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EP1173203A2 - Traitement therapeutique photodynamique de tumeurs secondaires par immuno-adjuvants - Google Patents

Traitement therapeutique photodynamique de tumeurs secondaires par immuno-adjuvants

Info

Publication number
EP1173203A2
EP1173203A2 EP00922383A EP00922383A EP1173203A2 EP 1173203 A2 EP1173203 A2 EP 1173203A2 EP 00922383 A EP00922383 A EP 00922383A EP 00922383 A EP00922383 A EP 00922383A EP 1173203 A2 EP1173203 A2 EP 1173203A2
Authority
EP
European Patent Office
Prior art keywords
photosensitizer
adjuvant
immuno
tumor
pdt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00922383A
Other languages
German (de)
English (en)
Inventor
P. Mark Curry
Julia G. Levy
Anna M. Richter
David W. C. Hunt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of British Columbia
Novelion Therapeutics Inc
Original Assignee
University of British Columbia
QLT Inc
Quadra Logic Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of British Columbia, QLT Inc, Quadra Logic Technologies Inc filed Critical University of British Columbia
Publication of EP1173203A2 publication Critical patent/EP1173203A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines

Definitions

  • the invention relates to the use of photodynamic therapy (PDT) treatment in combination with immuno-adjuvants to treat metastatic tumors.
  • PDT photodynamic therapy
  • the PDT may be conducted with any photosensitizer, but combinations comprising a benzoporphyrin derivative (BPD) are preferred for such PDT treatment.
  • BPD benzoporphyrin derivative
  • This invention relates to metastatic cancer.
  • the metastatic process which results in the growth of secondary tumors at sites distal to the primary tumor, is the cause of death in most cancers (Poste and Fidler, 1980). Although most patients with newly diagnosed solid tumors are free of detectable metastases, and about half of those patients can be cured of their disease by local cancer treatment, the remaining patients have clinically occult micrometastases that will become evident with time. Thus, at the time of primary tumor treatment, the total percentage of patients with either detectable metastases or microscopic disseminated disease is 60% (Liotta and Stetler-Stevenson, 1989).
  • the brain is the most favored site for metastatic spread, occurring in 25% to 30% of all cancer patients: the most frequent primary cancers, lung cancer, breast cancer and melanoma, are associated with high incidence of brain metastases (Wright and Delaney, 1989).
  • the lung is the second most common site of metastatic spread and pulmonary metastases most frequently originate from bone and soft-tissue sarcomas (Roth, 1989). Liver metastases commonly result from gastrointestinal tract tumors (Sugarbaker and Kemeny, 1989) and bone metastases from breast, lung and kidney primary tumors (Malawer and Delaney, 1989).
  • Management of a significant number of cancer cases therefore, depends upon treating multiple tumors, traditionally through the use of surgery, radiation therapy, chemotherapy, or adjuvant therapies consisting of combinations of the three modalities.
  • tumor-infiltrating lymphocytes from tumor-bearing mice and cancer patients with cytokines and irradiated tumor cells
  • cytokines and irradiated tumor cells can result in tumor regression
  • tumor antigens recognized by the cells of the immune system have been identified in both animal models and human tumors (Jaffee and Pardoll, 1996).
  • Tumor antigens recognized by T lymphocytes in human melanomas are the most fully characterized set of tumor antigens and may be non-mutated, widely distributed molecules, unique and mutated proteins, or normal proteins that are overexpressed in tumors (Robbins and Kawakami, 1996).
  • cancer immunotherapy One result from the observations concerning tumor immunity is cancer immunotherapy. For centuries it has been observed that many types of diseases, including cancer, can be improved or even cured following attacks of erysipelas, an acute skin infection. In 1909 William Coley reported several positive results following deliberate infection of cancer patients with bacteria in order to induce erysipelas. Although the contemporary theory explained tumor improvements or cures as the result of toxic products released during the bacterial infection, Coley's approach to cancer treatment may be regarded as the first instance of "biotherapy" (the original term) or cancer immunotherapy.
  • Immunotherapy of cancer in which the immune system is modulated through the use of specific and non-specific tumor vaccines, bioactive molecules such as cytokines, or adoptive transfer of activated lymphocytes is one of the most appealing approaches to the treatment of metastatic cancers .
  • the therapy is based on the concept that the patient's immunological tolerance of their cancer can be broken so that the cancer is recognized as foreign by the patient's immune system (Gore and Riches, 1996).
  • PDT photodyanamic therapy
  • SDT is based upon dye-sensitized photooxidation of diseased tissue and was originally developed as a treatment modality for solid tumors (Dougherty et al., 1975).
  • Singlet oxygen (O,) is generated, without radical formation, through energy transfer processes from light- activated photosensitizer molecules in the "type II mechanism", and it is widely accepted that 'O is responsible for the primary photodynamic effect in vivo (Weiswash et al., 1976).
  • Membrane damage brought about by O is thought to be the primary mode of cell killing by PDT (Henderson and Dougherty, 1992), although metabohcally regulated processes may also be involved in PDT-induced damage and cell death (Granville et al.. 1998; Tao et al., 1996).
  • Photosensitizers are usually delivered intravenously and selective destruction of tumor tissue is based upon preferential uptake of the drug by neoplastic tissue and localized exposure of the tumor to the wavelength of light best suited to tissue penetration and photosensitizer activation. Necrosis of tumor tissue is a result of the direct effects of 'O 2 on tumor cells, and also from the anoxic conditions that develop in the tumor following disruption of tumor vasculature by PDT (Henderson et al., 1985).
  • immune responses are initiated with the rapid induction of an inflammatory reaction (Henderson and Dougherty, 1992; Ochsner, 1997) involving the release of cytokines (Evans et al., 1990; Gollnick et al., 1997; Nseyo et al., 1989), eicosanoids (Fingar et al., 1991 ; Henderson and Donovan, 1989), and clotting factors (Fingar et al., 1990; Foster et al., 1991), and progresses to the activation of immune cells (Qin et al., 1993; Yamamoto et al., 1992; Yamamoto et al., 1994) and infiltration of immune cells into PDT-treated tissue (Korbelik et al., 1996).
