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WO2025003035A1 - Thérapie à base d'il -17 - Google Patents

Thérapie à base d'il -17 Download PDF

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Publication number
WO2025003035A1
WO2025003035A1 PCT/EP2024/067602 EP2024067602W WO2025003035A1 WO 2025003035 A1 WO2025003035 A1 WO 2025003035A1 EP 2024067602 W EP2024067602 W EP 2024067602W WO 2025003035 A1 WO2025003035 A1 WO 2025003035A1
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Prior art keywords
ici
subject
melanoma
treatment
therapy
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English (en)
Inventor
Alexander Rösch
Lisa ZIMMER
Renata VARALJAI
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Universitatsklinikum Essen
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Universitatsklinikum Essen
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/5743—Specifically defined cancers of skin, e.g. melanoma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin

Definitions

  • the present invention relates to a method of determining whether a subject who has been diagnosed with melanoma is amenable to a treatment with immune checkpoint inhibitor(s) ICI(s) wherein the method comprises determination of the level and/or amount of IL-17 in a biological sample obtained from the subject and drawing a conclusion as to the amenability of said subject to a treatment with ICI(s) from the level and/or amount of IL-17 determined in said biological sample.
  • the present invention relates to a method for determining the therapy regimen of a subject who has been diagnosed with melanoma whereby the therapy comprise a treatment with ICI(s).
  • Said method includes the measurement of the level and/or amount of IL-17 in a biological sample obtained from the subject and concluding whether the therapy regimen of said subject is amenable to a treatment with ICI(s) from the determined level or amount of IL- 17. Moreover, a method for determining responsiveness of the subject has been diagnosed with melanoma to a treatment with ICI(s) is disclosed. In a further aspect, the present invention relates to the use of IL-17 for predicting response to ICI therapy and/or for stratification of ICI in a subject who has been diagnosed with melanoma, in particular, metastatic melanoma. Moreover, the present invention relates to a pharmaceutical composition comprising a combination of IL-17 with at least one the ICI, in particular, being selected from anti-PD1 ICI and anti-CTLA-4 ICI.
  • Treatment with ICI has become a major pillar for therapy of metastatic melanoma. It is described that blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have shown clinical success and extended the survival of patients with melanoma, see e. g. Huang, A.C., Zappasodi, R., 2022, Nat. Immunol., 23, 660-670. Unfortunately, not all patients benefit to the same extent due to intrinsic mechanisms of tumor immune resistance or resistance that is acquired after an initial response to treatment, actually, the majority relapses or experiences severe immune-related adverse events (irAEs). Hence, it remains a challenge to identify patients who will benefit from treatment in the long term.
  • CTL-4 cytotoxic T-lymphocyte-associated protein 4
  • PD-1 programmed cell death protein 1
  • the interleukin 17 (IL- 17) family includes six structurally relevant members (IL- 17 A-F) and is a pro-inflammatory cytokine produced by a subset of CD4+ T-cells, primary Th17 cells, CD8+ T-cells and various innate immune cells types.
  • IL-17 has an essential role in a multitude of autoimmune diseases and inflammation.
  • IL- 17A is the hell mark cytokine of Th 17 cells and is the most potent induces of downstream cytokines and neutrophil recruitment among IL-17 family members.
  • the Th17 cells as well as IL- 17 have been reported to have both anti-tumor and pro-tumor effects.
  • Th17/IL-17-inflammation could have an anti-tumor effect in melanoma, particularly ICI therapy, e.g., see review of Chen, C. & Gao, F. H., Front. Immunol. 10,187 (2019).
  • the present invention relates to a method of determining whether a subject who has been diagnosed with melanoma is amenable to a treatment with immune checkpoint inhibitors(s) (I Cl)(s) wherein the method comprises: a) Measuring the level and/or the amount of IL-17 in a biological sample obtained from the subject; b) drawing a conclusion as to the amenability of said subject to a treatment with ICI(s) from the level and/or amount of IL-17 measured in step a).
  • I Cl immune checkpoint inhibitors
  • the present invention relates to a method of determining the therapy regimen of a subject who has been diagnosed with melanoma whereby the therapy comprises a treatment with ICI(s), wherein the method comprises: a) Measuring the level and/or the amount of IL-17 in a biological sample obtained from the subject; b) drawing a conclusion as to the therapy regimen of said subject to a treatment with ICI(s) from the level and/or amount of IL-17 measured in step a).
