Construction and methods of use of a therapeutic cancer vaccine library comprising fusion-specific vaccines

Abstract

Methods described herein relate to constructing therapeutic fusion-specific vaccine libraries, selecting a therapeutic fusion-specific vaccine for a cancer patient, and/or constructing a de novo therapeutic fusion-specific vaccine for patients having a gene fusion that is absent from a fusion-specific vaccine library.

What is claimed is: 
     
         1 . A method for constructing a therapeutic fusion-specific vaccine library for a cancer patient, the method comprising:
 a) identifying one or more tumor-specific gene fusions from patient data;   b) identifying one or more fusion-derived neoantigens, wherein the fusion-derived neoantigen comprises amino acid sequences corresponding to one or more tumor-specific gene fusions;   c) obtaining information relating to interaction between fusion-derived neoantigens with one or more HLA alleles; and   d) selecting at least one fusion-derived neoantigen for the therapeutic fusion-specific vaccine library.   
     
     
         2 . A method of selecting a therapeutic fusion-specific vaccine for a cancer patient, the method comprising:
 a) determining the presence of one or more tumor-specific gene fusions in a biological sample from the cancer patient;   b) obtaining information relating to one or more HLA alleles of the cancer patient;   c) analyzing a library of fusion-specific vaccines, wherein each fusion-specific vaccine in the library comprises one or more fusion-derived neoantigens having a nucleic acid sequence and/or an amino acid sequence corresponding to one or more tumor-specific gene fusions; and   d) selecting at least one fusion-specific vaccine in the library as the therapeutic fusion-specific vaccine for the cancer patient by selecting the fusion-specific vaccine comprising one or more fusion-derived neoantigens that
 i) correspond to one or more tumor-specific gene fusions of the cancer patient, and 
 ii) bind one or more HLA alleles of the cancer patient. 
   
     
     
         3 . A method of constructing a de novo therapeutic fusion-specific vaccine for a cancer patient, the method comprising:
 a) determining the presence of one or more tumor-specific gene fusions in a biological sample from the cancer patient;   b) obtaining information relating to one or more HLA alleles of the cancer patient;   c) constructing at least one fusion-specific vaccine as the de novo therapeutic fusion-specific vaccine for the cancer patient by constructing the fusion-specific vaccine comprising one or more fusion-derived neoantigens that
 i) correspond to one or more tumor-specific gene fusions of the cancer patient, and 
 ii) bind one or more HLA alleles of the cancer patient. 
   
     
     
         4 . The method of any one of the foregoing, further comprising administering the therapeutic fusion-specific vaccine to the cancer patient. 
     
     
         5 . The method of  claim 2  or  3 , wherein the biological sample is a tissue sample or fluid sample taken from the cancer patient. 
     
     
         6 . The method of  claim 2  or  3 , wherein the biological sample is analyzed by DNA sequencing, RNA sequencing, and/or protein sequencing. 
     
     
         7 . The method of  claim 2  or  3 , wherein one or more tumor-specific gene fusions are identified in the biological sample. 
     
     
         8 . The method of any one of the foregoing claims, wherein information relating to one or more HLA alleles of the cancer patient are obtained by analysis of the biological sample. 
     
     
         9 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more nucleic acid sequences corresponding to one or more tumor-specific gene fusions. 
     
     
         10 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having amino acid sequences corresponding to one or more tumor-specific gene fusions. 
     
     
         11 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides selected from Table A. 
     
     
         12 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 peptides corresponding to one or more tumor-specific gene fusions. 
     
     
         13 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises 20 or more peptides corresponding to one or more tumor-specific gene fusions. 
     
     
         14 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides that bind to one or more HLA alleles of the cancer patient with an IC50 less than 500 nM. 
     
     
         15 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides that bind to one or more HLA alleles of the cancer patient with an IC50 less than 250 nM. 
     
     
         16 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides that bind to one or more HLA alleles of the cancer patient with an IC50 less than 100 nM. 
     
     
         17 . The method of any one of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides that bind to one or more HLA alleles of the cancer patient with an IC50 less than 50 nM. 
     
     
         18 . The method of any of the foregoing claims, wherein the library of fusion-specific vaccines comprises at least 2-10 fusion-specific vaccines corresponding to distinct fusion-derived neoantigens. 
     
     
         19 . The method of any of the foregoing claims, wherein the library of fusion-specific vaccines comprises at least 5-10 fusion-specific vaccines corresponding to distinct fusion-derived neoantigens. 
     
     
         20 . The method of any of the foregoing claims, wherein the library of fusion-specific vaccines comprises at least 10-50 fusion-specific vaccines corresponding to distinct fusion-derived neoantigens. 
     
     
         21 . The method of any of the foregoing claims, wherein the library of fusion-specific vaccines comprises at least 50-100 fusion-specific vaccines corresponding to distinct fusion-derived neoantigens. 
     
     
         22 . The method of any of the foregoing claims, wherein the library of fusion-specific vaccines comprises 100 or more fusion-specific vaccines corresponding to distinct fusion-derived neoantigens. 
     
     
         23 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having 8-10 amino acids. 
     
     
         24 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having 10-25 amino acids. 
     
     
         25 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having 25-50 amino acids. 
     
     
         26 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having 50-100 amino acids. 
     
     
         27 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having 100 or more amino acids. 
     
     
         28 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having an amino acid sequence corresponding to a one or more tumor-specific gene fusions and one or more addition amino acid sequences. 
     
     
         29 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises two or more peptides having an amino acid sequence corresponding to two or more tumor-specific gene fusions and one or more addition amino acid sequences. 
     
     
         30 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more peptides having a modification. 
     
     
         31 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises one or more adjuvants. 
     
     
         32 . The method of any of the foregoing claims, wherein the fusion-specific vaccine comprises the peptide having a concentration of 100 ng-10 mg. 
     
     
         33 . The method of any of the foregoing claims, wherein the fusion-specific vaccine is administered once to the cancer patient. 
     
     
         34 . The method of any of the foregoing claims, wherein the cancer patient is treated with two or more doses of the fusion-specific vaccine. 
     
     
         35 . The method of any one of the foregoing claims, wherein the library of fusion-specific vaccines comprises fusion-derived neoantigens corresponding to gene fusions that are present in a type of cancer. 
     
     
         36 . The method of any one of the foregoing claims, wherein the type of cancer is melanoma, skin cancer, head and neck cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, prostate cancer, thyroid cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, testicular cancer, brain tumor, glioma, glioblastoma, solitary fibrous tumor, bladder cancer, colorectal cancer, renal cell carcinoma, sarcoma, myeloma, leukemia, and/or lymphoma. 
     
     
         37 . The method of any one of the foregoing claims, wherein the type of cancer is a metastatic tumor. 
     
     
         38 . The method of any one of the foregoing claims, wherein the type of cancer is any tumor type. 
     
     
         39 . The method of any one of the foregoing claims, wherein the cancer patient is administered dendritic cells or other antigen presenting cells that have been pulsed with at least one fusion-derived neoantigens from the fusion-specific vaccine library. 
     
     
         40 . The method of any one of the foregoing claims, wherein autologous T-cells can be collected from the cancer patient, stimulated ex vivo with fusion-derived neoantigens, and stimulated autologous T-cells are transfused into the cancer patient. 
     
     
         41 . The method of any one of the foregoing claims, wherein one or more fusion-specific vaccines are DNA or RNA molecules that encode fusion-derived neoantigens. 
     
     
         42 . The method of any one of the foregoing claims, wherein the cancer patient is administered dendritic cells or other antigen presenting cells comprising at least one fusion-derived neoantigens from the fusion-specific vaccine library.