against a cancer cell are well known in the art. Some tumor antigens can be recognized and targeted by the immune system. This property may be due to over-expression by the tumor tissue. Some of these antigens can be detected in normal tissue. Tumor antigens chosen as target by T cells are usually intracellularly processed proteins and presented as short peptide fragments bound in the groove of the MHC class I molecule of tumor that will be recognized by CD8 + cytotoxic T lymphocytes. The mere presence of a tumor antigen is not always sufficient to induce an immune response. Sometimes co-stimulatory molecules such as B7.1 are required. Once the antigen-specific T cells are stimulated, they can recognize and destroy the tumor. The conditions necessary for the activation of antigen-specific T cells are strict, but are open to genetic manipulation of target tumor cells and T cells. Antigens that can be used to treat infections, such as HIV, are also well known in The technique. The antigen can be delivered in any manner known in the art that leads to an immune response. An antigen can be, for example, original, recombinant or synthetic. The original antigens can be prepared, for example, by supplying cell lysates of a tumor cell. Vaccines can be prepared from one or more antigens. The preparation of vaccines containing an antigen is known to the person skilled in the art. Typically, such vaccines are prepared as injectables, or oral, either as liquid solutions or suspensions; It is also possible to prepare suitable solid forms to dissolve or suspend them in liquid before injection or oral consumption. The preparation can also be an emulsion, or the protein encapsulated in liposomes. The antigen is often mixed with vehicles / excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable vehicles / excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the vaccine may contain minor amounts of auxiliary substances such as wetting agents or emulsifiers, pH regulating agents, and / or adjuvants that increase the effectiveness of the vaccine.

Typically, the vaccines comprise an adjuvant. As used in the present invention, the term "adjuvant" means a substance that non-specifically increases the immune response to an antigen. Examples of adjuvants that may be effective include but are not limited to: N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine ( CGP 11637, known as nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanin-2- (1-2-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy) -ethylamine (CGP 19835A, known as MTP-PE), and RIBI, which contains three components extracted from bacteria, monophosphoryl lipid A, trehalose dimycolate and the cell wall skeleton (MPL + TDM + CWS) in a 2% squalene / Tween emulsion 80. Additional examples of adjuvants include aluminum hydroxide, aluminum phosphate, potassium aluminum sulfate (alum), bacterial endotoxin, lipid X, Corynebacterium parvum (Propionobacterium acnes), Bordetella pertussis, polyribonucleotides, sodium alginate, lanolin, lysolecithin, vitamin A, saponin, liposomes, levamisole, DEAE-dextran, blocked copolymers or other synthetic adjuvants. Such adjuvants can be obtained commercially from various sources, for example, Merck's Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.) or Freund's incomplete adjuvant and complete adjuvant, (Difco Laboratories, Detroit, Michigan). The proportion of antigen and adjuvant can be varied over a wide range while both are present in effective amounts. For example, aluminum hydroxide may be present in an amount of about 0.5% of the vaccine mixture (based on A1203). Conveniently, the vaccines are formulated such that they contain a final antigen polypeptide concentration in the range of 0.2 to 200 μg / ml, preferably 5 to 50 μg / ml, more preferred 15 μg / ml. After the formulation, the vaccine can be incorporated into a sterile container which is then sealed and stored at a low temperature, for example 4 ° C, or it can be lyophilized. Lyophilization allows long-term storage in a stabilized form. The vaccines are administered conventionally parenterally, by injection, for example, either subcutaneously or intramuscularly. Additional formulations that are appropriate for other modes of administration include suppositories and, in some cases, oral formulations. For suppositories, traditional binders and vehicles may include, for example, polyalkylene glycols or triglycerides; said suppositories can be formed from mixtures containing the active ingredient in the range of 0.5% to 10%, preferably 1% to 2%. Oral formulations include excipients such as those normally used, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10% to 95% active ingredient, preferably 25% to 70%. In cases where the vaccine composition is lyophilized, the lyophilized material can be reconstituted before administration, for example as a suspension. The reconstitution preferably takes place in pH buffer solution. Capsules, tablets and pills for oral administration to a patient can be provided with an enteric coating comprising, for example, Eudragit "S", Eudragit "L", cellulose acetate, cellulose acetate phthalate or hydroxypropylmethylcellulose. DNA vaccination involves the direct in vivo introduction of DNA encoding an antigen into the tissues of an individual for expression of the antigen by the cells of the individual's tissue. Said vaccines are referred to in the present invention as "DNA vaccines" or "nucleic acid-based vaccines". DNA vaccines are described in US 5 documents, 939,400, US 6,110,898, WO 95/20660 and WO 93/19183, the descriptions of which are incorporated in the present invention for reference in their entireties. To date, most DNA vaccines in mammalian systems have been based on viral promoters obtained from cytomegalovirus (CMV). These have had adequate efficiency in both muscle and skin inoculation in a number of mammalian species. One factor that is known to affect the immune response presented by DNA immunization is the method of DNA delivery, for example, parenteral routes of administration can produce low rates of gene transfer and produce considerable variability of gene expression. The high-speed inoculation of plasmids, using a gene gun, increases the immune responses of mice, possibly due to a higher efficiency of DNA transfection and to a more effective antigen presentation by dendritic cells. Vectors containing the nucleic acid-based vaccine of the invention can also be introduced into the desired host using other methods known in the art, for example, transfection, electroporation, micro-injection, transduction, cell fusion, DEAE-dextran, precipitation. with calcium phosphate, lipofection (lysosome fusion), or a DNA vector transporter. Transgenic plants that produce an antigenic polypeptide can be constructed using methods well known in the art. A number of edible vaccines obtained from plants for both animal and human pathogens are currently in development. Immune responses have also resulted from oral immunization with transgenic plants that produce virus-like particles (VLPs), or chimeric plant viruses that display antigenic epitopes. It has been suggested that the particulate form of these VLPs or chimeric viruses can result in greater antigen stability in the stomach, effectively increasing the amount of antigen available for absorption in the intestinal tract.