  • the present invention relates to a method of determining responsiveness of a subject who has been diagnosed with melanoma to a treatment with ICI wherein the method comprises a) Measuring the level and/or the amount of IL-17 in a biological sample obtained from the subject; b) drawing a conclusion as to the extent of responsiveness of said subject to a treatment with ICI (s) from the level and/or amount of IL-17 measured in step a).
  • the present invention relates to the use of IL-17 for predicting a response to ICI therapy and/or for stratification of ICI therapy a subject who has diagnosed with melanoma, in particular, metastatic melanoma.
  • a pharmaceutical composition comprising a combination of IL-17 with at least one of the ICI selected from anti-PD1 ICI and anti-CTLA4 ICI for use in treating melanoma in a subject who has been diagnosed with melanoma in particular, metastatic melanoma is disclosed.
  • Interleukin-17 pathway genes are associated with improved response to dual immune checkpoint inhibition, (a) Kaplan-Meier plot for OS according to the IL-17 signaling GES (KEGG: hsa04657) in the TCGA-SKCM cohort, (b-g) Kaplan-Meier plots for PFS (b-d) and OS (e-g) according to the IL-17 family GES ( L17A-F GES’: IL-17 family cytokines containing the six structurally related cytokines) in dual ICI- (b/e), mono CTLA-4- (c/f), and in mono PD-1 -treated patients (d/g). HR and 95% Cl are reported for high expression groups, p - values represent log rank test.
  • TCGA The Cancer Genome Atlas
  • SKCM Skin cutaneous melanoma
  • GES gene expression signature
  • KEGG Kyoto Encyclopedia of Genes and Genomes
  • OS overall survival
  • PFS progression-free survival
  • HR hazard ratio
  • Cl confidence intervals.
  • IL-17A supports anti-tumor effects of dual ICI.
  • FIG. 3 IL-17A/Th17 profiling for response prediction in ICI-treated melanoma patients,
  • the present invention relates to a method of determining whether a subject who has been diagnosed with melanoma is amenable to a treatment with immune checkpoint inhibitors(s) (I Cl)(s) wherein the method comprises: a) Measuring the level and/or the amount of IL-17 in a biological sample obtained from the subject; b) drawing a conclusion as to the amenability of said subject to a treatment with ICI(s) from the level and/or amount of IL-17 measured in step a).
  • I Cl immune checkpoint inhibitors
  • the present invention relates to a method of determining the therapy regimen of a subject who has been diagnosed with melanoma whereby the therapy comprises a treatment with ICI(s), wherein the method comprises: a) Measuring the level and/or the amount of IL-17 in a biological sample obtained from the subject; b) drawing a conclusion as to the therapy regimen of said subject to a treatment with ICI(s) from the level and/or amount of IL-17 measured in step a).
  • the present invention relates to a method of determining responsiveness of a subject who has been diagnosed with melanoma to a treatment with ICI wherein the method comprises a) Measuring the level and/or the amount of IL-17 in a biological sample obtained from the subject; b) drawing a conclusion as to the extent of responsiveness of said subject to a treatment with ICI (s) from the level and/or amount of IL-17 measured in step a).
  • the term "amenable to a treatment with ICI(s)” refers to a therapy or treatment with active agents falling under the definition of an immune checkpoint inhibitor. That is, beneficial effects in the treatment of individuals or subjects diagnosed with melanoma are described for the active agent.
  • Immune checkpoint inhibitor refers to active agents suitable in checkpoint inhibitor therapy which is a form of cancer immunotherapy.
  • Immune checkpoints are regulators of the immune systems and typically immune checkpoint inhibitors (ICI) allow potential use in multiple types of cancers. That is, drugs or drug candidates that inhibit/block the inhibitory checkpoint molecules are referred to as ICI(s).
  • ICI immune checkpoint inhibitor
  • the members of checkpoint inhibitors as described in the art and already approved checkpoint inhibitors target the molecules CTLA-4, PD-1, and PD-L1, respectively.
  • Other inhibitory checkpoint molecules include A2AR and A2BR, B7-H3, B7- H4, BTLA, IDO, KIR, LAG3, NOX2, TIM3, VISTA, SIGLEC7 and SIGLEC9.
  • CISH cytokine-inducible SH2-containing proteins
  • Approved immune checkpoint inhibitors include drugs targeting CTLA-4, like Ipilimumab, Tremelimumab as well as drugs targeting PD-1, like Nivolumab, Pembrolizumab and Cemiplimab. With respect to the PD-L1 target, Atezolizumab, Avelumab and Durvalumab have been described.