  • cytokines Evans et al., 1990; Gollnick et al., 1997; Nseyo et al., 1989
  • eicosanoids Feingar et al.
  • tumor cells pre-treated with PDT in vitro were sensitised to macrophage-mediated lysis (Korbelik et al. 1994) and at low photosensitizer levels, PDT activated macrophage phagocytic activity (Yamamoto et al. 1994).
  • Photofrin®-based PDT stimulated the release of the immunomodulatory molecules prostaglandin-E2 (Henderson et al. 1989) and tumour necrosis factor- ⁇ (TNF- ⁇ ) (Evans et al. 1990) from murine macrophages.
  • Photo frin® and light treatment induced the expression of interleukin (IL) IL-6 in HeLa cells (Kick et al.
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • PDT has also been shown to enhance both phagocytosis and tumor cytotoxicity when normal mouse peritoneal macrophages were treated in vitro (Yamamoto et al., 1992; Yamamoto et al., 1994) and similar treatments caused the secretion of tumor necrosis factor (TNF) (Evans et al., 1990).
  • TNF tumor necrosis factor
  • treating bladder cancer with PDT resulted in detectable levels of interleukin (IL-1) and TNF- ⁇ in the urine of patients within 3 hours of treatment and IL-2 within 24 h in a profile that resembled treatment of bladder cancer with Bacille Calmette Guerin (BCG).
  • BCG Bacille Calmette Guerin
  • elevated cytokine levels were associated with improvement (Evans et al., 1990).
  • adjuv ants Any matenal that increases the immune response towards an antigen is referred to as an adjuvant (see Appendix A) and while they have been used for at least 70 years in the production of traditional vaccines designed to prevent infectious diseases, adjuvants are also being developed for use in cancer vaccines
  • adjuvants are able to augment immune responses through several mechanisms including 1 ) causing depot formation at the site of inoculation, 2) acting as delivery vehicles which may target antigens to cells of the immune system, 3) acting as immune system stimulators
  • the ideal adjuvant would have safe local and systemic reactions (which would preclude general toxicity, autoimmune and hypersensitivity reactions, and carcinogenicity) be chemically defined so consistent manufacture is possible, would enhance protective (or in the case of cancer vaccines, therapeutic) immunity towards weak antigens, and would be biodegradable (Audibert and Lise, 1993, Cox and Coulter, 1997, Gupta and Siber, 1995)
  • the prototypical adjuvant which is also the most potent, is Freund's Complete Adjuvant (CFA) developed in 1937 by Jules Freund CFA consists of a preparation of killed Mycobacterium tuberculosis dispersed in mineral oil When emulsified with water soluble antigens, the vaccine stimulates both humoral (antibody-mediated) and cell- mediated immunity towards the antigens
  • CFA Freund's Complete Adjuvant
  • IFA Incomplete Freund's Adjuvant
  • IFA Incomplete Freund's Adjuvant
  • IFA Incomplete Freund's Adjuvant
  • IFA which lacks the mycobacte ⁇ al component of CFA, is less toxic but does not enhance cell- mediated immunity Nonetheless, IFA is currently undergoing clinical t ⁇ als in cancer vaccine formulations (for example NCI-T97-01 10, NCI-98-C-0142, NCI-H98-0010, NCI- T96-0033)
  • New adjuvants such as the Ribi Adjuvant System (RAS) have been designed to substitute highly pu ⁇ fied bacterial components for M tuberculosis in order to maintain the immune stimulatory properties of CFA without the side effects
  • RAS Ribi Adjuvant System
  • a va ⁇ ation of RAS, DetoxTM adjuvant is currently in clinical t ⁇ als as a component of cancer vaccines (NCI- V98-1489, NCI-96-C-0139)
  • Others such as Hunter's TiterMax, which is has not been approved for clinical use but has been extensively characte ⁇ zed in animal systems, use completely synthetic compounds
  • Korbehk's group reported results using immuno-adjuvant PDT in 1993 (Korbelik et al , 1993) Initially, the group administered the immunostimulant schizophyllan (SPG), a glucan derived from Schizophyllum communae, in a series of intramuscular injections into the hind leg of mice bearing a squamous cell carcinoma solid tumor grown mtradermally over the sacral region of the back. Photo frin-based PDT was administered either 48 hours after the last SPG treatment or 24 hours before the first SPG injection. SPG therapy before PDT enhanced the effect of PDT on tumor cure whereas immunotherapy after PDT had no effect (Krosl and Korbelik, 1994).
  • SPG immunostimulant schizophyllan
  • Nordquist et al. disclose that the treatment of primary tumors in a rat model with indocyanine green (ICG) as chromophore and glycated chitosan as an immuno-adjuvant in photothermal therapy.
  • ICG indocyanine green
  • This treatment resulted in some instances of reducing both primary and metastatic tumors as well as some instances of preventing the occurrence of metastatic tumors (see Figures 1 and 2 for effects against primary tumors; Figure 4 for effects against metastatic tumors; and Figure 5 for prevention of metastatic tumors).
  • GCG glycated chitosan gel
  • ICG indocyanine green
  • the treatment resulted in: a) no tumor response followed by death at 30 days post-treatment; b) reduced tumor burden and extended survival times to 45 days; and c) reduced tumor burden but continued growth of the treated tumor, followed by reduction of both the treated primary and untreated metastasis.
  • the present invention relates to a new therapeutic regime combining immunotherapy and PDT for the treatment and prevention of metastatic cancer.
  • the invention is directed to the use of photodynamic therapy (PDT) in combination with immuno-adjuvants to treat, prevent, or inhibit the development of any tumor, especially metastatic tumors.
  • photodynamic methods employing a photosensitizer, such as a benzoporphyrin derivative (BPD), a green porphyrin, are used in combination with an immuno-adjuvant against metastatic cancer after diagnosis. Additional applications of the combination are after any primary treatment method against a diagnosed tumor to prevent the onset of as yet undetected dissemination of metastatic tumors or to treat such tumors after their appearance.
