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EP-4739339-A1 - IMMUNOTHERAPY FOR THE TREATMENT OF PRAME-EXPRESSING CANCERS

EP4739339A1EP 4739339 A1EP4739339 A1EP 4739339A1EP-4739339-A1

Abstract

The present invention relates to the treatment of PRAME-expressing cancers, in particular by administration of a plurality of PRAME-based synthetic long peptides or nucleic acids encoding such SLPs. Furthermore, the invention relates to immunogenic compositions suitable for use in the method of treatment of the invention. Moreover, the invention relates to methods for selecting antigens suitable for use in immunization by determining their ability to increase CCR7 and/or CD40 levels in antigen-presenting cells.

Inventors

  • WIEKMEIJER, Anna-Sophia
  • VAN DER GRACHT, Esmé Teunisje Ida
  • MELIEF, CORNELIS JOSEPH MARIA

Assignees

  • Focus Fund-Isa LLC

Dates

Publication Date
20260513
Application Date
20240405

Claims (15)

  1. 1. A method for treating or preventing cancer, comprising administering to a human subject a plurality of immunogenic peptides, wherein the plurality of immunogenic peptides comprises: (a) a peptide of 33 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 1, and (b) a peptide of 33 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO:2.
  2. 2. The method according to claim 1, wherein the plurality of immunogenic peptides comprises: (a) a peptide consisting of the sequence set forth in SEQ ID NO: 1, and (b) a peptide consisting of the sequence set forth in SEQ ID NO:2, wherein preferably position 12 in SEQ ID NO:2 is a cystine.
  3. 3. The method according to any one of the preceding claims, wherein the plurality of immunogenic peptides further comprises one, two or all three of the following immunogenic peptides: (a) a peptide of 25 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 3, (b) a peptide of 35 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 4, and (c) a peptide of 32 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 5.
  4. 4. The method according to any one of the preceding claims, wherein the plurality of peptides further comprises one, two or all three of the following immunogenic peptides: (a) a peptide of 35 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 6, (b) a peptide of 32 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 7, and (c) a peptide of 35 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 8.
  5. 5. The method according to any one of the preceding claims, wherein the plurality of immunogenic peptides comprises, or consists of, the eight peptides set forth in SEQ ID NO: 1 to SEQ ID NO:8.
  6. 6. The method according to any one of the preceding claims, wherein the treatment: (i) does not comprise administration of peptides comprising, or consisting of, one of the sequences of the group consisting of SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, in SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, or (ii) does not comprise administration of peptides comprising or consisting of any of the sequences of the group consisting of SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, in SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15.
  7. 7. The method according to any one of the preceding claims, wherein the cancer is a PRAME-expressing cancer, preferably selected from the group consisting of: neuroblastoma, lymphoma, papillomas, breast or cervical carcinomas, acute and chronic leukemias, medulloblastoma, non-small cell lung carcinoma, head and neck cancer, renal carcinoma, pancreatic carcinoma, prostate cancer, small cell lung cancer, multiple myeloma, melanoma, uveal melanoma, sarcomas and hematological malignancies like chronic myeloid leukemia and acute myeloid leukemia.
  8. 8. The method according to any one of the preceding claims, further comprising administration of an adjuvant, wherein the adjuvant preferably is AMPLIVANT® or Montanide ISA-51.
  9. 9. A plurality of immunogenic peptides for use in the treatment or prevention of cancer, wherein the plurality of immunogenic peptides comprises: (a) a peptide of 33 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 1, and (b) a peptide of 33 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 2.
  10. 10. The plurality of immunogenic peptides for use according to claim 9, further comprising the features of any one of claims 2 to 8.
  11. 11. An immunogenic composition comprising a plurality of peptides, wherein the plurality of peptides comprises: (a) a peptide of 33 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 1, and (b) a peptide of 33 to 40 amino acids in length comprising or consisting of the sequence set forth in SEQ ID NO: 2.
  12. 12. The immunogenic composition according to claim 11, further comprising the features of any one of claims 2 to 8.
  13. 13. A method for selecting an antigen suitable for use in immunization comprising: (i) determining CCR7 and/or CD40 levels in antigen-presenting cells, such as dendritic cells or CD14+CD11C+ cultured monocyte-derived cells, upon incubation with a candidate antigen, and (ii) selecting a candidate antigen that is able to increase CCR7 and/or CD40 levels in said antigen-presenting cells, wherein the antigen preferably is a peptide.
  14. 14. A method for treating or preventing cancer, comprising administering to a human subject one or more polynucleotides encoding the immunogenic peptides as defined in any one of claims 1 to 6.
  15. 15. An immunogenic composition comprising one or more plurality of polynucleotides encoding the immunogenic peptides as defined in any one of claims 1 to 6.