  • irAEs severe immune-related adverse events
  • colitis hepatitis
  • pneumonitis pancreatitis
  • dermatitis thyroiditis
  • myositis myositis
  • carditis hypophysitis which are the most common to occur.
  • the term "therapy regimen” refers to a regimen defining the drugs to be used, their dosage, the frequency and duration of treatments and other considerations.
  • the therapy regimen is the output of therapeutic decision making and patient stratification upfront to treatment with suitable active agents.
  • the therapy is typically a therapeutic therapy; however, preventive therapy may be envisaged.
  • suitable biomarkers for responsive prediction and patient stratification in melanoma are not described in the art.
  • responsiveness of a subject... of a treatment with ICI the beneficial effect of the treatment to said subject is considered.
  • the level of responsiveness is determined.
  • the responsiveness may allow to determine whether a monotherapy is sufficient or whether a combination of two active agents, in particular, ICI is required.
  • IL-17 refers to a member of the interleukin 17 family including the six structurally relevant members of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.
  • an “increased level or amount” corresponds to an increase by at least 20% of the level or amount compared to the average level or amount of a total population of melanoma patients examined. It has been recognized that IL-17 and TH 17 cells in general represent suitable biomarkers associated with responses to ICI. In addition, it has been identified that combining IL-17 administration with at least one ICI is beneficial in the treatment of melanoma accordingly.
  • plasma I L-17/TH17 cytokines represent a valuable biomarker at therapy baseline (BL), namely, upfront to the treatment with the ICI response prediction and patient stratification in melanoma, specifically to predict a potential benefit of adding anti-CTLA4 to anti-PD-1 upfront to therapy.
  • IL-17 determined in a biological sample obtained from the subject represents a suitable biomarker identifying patients where a combinatorial therapy with ICI(s) in particular, anti-CTLA-4 ICI and anti-PD-1 ICI is beneficial as it is the use for TH17 gene expression signatures (GES) in general.
  • the ICI comprises at least one of an anti-PD-1 ICI and/or an anti-CTLA-4 ICI. In an embodiment, a combination thereof is administered.
  • the IL-7 measured is IL-7A.
  • the measurement in the biological sample is conducted by known means.
  • the biological sample may be a tissue or a liquid obtained from the subject.
  • the biological sample is blood, like plasma or serum or whole blood.
  • IL-17 level and/or amount is determined on protein level.
  • the melanoma may be any type of melanoma, like cutaneous melanoma, ocular melanoma, mucosal melanoma, melanoma of unknown primary and any stage of disease from primary tumor to local or systemic metastatic stage.
  • the melanoma is a metastatic melanoma of stages III and/or IV.
  • the method according to the present invention is a method wherein elevated levels of I L-17 measured in step a) is indicative for beneficial treatment with a combinatorial therapy of at least two different ICI(s), in particular, treatment with a combination of anti-PD-1 ICI and anti-CTLA-4 ICI, whereas when the IL-17 level or amount is not increased, monotherapy with a single ICI selected from an anti-PD-1 ICI or anti-CTLA-4 ICI is suitable, optionally the treatment or therapy is combined with an administration of I L-17.
  • the level and/or amount of I L-17 may be indicative for the combinatory therapy of at least two different ICI (s) or may be indicative for a monotherapy with a single ICI whereby the monotherapy may either be anti-PD-1 ICI or anti-CTLA-4 ICI.
  • the beneficial treatment may be a treatment wherein the administration of ICI is combined with administration of IL-17.
  • IL-17 administered before or during therapy is beneficial in survival rate as well as reduction of relapse of melanoma.
  • the administration of IL-17 allows to reduce the dosage of the (ICI(s) or allows to concentrate on monotherapy of ICI, thus, reducing the known adverse effects (irAEs) described in the art.
  • IL-17 pathway supports melanoma response to dual ICI therapy, thus, representing firstly a biomarker for patient stratification and secondly represents a possibility for combined therapy thus reducing adverse effects described for ICI accordingly.
  • the method according to the present invention is a method wherein, if i) it is determined that the subject has an increased level and/or amount of IL- 17 in the biological sample, typically blood, ii) the subject is diagnosed with melanoma, in particular, metastatic melanoma, and iii) ICI treatment is considered for the therapy of choice and the subject is likely to benefit from treatment with ICI, a therapeutic comprising a combination of two different ICI, in particular, an anti-PD-1 ICI and anti-CTLA-4 ICI, optionally, with IL-17, should be administered to the subject accordingly.