EXAMPLE EXAMPLE 1 Below are examples of typical tests used to monitor some acute phase inflammatory markers, as well as the CA125 ovarian cancer marker.

Reactive protein C Reactive protein C is measured using a DADE Behring Dimension RxL chemistry analyzer, with reagents and calibrators supplied by Dade Behring Diagnostics (Sydney, Australia) (reagent catalog No.

DF-34; calipers catalog No. DC-34). The CRP method is based on an enhanced turbidimetric immunological test technique with particles. Latex particles coated with antibody against reactive protein C are added in the presence of reactive protein C in the sample. The increase in turbidity that accompanies aggregation is proportional to the concentration of reactive protein C.

Accuracy within tests Accuracy between tests Average CV N Average CV N mg / l mg / ml 3.4 4.3% 20 4.6 5.6% 64 57. 5 2.3% 20 37.0 3.0% 64 225. 8 2.0% 20 Reference interval: 0-5 mg / ml Analytical range: 0.5-500 mg / ml Cancer antigen 125 (CA125) AxSym CA 125 is based on the micro-particle enzyme immunoassay (MEIA) technology performed on an Abbott Diagnostics AxSym with reagents and calibrators supplied by Abbott Diagnostics (AxSym-cat. No. 3B41-22, calibrators cat. No. 9C22-01). The sample, the micro-particles coated with CA 125 and the diluent for the specimen are pipetted into a cavity of the reaction vessel. CA 125 binds to the micro-particles coated with anti-CA 125 forming an Ab-ag complex. An aliquot of the reaction mixture containing the Ab-ag complex bound to the microparticles is irreversibly bound to the glass fiber matrix. The cell of the matrix is washed with the buffer solution for washing to remove the unbound materials. The specific ALP conjugate of the anti-CA 125 subunit is dispersed in the cell of the matrix and binds with the Ab-ag complex. The cell of the matrix is washed to remove unbound material. The substrate, 4-methyl umbelliferyl phosphate, is added to the matrix cell and the fluorescent product is measured using the MEIA optical assembly. Dilutions are made with the Abbott CA 125 specimen diluent (No. 3B41-50). The coefficient of variation as assessed from routine quality control serum at two levels (control of Abbott tumor marker (9C22-10 levels 1, 2 and 3) is as follows: Media SD CV N Level 1 U / ml 27 2.5 9.4 64 Level 2 U / ml 78 5.5 7.1 64 Level 3 ü / ml 211 21.4 10.2 54 Reference intervals: 0-35 U / ml Analytical range: 2-600 U / ml Interleukin 2 receptor (IL2R) Interleukin 2 (IL2R) cytokine receptor (IL2R) is measured using an automated commercial chemo-luminescent enzyme (EIA) immunological test using an Immulite Analyzer from Diagnostic Products Corporation (Los Angeles, CA, USA) . This is a competitive immunological test that uses IL2R labeled with alkaline phosphatase as the tracer and adamantyl dioxetane as the luminescent substrate for the ALP enzyme. All reagents and calibrators are supplied as a kit by DPC-Cat No. LKIPZ. Analytical performance: Media SD CV Level 1 213 U / ml 13 6.1 Level 2 752 U / ml 49 6.5 Level 3 2463 U / ml 189 7.7 Analytical range: 5-7,500 U / ml Reference range: 23-710 Uml * * Study conducted on 87 apparently healthy adults Interleukin 6 The cytokine interleukin 6 is measured using a commercial automated chemo-luminescent enzyme (EIA) immunological test using an Immulite Analyzer from Diagnostic Products Corporation (Los Angeles, CA, USA). This is an immunological competitive test that uses alkaline phosphatase-labeled IL-6 as the tracer and adamantyl dioxetane as the luminescent substrate for the ALP enzyme. All reagents and calibrators are supplied as a kit by DPC-Cat. No. LK6PZ. Analytical performance: Media SD CV% Level 1 88 pg / ml 4.5 5.1 Media SD CV% Level 2 230 pg / ml 12.2 5.3 Level 3 638 pg / ml 46.6 7.3 Analytical range: 2-1000 pg / ml Reference range: < 4.1 pg / ml * * Study carried out on 60 apparently healthy laboratory volunteers Interleukin 10 Interleukin 10 cytokine is measured using a commercial automated chemo-luminescent enzyme (EIA) immunological test using an Immulite device Analyst from Diagnostic Products Corporation (Los Angeles, CA, E.U.A.). This is an immunological competitive test that uses alkaline phosphatase-labeled IL-6 as the tracer and adamantyl dioxetane as the luminescent substrate for the ALP enzyme. All reagents and calibrators are supplied as a kit by DPC-Cat. No. LK6PZ. Analytical performance: Media SD CV% Level 1 18.2 pg / ml 1.8 9.9 Level 2 46.0 pg / ml 2.2 4.8 Level 3 177 pg / ml 8.0 4.5 Analytical range: 5-1000 pg / ml Reference range: < 9.1 pg / ml * * Study performed on 55 apparently healthy adults Serum amyloid A Polystyrene particles coated with antibodies to human SAA bind when mixed with samples containing SAA. The intensity of the scattered light in the nephelometer depends on the concentration of the analyte in the sample and therefore its concentration can be determined by comparison with dilutions of a reference standard of known concentration.

