JPWO2021219750A5 - - Google Patents

Claims (32)

(i) Group: at least one peptide comprising the amino acid sequence of a neo-antigen encoded by a mutant homologous recombination (HR) DNA repair gene selected from BRCA1, BRCA2, PALB2, CDK12, RAD51B, RAD51C, and RAD51D, wherein said neo-antigen is encoded by a portion of said mutant gene comprising a reversion mutation ; and/or (ii) at least one polynucleotide encoding at least one peptide of (i). 2. The anti-cancer vaccine of claim 1, wherein the neo-antigen comprises an amino acid sequence selected from the sequences set forth in SEQ ID NOs : 934, 889, 1-5, 19, 20, 30, 31, and/or 33-89 . 3. The anti-cancer vaccine of claim 1 or claim 2, wherein the neo-antigen comprises an amino acid sequence selected from any one of the neo-peptide sequences of SEQ ID NOs: 1, 2, 3, 4, 5, 19, 20, 30, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, and 89. The anti-cancer vaccine according to any one of claims 1 to 3 , wherein the vaccine comprises a DNA or RNA sequence encoding said neo-antigen. The anti-cancer vaccine of claim 4 , wherein the DNA or RNA sequence is provided in the form of a viral vector. The anti-cancer vaccine according to claim 5 , wherein the viral vector is an oncolytic virus. The anti-cancer vaccine of any one of claims 1 to 6, wherein the vaccine is in the form of a plurality of dendritic cells (DCs) that have been pulsed with the at least one peptide comprising a neo-antigen and that are capable of presenting the neo-antigen to one or more T cells when administered to a subject. The anti-cancer vaccine according to any one of claims 1 to 7 , wherein the neo-antigen is an MHC class I restricted peptide. 9. The anti-cancer vaccine of claim 8, wherein the neoantigen is predicted to be presented by at least 10%, 25%, 50%, or at least 75% of the HLA-A, HLA-B, and/or HLA-C allotypes of the 1000 Genomes dataset. The anti-cancer vaccine of any one of claims 1 to 9 , wherein the neo-antigen is predicted to be presented by MHC class I with a Best Rank (BR) score of 0.5 or less using NetMHCpan-4.0 neural network predictor. The anti-cancer vaccine according to any one of claims 1 to 10, wherein the vaccine comprises 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different neo-antigens and/or polynucleotides encoding the different neo-antigens. The anti-cancer vaccine according to any one of claims 1 to 11 , further comprising at least one adjuvant. The anti-cancer vaccine of claim 12 , wherein the at least one adjuvant is selected from Toll-like receptor (TLR) agonists. 14. The engineered T cell recognizing a neo-antigen encoded by a mutant HR DNA repair gene selected from the group: BRCA1, BRCA2, PALB2, CDK12, RAD51B, RAD51C, and RAD51D, wherein the mutant gene comprises a reversion mutation, and the T cell is selected from a chimeric antigen receptor T cell (CAR-T), an engineered T cell receptor (TCR) T cell, or a neo-antigen-reactive T cell (NAR-T) , and the neo-antigen is as defined in any one of claims 1 to 13 .
An anti-cancer vaccine according to any one of claims 1 to 13 or an engineered T cell according to claim 14 for use in medicine. An anti-cancer vaccine according to any one of claims 1 to 13 or an engineered T cell according to claim 14 for use in a method of treatment of a proliferative disorder in a mammalian subject. 17. The anti-cancer vaccine or engineered T cell for use according to claim 16 , wherein the proliferative disorder is a cancer exhibiting a homologous recombination (HR) defect. 18. The anti-cancer vaccine or engineered T cell for use according to claim 16 or claim 17 , wherein the proliferative disorder is selected from high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer (TNBC), castration-resistant metastatic prostate cancer, and pancreatic cancer. The anti-cancer vaccine or engineered T cell for use according to any one of claims 16 to 18 , wherein the method of treatment comprises inhibiting or preventing the onset, or reducing or reversing tumor resistance to PARP inhibitor therapy and/or platinum therapy. The anti-cancer vaccine or engineered T cells for use according to any one of claims 16 to 19 , wherein the subject has a mutation in the BRCA1 gene, the BRCA2 gene, the PALB2 gene, the CDK12 gene, the RAD51B gene, the RAD51C gene, and/or the RAD51D gene. 21. The anti-cancer vaccine or engineered T cell for use according to claim 20 , wherein the mutation in the BRCA1 gene, the BRCA2 gene, the PALB2 gene, the CDK12 gene, the RAD51B gene, the RAD51C gene, and/or the RAD51D gene is a somatic mutation. the BRCA1 mutation, the BRCA2 mutation, the PALB2 mutation, the CDK12 mutation, the RAD51B mutation, the RAD51C mutation, and/or the RAD51D mutation is a reversion mutation, and optionally the reversion mutation is selected from the group consisting of those listed in Table 6.
22. The anti-cancer vaccine or engineered T cell for use according to claim 20 or claim 21 , as depicted in: 23. The anti-cancer vaccine or engineered T cell for use according to any one of claims 20 to 22, wherein the method of treatment comprises the step of determining whether the BRCA1 mutation, the BRCA2 mutation, the PALB2 mutation, the CDK12 mutation, the RAD51B mutation, the RAD51C mutation, and/or the RAD51D mutation are present in the subject's tumor. 24. The anti-cancer vaccine or engineered T cell for use according to claim 23 , wherein the step of determining whether the mutation is present in the subject's tumor comprises sequencing ctDNA from a sample obtained from the subject. 25. The anti-cancer vaccine or engineered T cell for use according to claim 23 or claim 24, wherein the tumor is determined to have a BRCA1 gene, a BRCA2 gene, a PALB2 gene, a CDK12 gene, a RAD51B gene, a RAD51C gene or a RAD51D gene comprising a reversion mutation therein, which encodes a gene product comprising a neo-antigen amino acid sequence, and optionally the neo-antigen amino acid sequence is as defined in claim 2 or claim 3 . The anti-cancer vaccine or engineered T cell for use according to any one of claims 16 to 23 , wherein the subject is undergoing or is a candidate for undergoing treatment with a PARP inhibitor and/or a platinum-based chemotherapy agent. The anti-cancer vaccine or engineered T cell for use according to any one of claims 16 to 26 , wherein the method of treatment is a combination therapy further comprising treatment with an immune checkpoint inhibitor. The anti-cancer vaccine or engineered T cells for use according to any one of claims 16 to 27 , wherein the method of treatment is a combination therapy further comprising treatment with radiotherapy and/or chemotherapy. The anti-cancer vaccine or engineered T cells for use according to any one of claims 16 to 28 , wherein the method of treatment is a combination therapy comprising treatment with both the anti-cancer vaccine and the engineered T cells. The anti-cancer vaccine or engineered T cells for use according to any one of claims 16 to 28 , wherein the method of treatment further comprises the steps of HLA typing the subject and matching the neo-antigen to the subject's HLA allotype. 31. The anti-cancer vaccine or engineered T cell for use according to claim 30 , wherein the step of matching the neo-antigen to the HLA allotype of the subject comprises a step of predicting MHC class I presentation of the neo-antigen sequence by the subject, wherein the predicting step uses a computational tool. The anti-cancer vaccine or engineered T cells for use according to claim 31 , wherein said computational tool comprises NetMHCpan-4.