Description

IMMUNOTHERAPY FOR THE TREATMENT OF PRAME-EXPRESSING CANCERS FIELD OF THE INVENTION The present invention relates to the treatment of PRAME-expressing cancers, in particular by administration of a plurality of PRAME-based synthetic long peptides (SLPs) or nucleic acids encoding such SLPs. Furthermore, the invention relates to immunogenic compositions suitable for use in the method of treatment of the invention. Moreover, the invention relates to methods for selecting antigens suitable for use in immunization by determining their ability to increase CCR7 and/or CD40 levels in antigen-presenting cells. BACKGROUND OF THE INVENTION Tumor associated PRAME specific T cells were first described in 1997 (Ikeda et al. 1997 Immunity 6: 199) and were reported as a single CTL clone, derived from a patient with melanoma. These T cells recognized a peptide presented by HLA-A24. The antigen PRAME had a tissue distribution highly similar to cancer testis antigens with high expression on testis cells in the absence of HLA class I antigens and high expression in melanoma cancer cells, but low or absent expression on healthy cells. It was soon discovered that several other PRAME CTL epitopes were presented by HLA-A*02:01 and that such A2-restricted T cells could be generated from patients with melanoma or from healthy donor PBMC (Kessler et al. 2001 J. Exp. Med. 193:73; Griffioen et al. 2006 Clin Cancer Res 12(10): 3130). These CD8+ CTL were shown to kill HLA-matched melanoma cells, but not PRAME+ HLA- mismatched melanoma cells or PRAME-negative cells. Other immunogenic PRAME CTL epitopes were discovered by other groups (Quintarelli et al. 2011 Blood 117(12):3353; Stanojevic et al. 2021 Cytotherapy 23(8):694). In each case CTLs generated in vitro against these epitopes were capable of lysis of HLA-matched PRAME+ tumor cells. Attempts to generate clinical benefit from these insights has envisaged two strategies: 1) Generation of T cells ex vivo by stimulation with peptides, followed by T-cell expansion and reinfusion or 2) Vaccination with either adjuvanted PRAME peptides (W02008118017) or adjuvanted PRAME recombinant protein. Although reinfusion of ex vivo expanded T cells has been envisaged as a strategy, this has not been implemented yet with T cells exclusively stimulated with PRAME peptides. Positive direct in vivo immunogenicity of a combination of PRAME and PSMA peptides in patients with cancer was shown by Weber et al. 2011(J Immunther 34(7): 556), in some patients this was associated with stable disease > 6 months, but not with objective tumor regression. A PRAME peptide mixed with peptides from three other tumor-associated antigens, delivered together in Montanide ISA-51 adjuvant + azacytidine did not show immunogenicity in patients with myelodysplastic syndrome, possibly indicating failure of selection of immunogenic peptides (Holmberg-Thyden et al. 2022 Cancer Immunol Immunother. 71(2) :433). In three papers an account is given of PRAME recombinant protein vaccination of patients with cancer. In all three papers describing these vaccination studies, only vaccine induced CD4+ T helper cells were reported and no anti-PRAME CD8+ T cells were demonstrable (Pujol et al. 2016 J. Thoracic Oncol ll(12):2208; Gutzmer et al. 2016 ESMO Open l(4):e000068), explaining the lack of clinical benefit observed in these studies. The inefficient processing of recombinant PRAME protein for HLA class I presentation is the likely root cause of the failure of the recombinant PRAME vaccines to generate CD8+ CTL in the vaccinated patients (discussed in Meissen et al. 2022 J Immunother. Cancer 10(9):e004709). Thus, while important progress has been made, there is a clear need for improved PRAME-based antigens that are processed and presented efficiently and induce strong anti-tumor responses. In 1998 three reports described that CD8+ CTL responses crucially depend on delivery of CD4+ help. This help was clearly delivered to antigen presenting cells such as dendritic cells (DC) and involved interaction between CD40 ligand (CD40L) on CD4+ T helper cells and CD40 on dendritic cells (DC) (Ridge et al. 1998 Nature 393:4747; Bennett et al. 2998 Nature 393:478; Schoenberger et al. 1998 Nature 393:480). In an accompanying editorial, the three cell interaction between CD4+ T helper cells, DC and CD8+ T cells was dubbed the "license to kill" model for CD8+ CTL generation (Lanzavecchia 1998 Nature 393:413). In a recent review these pivotal findings were found to have been universally confirmed and expanded by countless papers in both experimental animals such as mice and in human immunology studies, constituting canonical knowledge regarding the interaction of CD4+ T cells, DC and CD8+ T cells (Borst et al. 2018 Nature Rev. Immunol. 18: 635). Interaction of CD40L on activated CD4+ T cells with the CD40 master switch molecule on DC was confirmed to be the crucial DC activating interaction that led to important upregulation of co-stimulatory molecules i