Imprecision CV 4.7% @ 0.20 g / 1 N = 404 CV 3.2% 80.53 g / 1 N = 40 Reference interval: In a population with normal serum CRP levels (95th percentile = 5.0 mg / l N = 483) it is found that the 95th percentile for N latex SAA is 6.4 mg / l Analytical range: 3.0-200 mg / l Complement C3 The automated method is used to measure complement C3 concentration in serum samples by nephelometric analysis using a Dade Behring ProSpect analyzer with reagents and calibrators supplied by Dade Behring Diagnostics (Sydney, Australia). The antigen solution (sample) and the specific antibodies (cat. No. 0SAP15 antiserum) are mixed in the reaction cells. Antigen-antibody-insoluble complexes are immediately formed, which produces turbidity in the mixture and increases the amount of light that is dispersed by the solution. After an incubation period, the absorbance of the solution is measured at the analytical wavelength.

Imprecision CV 5.5% @ 1.05 g / 1 N = 61 PS 3.2% T2.70 g / 1 N = 61 Reference interval: 0.81-1.85 g / 1 Analytical range: 0.10-3.50 g / 1 Complement C4 The automated method is used to measure complement C4 concentration in serum samples by nephelometric analysis using a Dade Behring ProSpect analyzer with reagents and calibrators supplied by Dade Behring Diagnostics (Sydney, Australia). The antigen solution (sample) and the specific antibodies (cat. No. OSA015 antiserum) are mixed in the reaction cells. Antigen-antibody-insoluble complexes are immediately formed, which produces turbidity in the mixture and increases the amount of light that is dispersed by the solution. After an incubation period, the absorbance of the solution is measured at the analytical wavelength.

Imprecision CV 4.7% @ 0.20 g / 1 N = 61 HP 3.8% @ 0.53 g / 1 N = 61 Reference interval: 0.10-0.40 g / 1 Analytical range: 0.03-1.50 g / 1 EXAMPLE 2 A female patient with ovarian cancer of older age is monitored for approximately 12 days with respect to fluctuations in the levels of reactive C protein, serum amyloid A and tumor marker CA125. Monitoring is performed using standard laboratory tests on blood samples collected every third day. The patient has not been recently exposed to any anti-cancer therapy. Also, there is no evidence that the patient has any other disease besides cancer. The CA125 marker (a marker of ovarian cancer) is monitored as an indicator of disease burden. As shown in figure 1A, the levels of reactive protein C (CRP) reach a maximum at the beginning of the monitoring period. Also, as shown in Figure IB, serum amyloid A levels are elevated at the same time as the CRP peak. These results indicate that: i) levels of acute phase inflammatory proteins are fluctuating in a cancer patient in the absence of any other known factors that could cause these fluctuations such as viral infection or chemotherapy, ii) elevated levels of inflammatory proteins of acute phase are associated with low levels of tumor antigen followed by the presence of effector cells, and iii) increased levels of tumor antigen are associated with low levels of acute phase inflammatory proteins suggesting that regulatory cells have counteracted the beneficial activity of the node effector cells such that these cells are no longer active against the tumor cells.

