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EP-4735889-A1 - IL-17 BASED THERAPY

EP4735889A1EP 4735889 A1EP4735889 A1EP 4735889A1EP-4735889-A1

Abstract

In a first aspect, 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. Moreover, 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.

Inventors

  • Rösch, Alexander
  • ZIMMER, Lisa
  • VARALJAI, Renata

Assignees

  • Universität Duisburg-Essen

Dates

Publication Date
20260506
Application Date
20240624

Claims (18)

  1. 1. 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).
  2. 2. 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).
  3. 3. 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).
  4. 4. The method according to any one of the preceding claims wherein the ICI(s) comprises at least one of an anti-PD-1 ICI and/or an anti-CTLA-4 ICI, preferably a combination thereof.
  5. 5. The method according to any one of the preceding claims wherein the melanoma is a metastatic melanoma.
  6. 6. The method according to any one of the preceding claims wherein the biological sample is tissue or blood, like plasma or serum.
  7. 7. The method according to any one of the preceding claims wherein the IL-17 measured is IL-17a.
  8. 8. The method according to any one of the preceding claims wherein elevated levels of IL- 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 IL- 17.
  9. 9. The method according to any one of the preceding claims wherein the subject having increased level and/or amount of IL- 17 will have an increased survival rate when treated with a combination of two different ICI(s), in particular, anti-PD-1 ICI in combination with anti-CTLA-4, ICI, optionally the treatment of therapy is combined with an administration of IL-17.
  10. 10. The method according to any one of claims 1 to 9 wherein if: a) It is determined that the subject has an increased level and/or amount of IL-17 in the biological sample and the subject is diagnosed with melanoma, in particular, metastatic melanoma, and b) it is determined that the subject is likely to benefit from treatment with ICI(s), then a therapeutic comprising a combination of two different ICI, in particular, an anti-PD-1 ICI and anti-CTLA-4 ICI, optionally combined with IL-17 is administered to the subject.
  11. 11. The use of IL-17 for predicting response to ICI therapy and/or for stratification of ICI therapy of a subject who has been diagnosed with melanoma, in particular, metastatic melanoma.
  12. 12. The use of IL-17 according to claim 11 for determining if the subject is likely to benefit from treatment with a combination of anti-PD-1 ICI and anti-CTLA-4 ICI eventually improving survival rate of said subject.
  13. 13. A pharmaceutical composition comprising a combination of IL-17 with at least one of the ICI 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.
  14. 14. The pharmaceutical composition according to claim 13 comprising 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 from said subject.
  15. 15. 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 according to any one of claims 1 to 10.
  16. 16. A method for treating melanoma in a subject in need thereof comprising i) determining whether a subject who has been diagnosed with melanoma is amenable to a treatment with ICI(s), ii) determining the therapy regimen of an individual has been diagnosed with melanoma whereby the therapy comprise a treatment with ICI(s) or iii) determing responsiveness of a subject who has been diagnosed with melanoma to a treatment with ICI(s) according to any one of claims 1 to 10, followed by administration of a pharmaceutical composition containing ICI(s) and IL- 17 whereby the different components of the pharmaceutical composition may be administered simultaneously, separately or sequentially wherein a) administration of IL-17 is followed by ICI administration (mono or combination) or b) administration of ICI (mono or combination) followed by IL-17 or c) administration of I L-17/ICI(s) in the same at the same time or d) administration of IL-17 followed by ICI mono or combination with different time intervals in between in infusions whereby IL-17 is administered intratumorally or peritumorally while ICI is administered i.v. or e) administration of ICI(s) (mono or combination) i.v. followed by IL-17 peritumorally or intratumorally or f) administration of ICI(s) (mono or combination) i.v. and IL-17 peritumorally or intratumorally at the same time.
  17. 17. The method according to claim 16 wherein the pharmaceutical composition is a pharmaceutical composition according to claim 13 or 14.
  18. 18. The method according to claim 16 or 17 wherein the melanoma is metastatic melanoma.

Description

IL-17 based therapy In a first aspect, 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. Moreover, 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. Prior Art 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. There is still a lack of feasible biomarkers and mechanistic understanding for risk stratification of melanoma patients prior to ICI therapy, and these lacks needs to be addressed. For example, dual ICI (anti-CTLA-4 in combination with anti-PD1) leads to higher tumor control, but also to more severe immune related adverse events than mono ICI like anti- PD1 , see e.g., Wolchok, J. D., et al., 2022, J Clin Oncol 40, 127-137. Recently, unexpected observations were reported from the Checkmade 067 and IMMUNED trials identifying that patients harbouring the BRAF V600 mutation (BRAF mt) had longer survival than patients with wild type BRAF (BRAF wt) when treated with the combination of anti-CTLA-4 ICI and PD-1 ICI. This is different to the observation with monotherapy of each of the ICI showing only small survival differences when stratified according to BRAF mutations. Prior art described various biomarker and treatment combination which may influence the survival rate and relapse of tumor affected individuals. As said, due to lack of physical biomarkers and mechanistic understanding, the risk stratification prior to the therapy ICI therapy, is highly demanded. 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. Prior art discloses, that 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. Several reports suggest that particularly inflamed tumors respond better to ICI in the presence of IL-17, it is controversial whether 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). In view of the above, there is still a need for suitable biomarkers in particular with respect to stratifying the therapy regimen including ICI therapy in advance. Thus, it is in an object of the present invention to provide suitable biomarker based methods for predicting responsiveness of a subject to a treatment with ICI(s) and determine whether the subject diagnosed with melanoma is amenable to a treatment with ICI(s) accordingly. Brief description of the present invention In a first aspect, the present invention relates to a method of determining whether a subject who has been diagnosed wit