  • BPD benzoporphyrin derivative
  • the instant methods offer the benefit of efficacy against non-localized metastatic tumors either before or after their detection.
  • the invention is directed to a method to treat metastatic tumors, which method comprises administering to a subject with such tumors an effective amount of a photosensitizer, such as a BPD, in combination with an immuno-adjuvant and irradiating the subject with light absorbed by the photosensitizer.
  • a photosensitizer such as a BPD
  • Such methods may be employed against metastatic tumors upon initial diagnosis of cancer in a subject or against metastatic tumors that arise after previous tumor or cancer therapy in the subject.
  • the invention is directed to a method to prevent or inhibit the development of metastatic tumors by the steps of administering to a subject previously having undergone cancer or tumor therapy, an effective amount of a photosensitizer, such as a BPD, in combination with an immuno-adjuvant and irradiating the subject with light absorbed by the photosensitizer.
  • a photosensitizer such as a BPD
  • Such methods are employed even before the detection of metastasis and as such prevent, or reduce the occurrence of, metastatic tumors.
  • BPDs such as those selected from the group consisting of BPD-DA, BPD-DB, BPD-MA (including BPD-MA-A also known as verteporfin) and BPD-MB (where BPDs are as presented in U.S. Patent 5, 171,749. which is hereby incorporated by reference as if fully set forth) as well as the derivatives of these compounds.
  • BPDs include BPD-MA, EA6 (including A-EA6. also known as QLT 0074) and B3, where EA6 (as set forth in U.S. Patent 5,929,105, which is hereby incorporated by reference as if fully set forth) and B3 (as set forth in U.S. Patent 5,990,149, which is hereby incorporated by reference as if fully set forth) have the following structures.
  • the methods of the present invention may be practiced with any immuno-adjuvant or combination of immunoadjuvants, including those set forth in Appendix A.
  • Particularly preferred immuno-adjuvants are those of microbial or crustacean (chitosan) derived products. These include the Ribi Adjuvant System, DetoxTM, glycated chitosan, and TiterMaxTM.
  • the Ribi Adjuvant System and its components are described in issued US Patents 4,436,727 and 4,866,034.
  • the immuno-adjuvant comprises a mycobacterial cell wall skeleton component (described in US patent 4,436,727) and a component derived from lipid A of a bacterial lipopolysaccharide.
  • the lipid A component is de-3-O-acylated monophosphoryl lipid A (described in US Patent 4,912,094. Additional adjuvants for use with the present invention include CFA. BCG, chitosan, and IFA. Delivery of the immuno-adjuvant may be systemic or localized.
  • the present invention includes pharmaceutical compositions to treat or prevent or inhibit the development of metastatic tumors, such compositions containing an amount of a photosensitizer in combination with an immuno- adjuvant effective to treat, prevent or inhibit development of metastatic tumors when administered to a subject followed by irradiation with light absorbed by the photosensitizer, and a pharmaceutically acceptable carrier or excipient.
  • compositions individually containing the photosensitizer and immuno-adjuvant for use together as needed are also encompassed.
  • Figure 1 shows biopsies containing experimental metastases in lungs of animals treated with immuno-adjuvant PDT, PDT only, and untreated controls.
  • FIG. 2 shows in vitro lymphocyte proliferation in the presence of tumor antigens. See Example 4 below.
  • the lymph nodes of mice bearing the Lewis Lung Carcinoma (LLC) cells were removed 7-10 days following treatment with PDT or PDV.
  • Single cell suspensions of lymphocytes were cultured in the presence of LLC and accessory cells and incubated for 5 days after which proliferation was assessed using MTS.
  • LLC Lewis Lung Carcinoma
  • the present invention is directed to a procedure in which immuno-adjuvant photodynamic therapy (PDT) targets tumors, especially metastatic tumors, in some instances even before they are detectable
  • PDT immuno-adjuvant photodynamic therapy
  • the invention may be applied against metastatic tumors including, but not limited to, those that o ⁇ gmate and/or result in melanoma, lung cancer, breast cancer, colon cancer, and prostate cancer
  • the invention may also be used in cases of lymphoid tumors that form masses
  • this treatment may be utilized as a primary therapy against the tumors
  • this treatment may be used as additional or follow-up therapy after p ⁇ mary therapy against a diagnosed tumor
  • an approp ⁇ ate photosensitizing compound preferably BPD-MA, EA6 or B3, will be administered to the subject in combination with an immuno-adjuvant
  • the order of administration of photosensitizer and immuno-adjuvant may vary, with light l ⁇ adiation following administration of the photosensitizer
  • the immuno-adjuvant may be administered immediately after light irradiation Simultaneous activation of the immune system by the immuno-adjuvant and PDT mediated damage to tumor cells, or initiation of immune reactions, may increase the effectiveness of treatment
  • the photosensitizer will localize in tumor cells for photoactivation while the immuno-adjuvant proceeds to activate/potentiate the immune response
  • Light of approp ⁇ ate frequency and intensity will be applied using an approp ⁇ ate light source, thereby activating the photosensitizer to destroy tumor cells and initiate immune responses, possibly by the rapid induction of an inflammatory reaction
  • the formulations and methods of the present invention generally relate to admmistenng a photosensitizer, including pro-drugs such as 5-am ⁇ nolevul ⁇ mc acid, porphy ⁇ ns and porphynn de ⁇ vatives e g chlo ⁇ ns, bacte ⁇ ochlo ⁇ ns, isobacte ⁇ ochlo ⁇ ns phthalocvanine and naphthalocyanines and other tetra- and poly-macrocyclic compounds, and related compounds (e.g pyropheophorbides) and metal complexes (such as, but not limited by, tin, aluminum, zmc, lutetium) to a subject undergoing the immuno-adjuvant PDT
  • Examples of photosensitizers useful m the invention include, but are not limited to, the green porphy ⁇ ns disclosed in a se ⁇ es of patents including US Patents 5,283,255, 4,920,143, 4,883,790, 5,095,030
  • Green porphy ⁇ ns are in the class of compounds called benzoporphy ⁇ n derivativ es (BPD)
  • BPD is a synthetic chlo ⁇ n- ke porphynn with va ⁇ ous structural analogues, as shown in U S Patent 5,171 ,749