  • the present invention relates to the use of IL-17 or TH17 GES in general for prediction a response to ICI therapy and for stratification of ICI therapy of the subject who has been diagnosed with melanoma, in particular, metastatic melanoma.
  • IL-17 represents a suitable biomarker for patent stratification, in particular, stratifying and determining whether the ICI therapy should be a combinatorial therapy, e.g. of anti-PD-1 ICI and anti-CTLA-4 ICI eventually improving the survival rate of said subject or whether a monotherapy with either anti-PD-1 ICI or anti-CTLA-4 ICI is sufficient.
  • the present invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of IL-17 with at least one ICI, in particular, with at least one of the ICI (s) selected from anti-PD-1 ICI and anti-CTLA-4 ICI for use in treating melanoma in a subject that has been diagnosed with melanoma.
  • the subject is a subject being diagnosed with metastatic melanoma.
  • the pharmaceutical composition according to the present invention comprises a combination of anti-PD-1 , anti-CTLA-4 and IL-17 for use in treating metastatic melanoma when an increased level and/or amount of IL-17 is determined in a biological sample, typically provided in vitro, from the subject upfront the therapy.
  • the pharmaceutical composition according to the present invention further comprises at least one pharmaceutically acceptable carrier.
  • the compounds according to the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof may be included in a pharmaceutically acceptable carrier.
  • carrier and “excipient” are used interchangeably herein.
  • Pharmaceutically acceptable carriers or excipients include diluents (fillers, bulking agents, e.g. lactose, microcrystalline cellulose), disintegrants (e.g. sodium starch glycolate, croscarmellose sodium), binders (e.g. PVP, HPMC), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal SiO2), solvents/co- solvents (e.g. aqueous vehicle, Propylene glycol, glycerol), buffering agents (e.g.
  • citrate, gluconates, lactates preservatives (e.g. Na benzoate, para-bens (Me, Pr and Bu), BKC), anti-oxidants (e.g. BHT, BHA, Ascorbic acid), wetting agents (e.g. polysorbates, sorbitan esters), anti-foaming agents (e.g. Simethicone), thickening agents (e.g. methylcellulose or hydroxyethylcellulose), sweetening agents (e.g. sorbitol, saccharin, aspartame, acesulfame), flavoring agents (e.g. peppermint, lemon oils, butterscotch, etc), humectants (e.g. propylene, glycol, glycerol, sorbitol).
  • preservatives e.g. Na benzoate, para-bens (Me, Pr and Bu), BKC
  • anti-oxidants e.g. BHT, BHA, Ascorbic
  • a non-exhaustive list of exemplary pharmaceutically acceptable carriers or excipients includes (biodegradable) liposomes; microspheres made of the biodegradable polymer poly(D,L)-lactic-coglycolic acid (PLGA), albumin microspheres; synthetic polymers (soluble); nanofibers, protein-DNA complexes; protein conjugates; erythrocytes; or virosomes.
  • Various carrier based dosage forms comprise solid lipid nanoparticles (SLNs), polymeric nanoparticles, ceramic nanoparticles, hydrogel nanoparticles, copolymerized peptide nanoparticles, nanocrystals and nanosuspensions, nanocrystals, nanotubes and nanowires, functionalized nanocarriers, nanospheres, nanocapsules, liposomes, lipid emulsions, lipid microtubules/microcylinders, lipid microbubbles, lipospheres, lipopolyplexes, inverse lipid micelles, dendrimers, ethosomes, multicomposite ultrathin capsules, aquasomes, pharmacosomes, colloi-dosomes, niosomes, discomes, proniosomes, microspheres, microemulsions and polymeric micelles.
  • SSNs solid lipid nanoparticles
  • polymeric nanoparticles polymeric nanoparticles
  • ceramic nanoparticles such as
  • the pharmaceutical composition of the invention will generally be designed for specific routes and methods of administration, for specific dosages and frequencies of administration, for specific treatments of specific diseases, with ranges of bio-availability and persistence, among other things.
  • the materials of the composition are preferably formulated in concentrations that are acceptable for the site of administration. Formulations and compositions thus may be designed in accordance with the invention for delivery by any suitable route of administration.
  • the routes of administration include:
  • enteral routes such as oral, gastrointestinal, sublingual, sublabial, buccal, rectal
  • parenteral routes such as intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, epidural, intrathecal, subcutaneous, intraperitoneal, extra-amniotic, intraarticular, intracardiac, intradermal, intralesional, intrauterine, intravesical, intravitreal, transdermal, intranasal, transmucosal, intrasynovial, intraluminal).