EXAMPLE 3 A human individual suffering from HIV infection is subjected to highly active anti-retroviral therapy (HAART) for at least 6 months and then removed from treatment. Reactive protein C levels are determined using standard techniques on samples obtained during and after completing the HAART treatment.

As can be seen in Figure 2, the results show that after concluding HAART the levels of reactive protein C begin to cycle, reaching a maximum every 14 days approximately.

EXAMPLE 4 Serum CRP is used to monitor the immune response in a patient with HIV who has stopped anti-retroviral therapy (figure 3). In this study, CRP levels mimic viral load fluctuations as the immune response is activated and deactivated (figure 3). It is interesting to note that these CRP fluctuations have a cycle of approximately 14 days.

EXAMPLE 5 A search of the "Pubmed" database http://www.ncbi.nlm.nih.gov/ is made with respect to the abstracts of periodical articles that describe the results of clinical trials in phase II or phase III using anti-cancer agents (such as vinblastine and taxol) for the treatment of cancer. Other criteria that are used to select the "abstracts" are that the cancer is in a late stage (stage III or stage IV) and that the disease has spread. Some studies use a single drug while others use combinations. Other criteria are not used and studies with an atypical full response rate are not discarded. The full response rate (as indicated in the summaries) is used for each test to determine the average complete response rate of each cancer type. The results are given as table 1. Notably, the average complete response rate varies only to a small degree, specifically between 5.1 to 8.2% for all cancers analyzed. The results provided in Table 1 are used to determine the total average complete response rate. This average complete response rate is 6.6% over at least 10 different types of cancers when considering the 144 tests analyzed. With respect specifically to the data provided for ovarian cancer, it should be noted that one study (Adachi et al., 2001) observes a complete response rate of 25% which is very large compared to the other 143 tests. This study observes 8 patients, in which two patients provide a complete response index. Although this is within the limits of possibility, if the study is ignored, the total complete response rate for the remaining ovarian cancer studies is 7.1%. The full response rates are notoriously consistent between the different cancers, and the treatment regimens for them, suggesting an underlying factor relevant to all cancers and treatments thereof. As described in the present invention, this factor is that the immune system cyclizes. Accordingly, it can be argued that the full response rates given in Table 1 are the result of the anti-cancer agent being administered at the appropriate time so as to maximize the numbers of effector cells while reducing them. or the numbers of regulatory cells are eliminated, or the activity is negatively regulated or put at risk, by the anti-cancer agent enough to present a complete response.

