Compositions And Methods For Viral Delivery Of Neoepitopes And Uses Thereof

Abstract

Cancer immunotherapy is enhanced by co-expression of cancer associated or tumor-specific (neo)epitopes with co-stimulatory molecules and/or other immune activators. Where desired, treatment may be enhanced by administration of a immune checkpoint inhibitor.

What is claimed is: 
     
         1 . A method of generating a recombinant nucleic acid, comprising:
 assaying deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and inferred protein from matched tumor and histologically normal tissue samples from a patient to identify a patient-specific cancer-related neoepitope of the patient;   determining binding of the patient-specific cancer-related neoepitope to an HLA-type of the same patient, and determining an expression level of the patient-specific cancer-related neoepitope;   selecting at least one co-stimulatory molecule; and   genetically modifying an expression vector to include a nucleic acid encoding the at least one costimulatory molecule and the patient-specific cancer-related neoepitope.   
     
     
         2 . The method of  claim 1 , wherein the expression level of the patient-specific cancer-related neoepitope is determined by omics analysis selected from the group consisting of DNA sequencing, RNA sequencing, protein sequencing, and mass spectroscopy based sequencing. 
     
     
         3 . The method of  claim 1  wherein the expression vector is an adenoviral expression vector. 
     
     
         4 . The method of  claim 1  wherein the cancer-related neoepitope of the patient is identified in silico by location-guided synchronous alignment of omics data of tumor and matched normal samples. 
     
     
         5 . The method of  claim 1  further comprising a step of predicting the HLA type of the patient in silico. 
     
     
         6 . The method of  claim 1  wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD155, ICOS-L, 4-1BB, GITR-L, LIGHT, TIM3, TIM4, ICAM-1, and LFA3 (CD58). 
     
     
         7 . The method of  claim 1  wherein the nucleic acid further comprises a sequence encoding a cytokine. 
     
     
         8 . The method of  claim 9  wherein the cytokine is selected from the group consisting of IL-2, IL-7, IL-12, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL-15RαSushi-Fc fusion complex. 
     
     
         9 . The method of  claim 1  wherein the nucleic acid further comprises a sequence encoding at least one component of a SMAC (supramolecular activation cluster). 
     
     
         10 . The method of  claim 11  wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, CD8, CD28, Lck, Fyn, LFA-1, CD43, and CD45 or their respective binding counterparts. 
     
     
         11 . The method of  claim 1  wherein the nucleic acid further comprises a sequence encoding an activator of a STING (Stimulator of Interferon Gene) pathway. 
     
     
         12 . The method of  claim 13  wherein the activator of the STING pathway comprises a chimeric protein in which a transmembrane domain of LMP1 of EBV is fused to a signaling domain of IPS-1. 
     
     
         13 . A recombinant nucleic acid, comprising:
 a nucleic acid encoding at least one costimulatory molecule and a patient-specific cancer-related neoepitope;   wherein the patient-specific cancer-related neoepitope of the patient is that is expressed in the patient and that has a mutation relative to a corresponding peptide sequence of a histologically normal tissue sample from the same patient; and   wherein the patient-specific cancer-related neoepitope is known to bind to an HLA-type of the same patient.   
     
     
         14 . The recombinant nucleic acid of  claim 13 , wherein the nucleic acid further comprises a sequence encoding a cytokine or cytokine analog. 
     
     
         15 . The recombinant nucleic acid of  claim 14 , wherein the cytokine is selected from the group consisting of IL-2, IL-7, IL-12, IL-15, an IL-15 superagonist (IL-15N72D), and an IL-15 superagonist/IL-15RαSushi-Fc fusion complex. 
     
     
         16 . The recombinant nucleic acid of  claim 13 , wherein the co-stimulatory molecule is selected from the group of B7.1 (CD80), B7.2 (CD86), CD30L, CD40, CD40L, CD48, CD70, CD112, CD155, ICOS-L, 4-1BB, GITR-L, LIGHT, TIM3, TIM4, ICAM-1, and LFA3 (CD58). 
     
     
         17 . The recombinant nucleic acid of  claim 13 , wherein the nucleic acid further comprises a sequence encoding at least one component of a SMAC (supramolecular activation cluster). 
     
     
         18 . The recombinant nucleic acid of  claim 17 , wherein the at least one component of the SMAC is selected form the group consisting of CD2, CD4, CD8, CD28, Lck, Fyn, LFA-1, CD43, and CD45 or their respective binding counterparts. 
     
     
         19 . The recombinant nucleic acid of  claim 13 , wherein the nucleic acid further comprises a sequence encoding an activator of a STING (Stimulator of Interferon Gene) pathway. 
     
     
         20 . The recombinant nucleic acid of  claim 19 , wherein the activator of the STING pathway comprises a chimeric protein in which a transmembrane domain of LMP1 of EBV is fused to a signaling domain of IPS-1.