  • the administration may be a parenteral route, in particular intravenous or intramuscular but also intratumoral or peritumoral.
  • the pharmaceutical composition, as disclosed herein is administered to a subject in need thereof in an amount effective to treat cancer.
  • the subject is preferably a human.
  • the term "amount effective" in the context of a composition or dosage form for administration to a subject refers to an amount of the composition or dosage form sufficient to provide a benefit in the treatment of cancer, to delay or minimize symptoms associated with cancer, or to cure or ameliorate cancer.
  • a therapeutically effective amount means an amount sufficient to provide a therapeutic benefit in vivo.
  • the term preferably encompasses a non-toxic amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of or synergies with another therapeutic agent.
  • Amounts effective will depend, of course, on the particular subject being treated; the severity of a condition, disease or disorder; the individual patient parameters including age, physical condition, size and weight; the duration of the treatment; the nature of concurrent therapy (if any); the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reason.
  • the administration of the different components of the pharmaceutical compositions may be simultaneously, separately or sequentially.
  • the administration and therapy regimen may be as follows: - administration of IL-17 i.v. followed by ICI i.v. (mono or combination), with different time intervals between the two infusions (like 1, 2, 3, 4, 5, 6, 7, 14 days), not to be bound by theory, it is considered that IL-17 primes the tumor immune environment, so that subsequent ICI works better, namely more efficient, e.g. at lower dosage, thus reducing adverse effects.
  • ICI(s) mono or combination
  • IL-17 peritumorally or intratumorally at the same time.
  • the present invention relates to the use of a kit for a) Determining whether a subject who has been diagnosed with melanoma is amenable to a treatment with ICI(s), or b) of determining the therapy regimen of a subject who has been diagnosed with melanoma whereby the therapy comprise the treatment with ICI(s) or c) determining responsiveness of a subject who has been diagnosed with melanoma to a treatment with ICI(s) wherein the kit comprises: i) means for measuring IL-17 in a biological sample and ii) instructions on how to use the kit in a method.
  • the discovery cohort consisted of pre-treatment tissue samples from 77 treatment naive BRAF V600E/K mutant melanoma patients from the Combi-v phase 3 study, and 79 treatment naive BRAFwt patients from the Dermatology Department of the University Hospital Essen. Custom designed CodeSet (containing 780 genes involved in phenotypic resistance) and the commercially available Immune Panel from NanoStringTM (800 genes involved in immune pathways) was used to generate expression data on the NanoStringTM platform (NanoString Technologies). Clinical parameters of the discovery patient cohort and corresponding gene expression data processing were previously described Brase, J.
  • the validation cohorts consisted of open-source bulk tumor tissue transcriptomic datasets from The Cancer Genome Atlas Skin Cutaneous Melanoma cohort (TCGA-SKCM, I Gland MAPKi - naive melanoma patients) and ICI (Liu, D. et al., Nature Medicine (2019).
  • MAPKi receiving melanoma patients Long, G. V. et al., Nature Communications (2014).
  • TPM transcripts per million
  • Riaz et al dataset: n 20 a-PD-1 ;
  • the IL-17 A-F GES gene family signature consisted of IL-17 family genes with reliable read counts (expression value > 0 in at least 60% of tumor samples). Gene expression values were summarised into a single GES score without weighing in the normalized dataset. Immune cell fraction enrichment analyses from RNA-seq datasets were computed according to the Bindea, G. et al., Immunity (2013) immune cell signature using the xCell algorithm, Aran, D., Hu, Z. & Butte,
  • the melanoma patient cohort size calculation for cytokine analyses was based on power analysis using Chi-squared statistic assuming a relative risk of 2.0 between outcome positive and outcome negative proportions (type l/ll errors at 0.05 and 0.20, respectively).
  • group size was determined based on data from preliminary experiments to detect >20% effect between groups (type l/ll errors at 0.05 and 0.20, respectively).
  • n 4 mice were used to ensure a balance between statistical needs and animal welfare.
  • no sample size calculation was performed, however, reproducibility of the method has been demonstrated on minimum three biologically independent samples. No patients or cohorts were excluded from the analyses. From public datasets only the samples with available baseline gene expression, mutational data and clinical annotation were analyzed.
  • ARPC1B 0.000942 0.2901 0.086 3.373 0.048924
  • ITGB3 0.000287 0.8011 0.2158 3.712 0.034369 p-values are from multiple unpaired t-test (two-tailed) with Benjamini, Krieger and Yekutieli test correction (q).