TABLE 1 complete response indices resulting from clinical trials with anti-cancer drugs against various cancers TABLE 1 complete response indices resulting from clinical trials with anti-cancer drugs against various cancers aTsavaris et al (1997), Monnet et al (2002), Pinto et al (2001), Kindler et al (1999), Yogelzang et al (1997), Planting et al (1995), Chahinian et al (1993), Raghavan et al (1990), Henss et al (1988) and Mbidde et al (1986). "Koll annsberger et al (2000), Sugimachi et al (2000), Jeen et al (2001), Yamada et al (2001), Aitini et al (2001), Cho et al (2002), Kornek et al (2002) , Hofheinz et al (2002), Constenla et al (2002), Kim et al (2002), Louvet et al (2002), Kikuyama et al (2002), Bar Sela et al (2002), Murad et al (1999) and Sakata et al (1998), Porta et al (1995), Pohl et al (2001), Oon et al (1980), Choi et al (1984), Zeng et al (1998), Carr et al (1997), Patt et al (2003) and eung et al (1999). "Murad et al (2003), ñshamalla et al (2003), Safran et al (2002) and Sherman et al (2001). eRetsas et al (1996), Nathan et al (2000), Bafaloukos et al (2002), Bafaloukos et al (2002), Buzaid et al (1998), Gibbs et al (2000), Atkins et al (2002), Gundersen et al (1989), Johnson et al (1985), Nystro et al (2003), Einzig et al (1991), Bedikian et al (1995), Einzig et al (1996), Nathan et al (2000) and Chapman et al. to the (2002). fHudes et al (1997), Kelly et al (2001), Savarese et al (1999), Small et al (2001), Savarese et al (2001), Trivedi et al (2000) and Picus et al (1999). Mariotta et al (2002), Recchia et al (2002), Perng et al (2000), Ginopoulos et al. (1999), Paccagnella et al (1996) and Agelaki et al (2001). hFreyer et al (2003), Morabito et al (2003), Kosmas et al (2003), Gebbia et al. (2003), Thomas et al (1994), Romero et al (1994), Pectasides et al (2001), Frasci et al (2002), Stathopoulos et al (2002), Gomez-Bernal et al (2003), Freyer et al. to the (2003), Kornek et al (1998), Michelotti et al (1996), Kakolyris et al (1999), T elves et al (1994), Fumoleau et al (1993) and Ibrahim et al (1999). xLi et al (2002), Sehouli et al (2002), Rose et al (2003), Faivre et al (2002), Dieras et al (2002), Adachi et al (2001), Sutton et al (1994), McClay et al (1995), Manetta et al (1994), Guastalla et al (1994), Covens et al (1992), Einzig AI. (1994), Kjorstad et al (1992), Ozols et al (1984), Planner et al (1996) and Amadori et al (1997). 3Cassinello et al (2003), Glimelius et al (2002), Calvo et al (2002), Scheithauer et al (2002), Neri et al (2002), Falcone et al (2001), Kouroussis et al (2001), Meropol et al (2001), Cornelia et al (2000), Cascinu et al (1999), Sobrero et al (1995), Gamelin et al (1998), Romero et al (1998), Beerblock et al (1997), Blanke et al (1997), Grem et al (1993), Jeremic et al (1993), Posner et al (1992), Sinnige et al (1990), LoRusso et al (1989), Petrelli et al (1989), Valdivieso et al. al (1981), Cassinello et al (2003), Reina et al (2003), Cornelia et al (1999), Neri et al (1998), Pyrhonen et al (1992) and Beck et al (1984). ^ Cancers included renal cell carcinoma, adenocarcinoma, squamous cell carcinoma, uterine cervical cancer, glioblastoma multiforme, metastatic osteosarco a, urothelial cancer and endometrial cancer. Described by Schornagel et al (1989), Liu et al (2001), Forastiere et al (1987), Okuno et al (2002), Takasugi et al. (1984), Hurteloup et al (1986), Kakolyris et al (2002), Morris et al (1998), Takeuchi et al (1991), Fountzilas et al (1999), Rosenthal et al (2000), Goorin et al ( 2002), Rodriguez-Galindo et al (2002), Ahmad et al (2002), DiPaola et al (2003) and Lissoni et al (1996).

If the typical cycle of effector / regulatory cell numbers is considered to be approximately 15 days, the data in Table 1 suggest a one-day window to administer anti-cancer therapy to achieve a complete response rate. Typically, partial response rates are observed in the order of 30%, which suggests that if the agent is administered at an interval of 24 to 36 hours on either side of this "window of a day" a beneficial effect can also be achieved.

EXAMPLE 6 Patient The patient is a 75-year-old woman designated in the present invention as "Mrs OM".

Clinical history Liver cirrhosis, ischemic heart disease, insulin-dependent diabetes. It was diagnosed with squamous cell carcinoma of the lower esophagus by endoscopy and biopsy / histology in May 2004. The cancer results in the patient encountering difficulties in swallowing.

Description of the tumor Circumferential mass of 5 cm at the base of the esophagus, partially occluding the lumen. Unknown epithelial / mural penetration.

Therapy regimen Radiotherapy approximately 33 courses of 15 minutes duration every third week for 6-8 weeks. More limited chemotherapy due to other underlying medical conditions. The oncologist agrees to administer two chemotherapy applications (8-hour infusion of 5-fluorousacyl and carboplatin). The application must be coordinated with the cycle / oscillation of the patient's immune response to attempt the synchronized negative regulation of the cyclization of tumor-specific regulatory cells.

Monitoring and therapeutic intervention To detect the oscillation of the immune response, monitoring of the patient's immune response begins on May 28, 2004, day 1, using the following tests: CRP, SAA, C3, C4 and CA125. CA125 is used to monitor the progression of the disease because it has been reported in the literature in the case of squamous cell carcinoma of the esophagus.