  • the BPD is a benzoporphy ⁇ n derivative di- acid or mono-acid ⁇ ng A (BPD-DA or BPD-MA, also known as verteporfm), which absorbs light at about 692 nm wa elength with improved tissue penetration properties
  • BPD-MA for example, is lipophihc, a potent photosensitizer, and it also appears to be phototoxic to neovascular tissues, tumors and remnant lens epithelial cells Because of its pharmokinetics, BPD-MA may be the best candidate for use in the instant invention, but other BPDs such as EA6 and B3 or other de ⁇ vatives may be used instead Other photosensitizers, such as phthalocyamnes, could be used m high concentrations sufficient to offset their relatively slower uptake
  • An optimal BPD for immuno-adjuv ant PDT treatment or prevention of metastatic tumors should be rapidly taken up by tumor cells and should be capable of initiating an immune response upon irradiation with light to act in concert with the immuno-adjuvant
  • photosensitizers which may be useful in the invention are photosensitizing Diels-Alder porphynes de ⁇ vatives, desc ⁇ bed in US Patent 5,308,608, porphy ⁇ n-hke compounds, desc ⁇ bed in US Patents 5,405,957, 5,512675, and 5,726,304, bacte ⁇ ochlorophyll-A de ⁇ vatives desc ⁇ bed in US Patents 5,171,741 and 5,173,504, chlo ⁇ ns, isobacte ⁇ ochlo ⁇ ns and bacte ⁇ ochlo ⁇ ns, as desc ⁇ bed in US Patent 5,831,088, meso-monoiodo-substituted and meso substituted t ⁇ pyrrane, desc ⁇ bed in US Patent 5,831,088, polypyrrohc macrocycles from meso-substituted tnpyrrane compounds, desc ⁇ bed in US Patents 5,703,230, 5,883,
  • the preferred compounds of the present invention are the photosensitive compounds including naturally occurring or synthetic porphyrins, pyrroles, chlorins, tetrahydrochlorins, pyropheophorphides, purpurins, porphycenes, phenothiaziniums, pheophorbides, bacteriochlorins, isobacteriochlorins, phthalocyanines, napthalocyanines, and expanded pyrrole-based macrocyclic systems such as, sapphyrins and texaphyrins, and derivatives thereof.
  • the photosensitive compounds including naturally occurring or synthetic porphyrins, pyrroles, chlorins, tetrahydrochlorins, pyropheophorphides, purpurins, porphycenes, phenothiaziniums, pheophorbides, bacteriochlorins, isobacteriochlorins, phthalocyanines, napthalocyanines, and expanded pyrrole-based macrocycl
  • photosensitizers for use in the present invention are described in Redmond et al, Photochemistry and Photobiology, 70(4):391-475 (1999), which is hereby incorporated by reference in its entirety as if fully set forth.
  • the photosensitizer is not PhotofrinTM (porfimer sodium).
  • a particularly preferred formulation according to the present invention will satisfy the following general criteria.
  • These criteria do not necessarily reflect a temporal sequence of events.
  • the methods of the invention are used against metastatic tumors after initial diagnosis.
  • the methods of the invention follow removal or eradication of a solid tumor by conventional treatments such as surgery, radiation, chemotherapy or PDT, including immuno-adjuvant PDT.
  • the latter embodiment may be used to prevent or inhibit the development of, metastatic tumors.
  • the immuno-adjuvant may be administered systemically or locally. Moreover, the immuno-adjuvant may be administered before, after or simultaneous with the photosensitizing BPD. This permits the adjuvant-mediated activation/potentiation of immune responses to overlap with PDT mediated damage to tumor cells and any PDT induced immune responses.
  • the elapsed time may be from less than about one minute to more than about three hours, preferably from about one minute to about three hours, and more preferably from about 10 to about 60 minutes
  • compositions and methods of the present invention provide a useful immuno- adjuvant PDT treatment to treat, prevent or inhibit the development of metastatic tumors
  • cytokines include those that are immunomodulatory in activity and include several cytokines
  • cytokines include interleukin, granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon-v (IFN- ⁇ ), which may be administered locally, systemically, or via expression vectors in combination with PDT
  • Another approach of the invention is to utilize a cytokine in combination with a factor that acts to promote the growth of hematopoietic progenitors in the presence of a cytokine FLT3 -ligand, isolated and cloned ia the corresponding FLT3 receptor [see refs Rosnet et -./ 1991, Matthews et al 1991, Rasko et al 1995, Lyman et al 1993, Lyman et al 1994] is an example of such a factor Alone, FLT3-hgand has relatively little activity but in combination acts synergistically with other cytokines including IL-3, IL-6, IL-7, IL- 1 1, IL-12 and colony stimulating factors to promote the growth of hematopoietic progenitors in vitro (Jacobsen et al 1995) Following the repeated administration of recombinant FLT3-hgand to mice, splenomegaly, hepatomegaly as well as substantial increases in
  • mice given multiple FLT3-l ⁇ gand injections displayed dramatic increases in numbers of functionally mature dend ⁇ tic cells (DC) in multiple organs (Maraskovsky et al 1996, Shu ⁇ n et al 1997, Steptoe et al 1997)
  • Bone ma ⁇ ow-de ⁇ ved DC are potent APC that perform a sentinel role for the immune system These cells are normally present at low numbers within most tissues
  • MHC major histocompatibihty complex
  • adhesion and co-stimulatory molecules is a receptor repertoire that serves in the productive activation of naive and resting T lymphocytes (Steinman 1991 , Banchereau et al 1998)
  • DC may interact w ith and activate B cells and thereby regulate the formation of humoral immunity (Banchereau et al 1998)
  • DC are significant sources of interleukin- 12 (IL-12), a pro-inflammatory cytokine that strongly promotes the formation of cellular immunity (Steinman 1991
  • IL-12 interleuk
  • tumour cells A low capacity of tumour cells to present tumour-specific antigens to T cells
  • tumour-related antigens by tumour cell types
  • DC are a unique immune cell population that is likely de ⁇ ved from a myeloid linage precursor cell DC differentiation from bone marrow precursors is d ⁇ ven by the cytokines GM-CSF and TNF- ⁇ (Bancheereau et al 1998) Additional cytokines including IL-4 and c-kit gand regulate the differentiation and maturation of DC at different developmental stages (Bancheereau et al 1998) After multiple FLT3-hgand injections, elevated DC numbers were found in immune and non-immune tissues including the spleen, pe ⁇ pheral blood, thymus, liver, lungs, pe ⁇ toneal cavity, mesente ⁇ c lymph nodes and Peyer's patches.