  • Meier plots were computed using survival data categorized according to the biomarker threshold determined using X-tile and curves were compared using the log rank test.
  • GSEA was done using WebGestalt (v.2019), Liao, Y., et. al., Nucleic Acids Research using KEGG, functional database, with FDR ⁇
  • Murine cell lines The CM and LN (primary cutaneous melanoma - CM, and lymph node metastasis - LN, derived from ref-transgenic melanoma model, Helfrich, I., et. al., cells were cultured in RPMI medium supplemented with 10% FBS.
  • DMEM/F-12 supplemented with 10% FBS, 1% NEAA.
  • mice melanoma cells were injected subcutaneously (s.c.) in PBS (YUMM/ER1.7), or in 1:1 mixture of PBS with Matrigel® (CM).
  • the following treatments in different combinations were administered by intraperitoneal injection: control IgG (lgG2a isotype control clone 2A3, BioXCell, 10 mg/kg body weight, 3x/week) a-CTLA-4 (anti-mouse CTLA-4 clone 9D9, BioXCell, 8 mg/kg body weight, 3x/week), a-PD-1 (anti-mouse PD-1 clone RMP1-14, BioXCell, 10 mg/kg body weight, 3x/week), recombinant mouse IL-17A (IL-17A mouse recombinant, Prospec, 0.01 mg/kg body weight, daily), O-IL-17A (Ultra- LEAFTM purified anti-mouse IL-17A antibody
  • Pre-treatm ent with ICI was done for the CM model. Mice were randomized to different combinatorial treatment groups when tumors became palpable. Treatment continued until tumors had reached the maximal volume (not exceeding 1500 mm 3 ) or became ulcerated. Tumor growth kinetics were analyzed in a long-term experiment, while short-term experiments (end of treatment on day 9 or day 12) were set up to analyze the immune infiltration by multiplex immunofluorescence or flow cytometry and serum cytokine profiles by multiplex cytokine array. Tumor volume was assessed by caliper measurement (calculated as WxWxL/2). At the end of the treatment animals were sacrificed and tumor and blood samples were collected. Tumor samples were fixed in formalin for histological assessment and immunostaining.
  • IF multiplex immunofluorescence staining of 4-micron sections, formalin-fixed paraffin-embedded (FFPE) mouse tumor tissues (3 mice/each combination drug treatment group) was executed. De-paraffinization and antigen retrieval was performed using the DAKO PT-Link heat-induced antigen retrieval solution with high pH (pH 9) target retrieval solution (DAKO). Next, each tissue slide was stained in three consecutive rounds of antibody staining, using the Opal Multiplex IHC Kit (Akoya). The slides were washed with Tris-buffered saline containing 0.05% Tween-20® and the microwave treatment was performed in Tris-EDTA buffer (pH 9).
  • the IF panels consisted of Melan A (EPR20380, 1 :1000, Abeam), Ly6G (RB6-8C5, 1:100, BioLegend), CD8a (C8/144B, 1 :100, BioLegend), and Cd11c (N418, 1:100, BioLegend), CD4 (RM4-5, 1:100, BioLegend), IL-17A (TC11-18H10.1 , 1 :100, BioLegend) primary antibodies. Nuclei were stained by DAPI. Imaging was performed on Zeiss Axio Scan (20x objective) microscopy. The relative contribution of immune cells was calculated by quantitating the background corrected mean fluorescence intensity of each marker at five random fields per tumor tissue and normalized to DAPI.
  • PDTF cultures were performed as previously described, Voabil, P. et al., Nature Medicine In short, tumor specimens were collected from three patients with melanoma undergoing surgery. The tissue was manually dissected into fragments of 1-2 mm 3 and cryo-preserved in freezing medium (FCS supplemented with 10% DMSO) until use.
  • FCS freezing medium
  • Tumor fragments were thawed and embedded in artificial matrix (Cultrex UltiMatrix (Biotechne, 2mg/mL), rat-tail collagen I (Corning, 1mg/mL), sodium bicarbonate (Sigma-Aldrich, 1.1%), and DMEM tumor medium (Thermo Fisher Scientific) supplemented with 1 mM of sodium pyruvate (Sigma-Aldrich), 1x MEM nonessential amino acids (Sigma-Aldrich), 2 mM of L-glutamine (Thermo Fisher Scientific), 10% FBS and 1% penicillin-streptomycin) in a 96 well plate, using 8-10 fragments for each treatment condition.