During the initial stages of monitoring, the patient reports increased difficulty in swallowing, most likely due to tumor growth. This is corroborated by a consistent elevation in all the measured parameters (see Figures 4 to 7). As an interesting aspect the scaling of CA125 briefly shows a plateau over an approximate period of 24 hours (figure 6, days 12-14) only to rise to a steeper gradient past this point. This is interpreted as the patient's immune response is activated and modulates the growth and tumor marker (CA125), only to deactivate due to immune regulation at the end of the period of approximately 24 hours. This approximate period of 24 hours establishes the end of a cycle of approximately 1 to 14 days and the beginning of the next one, and therefore a potential intervention point or a reference point to plan in advance for subsequent intervention points. Having defined the beginning and end of the cycle of approximately 14 days it is now possible to anticipate and project in advance a number of days to better calculate two potential chemotherapeutic intervention points with a separation of approximately 2 weeks. It was decided to take blood / measurements from the patient on Tuesdays, Wednesdays and Thursdays (figures 7, 13, 14 and 15 of July, days 46, 47 and 48, indicated with an arrow as B) to define exactly the point or window of therapeutic intervention. If the cycle has been determined exactly, a peak should be observed followed by a decrease in the CRP through those days in which the analysis is performed (figure 7). This pattern in CRP should be repeated approximately 14 days later and maintained with the persistent periodicity of the oscillation of the immune response. It was found that this is the case (figure 7). Based on the CRP results, the inventor recommends the oncologist to administer the first chemotherapy application on or about Wednesday, July 14, 2004 or Tuesday, July 15, 2004. However, Mrs OM had already been scheduled for chemotherapy on Friday 16 July 2004, and the oncologist decides not to change his appointment. Because this appointment was just after the maximum in the CRP (figure 7, marked with arrow as C), the inventor considers that the window of opportunity had been lost because the application of the therapy could be 24 hours later. The inventor expects that the moment therapy is administered, the CRP will begin to rise again. This prediction was correct because no effect on the tumor is evident after the administration of chemotherapy. A second intervention point is determined / predicted and blood is taken on Wednesday and Thursday (Figures 7, 28 and 29 of July, days 63 and 64, marked with arrows as D). The prediction is confirmed by a maximum in the CRP analysis indicating that on Friday, July 30, 2004, day 65 (figure 7, marked with an arrow as E) as the optimal intervention point for the application of chemotherapy. Chemotherapy is given as an 8-hour infusion on Friday. On this occasion, the inventor predicts that this may be the appropriate time to administer the therapy because the CRP could continue to decrease. By Saturday, the patient develops a slight fever and usually feels uncomfortable. Early in the afternoon on Sunday, August 1, day 67, figure 7, marked with arrow as F), the patient presents hemorrhage coming from the site of the tumor and therefore the hospital is admitted. The patient loses approximately 150 ml of blood and receives two units of blood that day and fluid / intravenous nutrition for the next 9 days. The CRP is measured on August 4, 2004, day 69 (figure 7, marked with arrow as G), and it is found that it has fallen significantly. On the last day of hospitalization, the patient's esophagus is examined endoscopically. There is no evidence of tumor (figure 7, marked with arrows as H).

Interpretation The anti-tumor tumor immune response of the patient is released from regulation by the choice as a synchronized target of tumor specific regulatory cells by individual administration of the chemotherapeutic agents at the correct designated time. This is when the immune regulatory cells are active from the clonal point of view, in mitosis and therefore vulnerable to negative regulation. Once released from regulation, the anti-tumor immune response results in an episode of fever such as that reported by the patient on day 66 and the subsequent destruction of the tumor. The tumor destruction mediated by the immune response results in a hemorrhage caused by the potential invasive involvement of the tumor in the epithelium / wall of the esophagus. The actions and observations above demonstrate the following: • It is possible to detect a persistent regular oscillation in the patient with cancer. • This oscillation is associated with the tumor burden. • the oscillation has an approximate periodicity of 14 days with a sub-cycle of 7 days. • The start and end of the cycle can be determined using different parameters, such as, but not limited to, CRP, SAA, C3, C4 and tumor antigen levels. "The narrow window of opportunity for the application of a single administration of chemotherapy can be determined. • A sol administration chemo-therapeutic at the right time directed against the immune system of the patient with cancer can lead to a successful therapeutic outcome.

EXAMPLE 7 The patient is an individual of the female gender of 71 years of age designated in the present invention as "Mrs FO". Previously Mrs FO was diagnosed with ovarian cancer, received surgery and several rounds of standard chemotherapy. The patient presents with elevated CA125 at 200 U / ml before monitoring.

The patient is monitored (blood sample) every Monday, Wednesday and Friday for 4 weeks. An irregular, almost synchronous oscillation adequately described with a periodicity of 7/14 days shows a close co-relation between the serum measurements of CRP, SAA and IL-2 (see figures 8 and 9). More interestingly, Figure 10 which shows CRP and CA125 against time, the oscillations of CRP and CA125 are out of phase, indicating an inverse relationship between the immune system and the cancer marker. Figure 11 shows the relationship with respect to the time between SAA and C3 of the complement factor. Notice that the two major peaks of C3 are separated by approximately 14 days and coincide with alternating peaks of SAA which are also separated by approximately 14 days. This supports the hypothesis that the 7-day peaks represent expansions of alternating T and B cell clones and that major peaks of C3 are associated with the B cell in the way that the complement is associated with antibody-mediated lysis. This observation can help establish the beginning and end of a cycle and can therefore help determine the point of therapeutic intervention.