  • FLT3 -ligand treated mice implanted with syngeneic fibrosarcoma tumour cells exhibited either no development of the tumour or a significantly lower tumour size (Lynch 1998).
  • FLT3-ligand had no direct effect upon tumour cell growth (Lynch 1998).
  • FLT3-ligand produces a therapeutic effect against non-immunogenic tumours (Fernandez et al. 1999), murine melanoma (Esche et al. 1998), murine lymphoma (Esche et al. 1998) and limited the spread of metastases to the liver (Peron et al. 1998).
  • the increased availability of DC in tumour-bearing FLT3-ligand-treated subjects may foster the recognition of tumour-associated structures by DC.
  • the interaction of DC with NK cells may simulate NK cell-mediated tumour cell lysis releasing apoptotic or necrotic cell bodies that are taken up, transported, processed and presented by DC to T lymphocytes (Fernandez et al.
  • FLT3-ligand is currently available from Immunex (Seattle, Washington) as MOBISTTM, while recombinant human and mouse FLT3-ligand is available commercially from the biological reagent supplier R&D (Minneapolis, Minnesota): Based on mouse studies, FLT3 -ligand may be adminstered to effect an increase in peripheral DC numbers. This may be accomplished by a regimen of regular administrations, such as a number of days for higher animals (e.g. humans). Standard PDT could be administered via intravenous injection of a photosensitiser followed later at a pre-determined time with light irradiation. FLT3-ligand administration may be continued for a number of days after PDT.
  • FLT3-ligand should be administered in a manner that when PDT is applied there is a high availability of DC within the body.
  • the interaction of DC with dying tumour cells would be optimal This circumstance would provide the patient's immune system the greatest opportunity to generate a specific and effective response to tumour antigens - potentially providing the potential to limit residual and metastatic cancer through lmmunologic mechanisms
  • tumour cells may lack the capacity to directly stimulate T cell responses due to a lack of the approp ⁇ ate repertoire of accessor ⁇ structures (MHC, co-stimulatory molecules, etc ) for instigating the responses, the acquisition of tumour cell material by DC could lead to the formation of specific anti- tumour immunity
  • DC dend ⁇ tic cell
  • peripheral blood DC being prepared and cultured in vitro for 24-48 hours with inactivated (optionally by PDT) tumor cells, tumor antigens, and/or any other tumor specific or related factor
  • PDT inactivated tumor cells
  • tumor antigens tumor antigens
  • any other tumor specific or related factor are re-introduced into the subject, with PDT applied to the subject either before or after the re-introduction
  • Green porphy ⁇ ns refer to porphynn denvatives obtained by reacting a porphynn nucleus with an alkyne in a Diels-Alder type reaction to obtain a monohydrobenzoporphynn
  • green porphynns are selected from a group of porphynn de ⁇ vatives obtained by Diels-Alder reactions of acetylene denvatives with protoporphynn under conditions that promote reaction at only one of the two available conjugated, nonaromatic diene structures present in the protoporphy ⁇ n-IX nng system ( ⁇ ngs A and B)
  • Dime ⁇ c forms of the green po ⁇ hy ⁇ n and dime ⁇ c or multimenc forms of green porphy ⁇ n porphy ⁇ n combinations can be used
  • the dimers and o gomenc compounds of the inv ention can be prepared using reactions analogous to those for dime ⁇ zation and ohgome ⁇ zation of po ⁇ hy ⁇ ns er se
  • po ⁇ hy ⁇ n linkages can be made directly, or po ⁇ hynns may be coupled, followed by a Diels-Alder reaction of either or both terminal po ⁇ hy ⁇ ns to con ert them to the corresponding green po ⁇ hy ⁇ ns
  • the green po ⁇ hynn compounds used in the inv ention may be conjugated to v a ⁇ ous gands to facilitate targeting to target tumor cells
  • hgands include those that are receptor-specific, or immunoglobulins as well as fragments thereof
  • Preferred hgands include antibodies in general and monoclonal antibodies, as well as lmmunologically reactive fragments of both
  • the green po ⁇ hy ⁇ n compounds of the invention may be administered as a single compound, preferably BPD-MA, or as a mixture of various green po ⁇ hy ⁇ ns Suitable formulations include those approp ⁇ ate for administration of therapeutic compounds in vivo Additionally, other components may be mco ⁇ orated into such formulations These include, for example, visible dyes or va ⁇ ous enzymes to facilitate the access of a photosensitizing compound to target tumor cells
  • the photosensitizers and immuno-adju ants of the invention may be formulated into a variety of compositions These include posomes, nanoparticles, and pluromc (Poloxamer) containing formulations These compositions may also comprise further components, such as conventional delivery vehicles and excipients including isotonising agents, pH regulators, solvents, solubi zers, dyes, gelling agents and thickeners and buffers and combinations thereof Approp ⁇ ate formulations and dosages for the administration of immuno-adjuvants are known in the art Suitable excipients for use with photosensitizers and immuno-adjuvants include water, saline, dextrose, glycerol and the like.
  • the photosensitizing agent is formulated by mixing it, at an appropriate temperature, e.g., at ambient temperatures, and at appropriate pHs, and the desired degree of purity, with one or more physiologically acceptable carriers, i.e., carriers that are nontoxic at the dosages and concentrations employed.
  • physiologically acceptable carriers i.e., carriers that are nontoxic at the dosages and concentrations employed.
  • the pH of the formulation depends mainly on the particular use, and concentration of photosensitizer, but preferably ranges anywhere from about 3 to about 8.