  • artificial matrix Cultrex UltiMatrix (Biotechne, 2mg/mL)
  • rat-tail collagen I Corning, 1mg/mL
  • sodium bicarbonate Sigma-Aldrich, 1.1%
  • DMEM tumor medium Thermo Fisher
  • the medium was supplemented with a-PD-1 (10 pg/mL, Nivolumab, Bristol-Myers Squibb), a-CTLA-4 (10 pg/mL, Ipilimumab, Bristol-Myers Squibb) and O-IL-17A (10 pg/mL, clone BL168, Biolegend).
  • a-PD-1 10 pg/mL, Nivolumab, Bristol-Myers Squibb
  • a-CTLA-4 10 pg/mL, Ipilimumab, Bristol-Myers Squibb
  • O-IL-17A 10 pg/mL, clone BL168, Biolegend
  • CR complete response
  • PR partial response
  • MR mixed response
  • PD progressive disease
  • Resected tumor samples were collected from patients with melanoma undergoing surgical treatment at the Netherlands Cancer Institute (NKI-AVL), The Netherlands.
  • the study was approved by the institutional review board of the NKI-AVL (CFMPB484) and executed in compliance with the ethical regulations. All patients consented to the research usage of material not required for diagnostics via prior informed consent.
  • the bead-based LEGENDplexTM panels (Human Th17 7-plex Panel; Human Th 12-plex Panel, Mouse Th17 7-plex Panel; I L-1 p, IL-23, I L-12p70 from the Inflammation Panel 1; Granzyme A, Granzyme B from the CD8/NK Panel, pre-defined and custom- designed mix and match system from BioLegend) were used as per the manufacturer’s instruction.
  • Flow cytometry reading was performed on the FACSAriaTM III (BD).
  • Mean fluorescence intensity (MFI) values were recorded from the LEGENDplexTM analysis software (version 2021.
  • the IL-17 pathway predicts clinical response to dual ICI
  • IL-17 signaling requires mitogen-activated protein kinase (MAPK) activation
  • MAPK mitogen-activated protein kinase
  • IL-17 signaling GES defined according to KEGG hsa04657
  • MAPK-PROGENY the transcriptional oncogenic activation signature of the MAPK pathway
  • IL-17-inducing genes were expressed at higher levels in BRAF mt as compared to BRAF wt tumors in the SKCM cohort, and that their expression was significantly decreased in MAPK inhibitor (MAPKi)-treated melanoma tissue biopsies.
  • MAPKi MAPK inhibitor
  • IL-17-inducing genes can be expressed by BRAF mt melanoma cells themselves, and dual MAPKi (dabrafenib plus trametinib) leads to decreased transcription of IL-17 regulatory genes.
  • RNA-seq datasets from ICI-treated patient cohorts with metastatic melanoma of various genotypes were analysed (combined cohorts of a-CTLA- 4-, a-PD-1-, or a-CTLA-4 + a-PD-1, Van Allen et al; Liu et al, Riaz et al, and Gide et al, exact patient numbers are provided in the Methods section).
  • IL-17 pathway activity is probably not restricted to (known) oncogenic MAPK activators and may instead be a more universal predictor of response to ICI.
  • IL-17A is required for the anti-tumor effect of dual ICI
  • IL-17A is also a relevant contributor to CTLA-4+PD-1 blockade in human melanomas
  • PDTFs patient-derived tumor fragments
  • TME tumor microenvironment
  • CD4+, IL-17A+, CD11c+ cells, and Ly6G+ neutrophils that are potential downstream effectors of IL- 17 functions also were significantly enriched in tumors treated with dual ICI alone or in combination with rm-IL-17A, whereas the addition of O-IL-17A counteracted the effect of dual ICI and prevented immune cell infiltration.
  • IL-17 could improve ICI responsiveness also in an intrinsically resistant tumor scenario and applied the YUMM1.7 mouse model, which was reported to lack response to ICI (PTENdel, CDKN2Adel, BRAF V600E mt melanoma).
  • YUMM1.7 tumors treated with dual ICI showed no response and developed tumors similar to the control (p > 0.05 vs. control).
  • IL-17A/Th17 cytokines predict the response to dual ICI
  • BL IL-17A levels could be used as a biomarker for pre-therapeutic therapy stratification
  • patients were categorized according to their BL IL-17A plasma concentrations.
  • a bead-based multiplex cytokine array including several known Th17, Th1/Th2, inflammatory, and CD8+ T cell/NK (CD8/NK) activation-associated cytokines were applied.