EXAMPLE 8 The patient is a male subject of 64 years of age designated in the present invention "Mr GA". First he was diagnosed with bowel cancer in 1997 after which the patient underwent surgery, chemotherapy and radiotherapy. In February 2004 he was diagnosed with lung recurrence by needle biopsy. It is determined that the patient has multiple lesions and undergoes 12 rounds of chemotherapy. In September 2004. The most recent scan identifies at least 2 cm lesion in the upper left lung. Currently, relatively well / active (mid-October 2004). Blood is taken every third day (Monday, Wednesday, Friday) for 15 days. The CRP is measured, and the result shows an approximate and regular CRP oscillation of 7/14 days.

EXAMPLE 9 A post-menopausal patient undergoing oophorectomy (WB) with re-emergent tumor and elevated levels of CA125 who register the frequency of hot flushes or febrile episodes and who qualifies them as light, moderate or severe. The intensity of these episodes is compared to the CRP oscillation of the immune response. The most intense episodes and their increased frequency coincide with the large peaks. Therefore, body temperature records can be used as an adjunct to define the beginning and end of the oscillation of the immune response for the purposes of synchronizing the therapy application.

Cross reference with related applications The present application claims priority from the provisional patent application No. 2003905858 filed on October 24, 2003, the contents of which are incorporated in the present invention for reference. Those skilled in the art will appreciate that numerous variations and / or modifications to the invention can be made as shown in the specific embodiments without departing from the scope or scope of the invention as broadly described. Therefore, these modalities should be considered in all respects as illustrative and not restrictive. All publications discussed above are incorporated in the present invention in its entirety.

Any discussion of documents, acts, materials, devices, articles or the like that have been included in the present description is solely for the purpose of providing a context for the present invention. It should not be taken as an admission that any or all of these topics form part of the background of the prior art or that they are general knowledge common in the field relevant to the present invention because they already existed prior to the priority date of the invention. each claim of this request.

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Claims (24)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS

1. - A method to determine at what time an agent should be administered to a patient suffering from a disease characterized by the production of regulatory cells, the method comprises monitoring the patient, or the samples obtained therefrom, with respect to at least one of: a) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or d) a marker of the immune system.

2. - A method for treating a disease characterized by the production of regulatory cells, the method comprises; i) monitoring a patient suffering from the disease with respect to at least one of: a) number and / or activity of regulatory cells, b) number and / or activity of effector cells, c) a molecule associated with the disease, and / or d) a marker of the immune system, and ii) exposing the patient to an agent for treating the disease, characterized in that the timing of administration of the agent is selected such that the activity of the effector cells is not significantly reduced. .

3. The method according to claim 1 or claim 2, characterized in that the disease characterized by the production of regulatory cells is cancer and an infection.

4. - The method according to claim 3, characterized in that the infection is a chronic persistent infection characterized because the patient's immune system can not eliminate the infection.

5. The method according to claim 4, characterized in that the patient is infected with HIV, Hepatitis B virus or HIV virus. Hepatitis C.

6. The method according to any of claims 1 to 5, characterized in that the marker of the immune system reflects the number and / or activity of the regulatory cells, and / or the number and / or activity of the cells. effector

7. - The method according to any of claims 1 to 5, characterized in that the marker of the immune system is an acute phase inflammatory marker

8. - The method according to claim 7, characterized in that the acute phase inflammatory marker is selected from the group consisting of serum amyloid A, serum amyloid P and reactive protein C.

9. The method according to any of claims 2 to 5, characterized in that the agent is administered between the time when the levels of an acute phase inflammatory marker has reached a maximum and before the marker begins to rise in the next cycle.

10. The method according to any of claims 1 to 9, characterized in that the regulatory cells are CD4 + CD8- T cells.

11. The method according to any of claims 2 to 5, characterized in that the agent is administered approximately at the time when CD4 + CD8 + T cells are detected.

12. The method according to any of claims 1 to 11, characterized in that the effector cells are CD8 + CD4 + T cells.

13. The method according to any of claims 2 to 5, characterized in that the agent is administered approximately at the time when the CD8 + CD4 + T cell numbers have reached a maximum.

14. The method according to any of claims 1 to 13, characterized in that the molecule associated with the disease is an antigen produced by a cancer cell or an infectious agent.

15. The method according to any of claims 2 to 5, characterized in that the agent is administered approximately when they begin to decrease the levels of the molecule associated with the disease.

16. The method according to any of claims 1 to 5, characterized in that the patient is monitored for an acute phase inflammatory marker, and a molecule associated with the disease.