  • the photosensitizer is maintained at a pH in the physiological range (e.g., about 6.5 to about 7.5).
  • the presence of salts is not necessary, and, therefore the formulation preferably is not an electrolyte solution.
  • Appropriate nonantigenic ingredients, such as human serum albumin may optionally be added in amounts that do not interfere with the photosensitizing agent being taken up by lens epithelial cells.
  • the particular concentration of a given BPD should be adjusted according to its photosensitizing potency.
  • BPD-DA can be used but at about a five-fold higher concentration than that of BPD-MA.
  • the BPD may be solubilized in a different manner than by formulation in liposomes.
  • stocks of BPD-MA or any other BPD may be diluted in DMSO (dimethylsulfoxide), polyethylene glycol or any other solvent acceptable for use in the treatment of tumors.
  • the adjustment of pH is not required when liposomal BPD-MA is used, as both components have a neutral pH.
  • the pH may require adjustment before mixing the BPD with the other material. Since antioxidants may interfere with the treatment, they should generally should be avoided.
  • Preparation of dry formulations that are reconstituted immediately before use also are contemplated.
  • the preparation of dry or lyophilized formulations of the compositions of the present invention can also be effected in a known manner, conveniently from the solutions of the invention.
  • the dry formulations of this invention are also storable.
  • a solution can be evaporated to dryness under mild conditions, especially after the addition of solvents for azeotropic removal of water, typically a mixture of toluene and ethanol The residue is thereafter conveniently d ⁇ ed, e g for some hours in a drying oven.
  • Suitable lsotomsmg agents are preferably nomonic isotonising agents such as urea, glycerol, sorbitol, manmtol, ammoethanol or propylene glycol as well as ionic isotonising agents such as sodium chlo ⁇ de
  • the solutions of this invention will contain the isotonising agent, if present, in an amount sufficient to b ⁇ ng about the formation of an approximately isotomc solution
  • the expression "an approximately isotomc solution” will be taken to mean in this context a solution that has an osmolanty of about 300 milhosmol (mOsm), conveniently 300 + 10 % mOsm It should be borne in mind that all components of the solution contnbute to the osmolanty
  • the nomonic isotonising agent, if present, is added in customary amounts, I e . preferably in amounts of about 1 to about 3 5 percent bv weight, preferably in amounts of about 1 5
  • Solubihzers such as Cremophor types, preferably Cremophor RH 40, or Tween types or other customary solubihsers, may be added to the solutions of the invention in standard amounts
  • a further prefe ⁇ ed embodiment of the invention relates to a solution compnsmg a BPD compound, and a partially ethe ⁇ fied cyclodextnn.
  • approp ⁇ ate cvclodextnns should be of a size and conformation appropnate for use with the photosensitizing agents disclosed herein
  • the treatment of the present invention is earned out m tissues either maligned with metatstatic tumors or susceptible to their occu ⁇ ence, in an afflicted subject
  • the photosensitizer and immuno-adjuvant containing preparations of the present invention may be administered systemically or locally and may be used alone or as components of mixtures
  • Prefe ⁇ ed routes of administration are intravenous, subcutaneous. intramuscular, or intraperitoneal injections of the photosensitizers and immuno-adjuvants in conventional or convenient forms. Injection of the adjuvant into a tumor, whether primary or resulting from metastasis, is preferred. Intravenous delivery of photosensitizers.
  • intratumor injection may also be used when desired, as in pigmented tumor situations where the dose of PDT would be increased, for example.
  • Oral administration of suitable oral formulations may also be appropriate in those instances where the photosensitizer may be readily administered to the tumor or tumor-prone tissue via this route.
  • the invention also includes the use of repeat treatments as deemed necessary by a suitable clinician or skilled worker in the field.
  • the treatment is repeated from 1 to about 10 times at intervals of about 1 to about 2 weeks. More preferably, the treatment is repeated from 1 to about 5 times, or most preferably for a total of 3 times, at approximately 2 week intervals.
  • the photosensitizers may be topically administered using standard topical compositions including lotions, suspensions or pastes.
  • the dose of photosensitizers and immuno-adjuvants can be optimized by the skilled artisan depending on factors such as, but not limited to, the physical delivery system in which it is carried, the individual subject, and the judgment of the skilled practitioner. It should be noted that the various parameters used for effective PDT in the invention are interrelated. Therefore, the dose should also be adjusted with respect to other parameters, for example, fluence, i ⁇ adiance, duration of the light used in PDT, and time interval between administration of the dose and the therapeutic i ⁇ adiation.
  • fluence, i ⁇ adiance duration of the light used in PDT
  • time interval between administration of the dose and the therapeutic i ⁇ adiation are interrelated. Therefore, the dose should also be adjusted with respect to other parameters, for example, fluence, i ⁇ adiance, duration of the light used in PDT, and time interval between administration of the dose and the therapeutic i ⁇ adiation.
  • One means of rapidly evaluating parameters for PDT/adjuvant administration is set forth below in Example 4. All of these parameters should be adjusted to
  • photosensitizers for example, the form of administration, such as in liposomes or when coupled to a target-specific ligand, such as an antibody or an immuno logically active fragment thereof, is one factor considered by a skilled artisan. Depending on the specificity of the preparation, smaller or larger doses of photosensitizers may be needed.
  • compositions which are highly specific to the target tumors such as those with the photosensitizer conjugated to a highly specific monoclonal antibody preparation or specific receptor ligand
  • dosages in the range of 0 05-1 mg'kg are suggested
  • larger dosages, up to 1- 10 mg/kg may be desirable
  • the foregoing ranges are merely suggestive in that the number of vanables with regard to an individual treatment regime is large and considerable deviation from these values may be expected
  • the skilled artisan is free to vary the foregoing concentrations so that the uptake and cellular destruction parameters are consistent with the therapeutic objectives disclosed above
  • the time of immuno-adjuvant deliver may be before or after madiation with light as well as before or after administration of the photosensitizer, although madiation will occur after administration of the photosensitizer
  • the immuno-adjuvant may be delivered immediately after madiation This may be of particular relevance with immuno-adjuvants that are opaque or otherwise interfere with irradiation
  • BPDs being used as the photosensitizer, ⁇ adiation is thought to result in the interaction of BPD in its triplet state with oxygen and other compounds to form reactive intermediates, such as singlet oxygen, which can cause disruption of cellular structures
  • Possible cellular targets include the cell membrane, mitochond ⁇ a, lysosomal membranes
  • Each photosensitizer requires activation with an appropnate wavelength of light
  • an approp ⁇ ate light source preferably a laser or laser diode, in the range of about 550 to about 695 nm, is used to destroy target cells
  • An approp ⁇ ate and prefe ⁇ ed wavelength for such a laser would be 690-c 12 5 nm at half maximum.