  • dual ICI therapy responders had higher Th17-associated cytokines (IL-10, IFN-y, IL-17A, and IL-22, p ⁇ 0.05), particularly at BL. While other inflammatory and CD8/NK cytokines were also elevated in BL and FU samples from responders, they did not statistically stratify patients.
  • plasma IL-17/Th17 cytokines is a valuable BL biomarker for response prediction and patient stratification in melanoma, specifically to predict a potential benefit of adding a-CTLA-4 to a-PD-1 upfront to therapy.
  • IL-17 signaling and Th17 cells have been controversially discussed so far, e.g., Ruiz de Morales, J. M. G. et al. in Autoimmunity Reviews (2020). Studies that evaluated the association between IL-17 and patients’ prognoses are inconsistent across cancer types including melanoma. Th17 cells and IL-17 are known to have both anti-tumor and pro-tumor effects. However, the underlying mechanism of IL- 17 for its anti- or pro-tumor effects in melanoma is not well understood.
  • High IL-17 signature expression in ICI treated patient cohorts was additionally positively correlated with higher infiltration of T cells, Th17 cells, dendritic cells, and neutrophils. This suggests that the role of the pre-existent cytokine milieu and that the associated immune cell populations like neutrophils, which are commonly considered a negative predictive marker for ICI, might differ depending on the exact therapeutic ICI context.
  • IL-17A is the hallmark cytokine of Th17 cells, and is the most potent inducer of downstream cytokines and neutrophil recruitment among IL-17 family members.
  • a high baseline IL-17A level in patient plasma samples was indicative of a higher global baseline Th17 cytokine profile preceding clinical response to dual ICI in the metastatic setting, but not mono a-PD-1.
  • BRAF mt patients had longer median OS as compared to BRAF wt patients with the high 10 mg/kg but also the standard 3 mg/kg dose of ipilimumab (33.2 vs. 8 months and 19.7 vs. 2 months, respectively), Ascierto, P. A.
  • IL-17 is suitable as a biomarker for predicting response to dual ICI therapy.
  • IL-17 cytokine levels can be measured by common analytical biochemistry assays (e.g., ELISA) that are easily accessible and applicable in the clinical routine across institutions.

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Abstract

Dans un premier aspect, la présente invention concerne un procédé permettant de déterminer si un sujet qui a été diagnostiqué avec un mélanome peut être traité avec un ou plusieurs inhibiteurs de point de contrôle immunitaire (ICI), le procédé comprenant les étapes consistant à déterminer le taux et/ou la quantité d'IL-17 dans un échantillon biologique prélevé sur le sujet et conclure quant à la pertinence de traiter ledit sujet avec un ou plusieurs inhibiteurs de point de contrôle immunitaire sur la base du taux et/ou de la quantité d'IL-17 déterminé dans ledit échantillon biologique. En outre, la présente invention concerne un procédé de détermination du régime thérapeutique d'un sujet qui a été diagnostiqué avec un mélanome, la thérapie comprenant un traitement avec un ou plusieurs inhibiteurs de point de contrôle immunitaire . Ledit procédé comprend les étapes consistant à mesurer le taux et/ou la quantité d'IL-17 dans un échantillon biologique prélevé sur le sujet et conclure que le régime thérapeutique dudit sujet peut être ou non un traitement avec un ou plusieurs inhibiteurs de point de contrôle immunitaire sur la base du taux ou de la quantité déterminé d'IL-17. En outre, l'invention concerne un procédé de détermination de la sensibilité du sujet ayant été diagnostiqué avec un mélanome à un traitement avec un ou plusieurs inhibiteurs de point de contrôle immunitaire. Selon un autre aspect, la présente invention concerne l'utilisation de l'IL-17 pour prédire une réponse à une thérapie par inhibiteur de point de contrôle immunitaire et/ou pour la stratification d'inhibiteurs de point de contrôle immunitaire chez un sujet qui a été diagnostiqué avec un mélanome, en particulier, un mélanome métastatique. En outre, la présente invention concerne une composition pharmaceutique comprenant une combinaison d'IL-17 avec au moins un des inhibiteurs de point de contrôle immunitaire, en particulier choisi parmi un inhibiteur de point de contrôle immunitaire anti-PD1 et un inhibiteur de point de contrôle immunitaire anti-CTLA-4.
PCT/EP2024/067602 2023-06-30 2024-06-24 Thérapie à base d'il -17 Pending WO2025003035A1 (fr)

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