17. The method according to any of claims 2 to 5 or 16, characterized in that the agent is administered between the time when the acute phase inflammatory marker levels have reached a maximum and before the marker begins to rise in the next cycle, and at the moment when the levels of the molecule associated with the disease begin to decrease or have been predicted to begin to decrease based on previous analyzes of the molecule.

18. The method according to any of claims 1 to 17, characterized in that the patient is monitored for a period of at least 7 days.

19. The method according to any of claims 1 to 18, characterized in that the patient is monitored at least every 3 days approximately.

20. The method according to any of claims 1 to 19, characterized in that the agent inhibits the production of, limits the function of, and / or destroys, the regulatory cells.

21. The method according to claim 20, characterized in that the agent is selected from the group consisting of anti-proliferative drugs, radiation, dsRNA and antibodies that inhibit the production and / or activity of regulatory cells.

22. The method according to claim 21, characterized in that the anti-proliferative drug is selected from the group consisting of: taxol, vincristine, vinblastine and anhydro vinblastine.

23. The method according to claim 21, characterized in that the antibody is selected from the group consisting of: anti-CD4 +, anti-CTLA-4 (antigen 4 associated with cytotoxic lymphocyte), anti-GITR (receptor of the tumor necrosis factor induced by glucocorticoid), anti-CD28 and anti-CD25.

24. The method according to any of claims 1 to 23, characterized in that the patient has not been exposed to a treatment for the disease for at least 14 days. The method according to any of claims 1 to 24, characterized in that the patient is a human. 26.- A method for diagnosing a disease characterized by the production of regulatory cells, the method comprises monitoring the patient, or samples obtained from it, with respect to at least one of: a) numbers and / or cell activity effector, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or d) a marker of the immune system, characterized in that the cyclization of any of a) to d) indicates that the disease may be present . 27.- A method to determine the time at which a vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells, the method comprises monitoring the patient, or the samples obtained from it, with respect to to at least one of: a) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or d) a marker of the immune system. 28. A method for treating a disease characterized by the production of regulatory cells, the method comprising: i) monitoring a patient suffering from the disease with respect to at least one of: a) the number and / or activity of cells regulators, b) number and / or activity of effector cells, c) a molecule associated with the disease, and / or d) a marker of the immune system, and ii) exposing the patient to a vaccine to treat the disease, characterized by the synchronization The administration of the vaccine is selected such that the activity of the effector cells is not significantly reduced. 29. The method according to claim 28, characterized in that the vaccine is administered at approximately the time when effector cell levels are increased. 30. The method according to claim 28, characterized in that the vaccine is administered at approximately the time when the levels of a molecule associated with the disease begin to decrease. 31. The method according to claim 28, characterized in that the vaccine is administered at approximately the time when the levels of an acute phase inflammatory marker begin to increase. 32. - The use of a test that detects an immune system marker to determine the time when an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells. 33.- The use in accordance with the claim 32, characterized in that the marker is an acute phase inflammatory marker. 34.- The use in accordance with the claim 33, characterized in that the acute phase inflammatory marker is selected from the group consisting of: serum amyloid A, serum amyloid P and reactive protein C. 35.- The use of a test that detects the numbers and / or activity of cells effector to determine the time at which an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells. 36. The use according to claim 35, characterized in that the test detects the number of CD8 + CD4- T cells. 37.- The use of a test that detects the numbers and / or activity of the regulatory cell to determine the moment in which an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells. 38.- The use in accordance with the claim 37, characterized in that the test detects the number of CD8 + CD4- T cells. 39.- The use of a test that detects a molecule associated with a disease characterized by the production of regulatory cells to determine when an agent or vaccine should be administered to treat the disease. 40.- The use in accordance with the claim 39, characterized in that the test detects an antigen produced by a cancer cell or an infectious agent. 41. The use according to any of claims 32 to 40, characterized in that a patient with the disease has not been exposed to treatment for the disease for at least 14 days. 42.- The use of an agent for the manufacture of a medicament for administering to a patient suffering from a disease characterized by the production of regulatory cells, characterized in that the agent is administered at a time that is selected in such a way that the activity of effector cells is not significantly reduced, and because the patient has not been exposed to a treatment for the disease for at least 14 days. 43. The use according to any of claims 32 to 42, characterized in that the agent inhibits the production of, limits the function of, and / or destroys, the regulatory cells. 44.- A kit to determine the moment in which an agent or vaccine should be administered to a patient suffering from a disease characterized by the production of regulatory cells, the kit comprises at least one reagent to monitor the patient, or samples obtained from it, with respect to at least one of: a) numbers and / or effector cell activity, b) numbers and / or regulatory cell activity, c) a molecule associated with the disease, and / or d) a marker of the immune system.