  • cell destruction occurs within 60 seconds, and likely is sufficiently complete within about 15 to about 30 seconds.
  • the light dose administered dunng the PDT treatment contemplated herein can vary, but preferably ranges between about 10 to about 150 J/cm 2 The range between about 50-100 J/cm 2 is prefe ⁇ ed. Increasing madiance may decrease the exposure times.
  • Loca zed delivery of light is prefe ⁇ ed, and delivery localized to the tumor is more preferred. Delivery of light p ⁇ or to photosensitizer activating light is also contemplated to improve penetration of the activating light. For example, irradiation of pigmented melanomas with infrared light before visible red light bleaches the melanin to improve penetration of the red light.
  • the time of light l ⁇ adiation after administration of the green po ⁇ hy ⁇ n may be important as one way of maximizing the selectivity of the treatment, thus minimizing damage to structures other than the target tumor cells
  • Example 1 Sample Animals and Tumor Model Male, C57BL/6 mice were obtained from Charles River Canada (Montreal, QC) at 6 to 8 weeks of age.
  • the B16-F0 and B16-F1 melanoma cell lines were obtained from the Amencan Type Tissue Collection (Manassas, Virginia) and grown as cell cultures in Dulbecco's Modified Eagle Medium (DMEM) (Gibco) supplemented with 10% fetal bovine serum (Sigma)
  • DMEM Dulbecco's Modified Eagle Medium
  • EDTA ethylenediaminetetraacetic acid
  • mice were injected with 5 X 10 5 tumor cells in a total volume of 50 ⁇ L subcutaneously into the shaved, ⁇ ght flank.
  • the tumor size was monitored daily by measunng the diameter with vernier calipers and were treated when the tumors reached approximately 5 mm m diameter
  • the B16-F0 and B16-F1 were characterized with respect to in vivo growth rates and metastatic potential and were found to be identical. Subsequently the B16-F1 cell line was used for all expe ⁇ ments.
  • mice Sample Immuno- Adjuvant PDT PDT treatment of mice bea ⁇ ng the B 16-F1 tumor as performed as previously desc ⁇ bed for the Ml rhabdomyosarcoma mouse tumor (Richter et al , 1987, Richter et al , 1988, Richter et al , 1991)
  • Each mouse was weighed, warmed under infrared light for less than 5 min to dilate the blood vessels, restrained, and injected intravenously (tail vein) with Verteporfin at a concentration of 1 0 mg/kg bodv w eight using a 28G needle
  • Verteporfin at a concentration of 1 0 mg/kg bodv w eight using a 28G needle
  • animals were restrained and half of the animals were injected mtratumorally with 50 uL of Titermax adjuvant (Sigma) prepared as an emulsion w ith sterile phosphate buffered saline (PBS) according to the manufacturers specifications
  • Example 3 Sample Expe ⁇ mental Metastases Pulmonary metastases were generated by intra enous injection of tumoi cells according to standard methods described by several groups (Chapoval et al , 1998. Lin et al , 1998, Volpert et al., 1998, Wang et al , 1998) Pulmonary metastases were initiated in each group of treated mice, as descnbed in Example 2 above, when the tumor was considered cured.
  • mice This involved multiple treatments some of the mice and all test animals were injected intravenously with tumor cells on the same day Following PDT or immuno-adjuvant PDT animals were monitored for tumor response and if positive, Test (PDT and immuno-adjuvant PDT) and Control (naive) animals were injected with 5 X 10" tumor cells in 250 ⁇ l PBS via the lateral tail vein The animals were monitored for tumor recu ⁇ ence and general health for 14 days after which the animals were sac ⁇ ficed using CO, inhalation and their lungs removed Pulmonary metastases were clearly visible as black tumor colonies against the normal, pink lung tissue. Results from the above are shown in Figure 1.
  • the B16 melanoma tumor model is inherently difficult to treat with PDT because of the abso ⁇ tion of light by the black melanin pigment secreted by the tumor cells.
  • 10 animals completed the entire course of the experimental procedure.
  • All of the animals that had been treated with immuno-adjuvant PDT developed between 1 and 7 lung tumors at the time of dissection.
  • One of the animals treated with PDT alone developed 6 lung colonies but the remaining 4 animals developed between 30 and 60 lung colonies.
  • All of the control animals developed 200 to 300 lung colonies but the density of tumor growth made accurate quantification impossible (Fig. 1)
  • immuno-adjuvant PDT evidently augments tumor immunity that develops du ⁇ ng tumor growth and/or following PDT.
  • the above example uses pigmented tumors in an expe ⁇ mental metastases approach, the results indicate that the combination of an immuno-adjuvant with PDT can be used for the treatment of metastatic cancer
  • tumour-specific lymphocyte tumor immunity
  • mice Female C57B1/6 mice are implanted subcutaneously on the shaved right flank with the Lewis Lung Carcinoma (LLC) cell line.
  • LLC Lewis Lung Carcinoma
  • Animals treated with PDV receive a single 50 ⁇ l mtratumoral injection of adjuvant immediately following illumination Animals are monitored for general health and re-growth of the tumour following therapy
  • lymph nodes Seven to 10 days following therapy, animals are sac ⁇ ficed and inguinal, axillary, cervical, and pe ⁇ aortic lymph nodes are aseptically removed A single cell suspension is produced from the lymph nodes and this is cultured m half-area, 96-well tissue culture plates (Corning) in the presence of titrations of freeze/ hawed tumour cells and irradiated syngeneic splenocytes depleted of erythrocytes as accessory cells The cells are cultured in the presence of recombinant ⁇ nterleukm-2 (Sigma), and concanavalin A (ConA) (Sigma) is utilized as a positive control to assess the prohferativ e capacity of lymphocytes Following 3 to 5 days of culture, the degree of proliferation is assessed using 3-(4,5- d ⁇ methylth ⁇ azol-2-yl)-5-(3-carbo ⁇ ymethoxyphenyl)-2-(4-sulfophen l)-2H-tetraz
  • the assays may be performed using the commercial, expe ⁇ mental adju ant, Ribi Adjuvant System (RAS) (Co ⁇ xa) or Detox B-SE (Conxa) and alum for comparison
  • Ribi Adjuvant System Ribi Adjuvant System
  • Conxa Detox B-SE
  • Animals treated with PDT alone proliferated to 108 3- 1 1%
  • Controls using naive animals, tumour-bea ⁇ ng animals treated with adjuvant alone, and proliferation in the presence of another syngeneic tumour to test specificity have also been tested
  • This protocol may be used for a vanety of metastatic tumors, including metastatic melanoma.
  • Liposomal verteporfin is injected at a dosage of 14 mg/m2 of body surface area, which is a higher dose than for treating AMD
  • diode laser light is applied at a rate of approximately 200mW/cm2 for a total dosage of 120-180J/cm2 to the lesion being treated.
  • the dosage of the Detox adjuvant which is injected into the lesion after PDT, provides in the range of 100-200 ⁇ g of the cell wall skeleton component, and 20-30 ⁇ g of the monophosphoryl lipid A component. This procedure is carried out at approximately 2 week intervals. Perferably there are 3 treatments.
  • Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86-89.
  • Korbelik, M Krosl, G., Krosl, J. and Dougherty, G J. (1996) The role of host lymphoid populations in the response of mouse EMT6 tumor to photodynamic therapy. Cancer Research, 56:5647-5652. Korbelik, M., Naraparaju, V.R. and Yamamoto, N. (1997) Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer. British Journal of Cancer, 75:202-7.
  • Section 3 Treatment of metastatic cancer to bone.
  • DeVita Jr. V.T.. Hellman, S. and Rosenberg, S.A. (eds.), Cancer: Principles and Practice . J.B. Lippincott Company, Philadelphia, Vol. 2, pp. 2298-2317.
  • Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity. J Exp Med 186,1247-1256.
  • the immunogen must be inco ⁇ orated into or associated with the particle.
  • FCA Freund's Complete Adjuvant
  • FIA Freund's Incomplete Adjuvant
  • Montanide Incomplete Seppic Adjuvant Adjuvants a group of oil/surfactant based adjuvants in which different surfactants are combined with either a non-metabolizable mineral oil, a metabolizable oil, or a mixture of the two. They are prepared for use as an emulsion with aqueous Ag solution.
  • the surfactant for Montanide ISA 50 is mannide oleate, a major component of the surfactant in Freund's adjuvants.
  • the surfactants of the Montanide group undergo strict quality control to guard against contamination by any substances that could cause excessive inflammation, as has been found for some lots of Arlacel A used in Freund's adjuvant.
  • the various Montanide ISA group of adjuvants are used as water- in-oil emulsions, oil-in-water emulsions, or water-in-oil-in-water emulsions.
  • the different adjuvants accommodate different aqueous phase/oil phase ratios, because of the variety of surfactant and oil combinations.
  • the performance of these adjuvants is said to be similar to Incomplete Freunds Adjuvant for antibody production; however the inflammatory response is usually less. Seppic, Paris, France
  • Ribi Adjuvant System Ribi Adjuvant System
  • MPL monophosphoryl lipid A
  • TDM trehalose dimycolate
  • CWS cell wall skeletons
  • STM S. typhimurium mitogen
  • MTP-PE N-acety-muramyl-L-alanyl-2-( ,2'- dipalmitolyl-sn-glycero-3'-phospho)ethylamide
  • DetoxTM active ingredients include MPL ® (derivative of the lipid A molecule found in gram negative bacteria) and mycobacterial cell wall skeleton
  • Corixa Co ⁇ oration http://www.corixa.com v. Detox B-SETM for investigational use is supplied in clear glass vials.
  • Each vial contains: 145 micrograms CWS from M. phlei, 25 micrograms MPL from S. minnesota R595, 8.1 milligrams Squalane F, 0.38 milligrams Polysorbate 80 (USP/NF), 1.62 milligrams Soy Lecithin (NF), and 88 micrograms Sterile Water for Injection (USP)
  • Detox B-SE must be stored refrigerated between 2 and 8°C D.
  • Immune stimulating complexes ISCOM
  • -single or multilamellar bilayer membrane vesicles comprised of cholesterol and phospholipid
  • the immunogen may be membrane-bound or within the intermembrane spaces
  • MDP Muramyl dipeptide
  • Adjuvant peptides Adjuvant peptides
  • -N-acetyl muramyl-L-alanyl-D-isoglutamine is the active component of peptidoglvcan extracted from Mycobacterium, derivatives are less toxic i. threonyl MDP ii. murabutide ⁇ V-acetylglucosaminyl-MDP (GMDP) a.
  • Gerbu Adjuvant i. threonyl MDP ii. murabutide ⁇ V-acetylglucosaminyl-MDP (GMDP)
  • FCA Oil is replaced by water-soluble, aliphatic quaternary amines or bio-degradable esterquats.
  • Mycobacterium is replaced by GMDP. Gerbu Biotechnik GmbH, Gaiberg, Germany C-C Biotech 16766 Espola Road Poway, CA 92064 USA iii. murametide iv. nor-MDP
  • MPL monophosphoryl lipid A

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Abstract

L'invention concerne une thérapie photodynamique destinée à traiter et à prévenir le cancer métastatique au moyen de photosensibilisants en combinaison avec des immuno-adjuvants pour détruire les cellules métastatiques.
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