Iterative Discovery Of Neoepitopes And Adaptive Immunotherapy And Methods Therefor
Contemplated cancer treatments comprise recursive analysis of patient-, cancer-, and location-specific neoepitopes from various biopsy sites of a patient after treatment or between successive rounds of immunotherapy and/or chemotherapy to inform further immunotherapy. Recursive analysis preferably includes various neoepitope attributes to so identify treatment relevant neoepitopes.
1 . A computer-assisted method of making an immunotherapeutic composition, the method comprising:
obtaining and storing, from a patient, in a computer-readable memory, digital omics data from a tumor tissue and a matched normal tissue, wherein the digital omics data comprise whole genome data, whole transcriptome data and/or whole proteome data;
comparing, via at least one processor, the digital omics data of the tumor tissue with the omics data of the normal tissue to identify neoepitopes and RNA sequences having a cancer- and patient-specific mutation;
determining, via the at least one processor, the level of expression for identified RNA sequences; and
generating an immunotherapeutic composition prepared for administration, the composition comprising the expressed RNA sequences and/or the neoepitopes having the cancer- and patient-specific mutation.
2 . The method of claim 1 wherein the omics data have a BAMBAM format, a SAMBAM format, a FASTQ format, or a FASTA format.
3 . The method of claim 1 wherein the neoepitopes in the comparing step are determined in silico by a process that performs a location-guided synchronous alignment of omics data for the tumor cells and matched normal omics data.
4 . The method of claim 1 , wherein the RNA comprises mRNA, hnRNA, polyA + RNA, non-polyadenylated RNA, siRNA, and/or miRNA.
5 . The method of claim 4 , wherein the RNA is a specific modRNA translation (SMRT) miRNA that specifically targets the neoepitope.
6 . The method of claim 1 , wherein the immunotherapeutic composition comprises a recombinant adenoviral vaccine engineered to express the RNA sequences and/or the neoepitopes having the cancer- and patient-specific mutation.
7 . The method of claim 1 , further comprising determining omics data from a second location of the patient.
8 . The method of claim 7 , wherein the second location is selected from the group consisting of a locoregional metastasis, a distant metastasis, a lymph node, and a circulatory system.
9 . The method of claim 1 , further comprising determining a HLA type of the patient.
10 . The method of claim 1 wherein the HLA type of the patient is determined from the matched normal omics data.
11 . The method of claim 1 wherein the binding affinity of the high-affinity neoepitopes to the determined HLA type of the patient is less than 500 nM.
12 . The method of claim 1 wherein the patient was previously treated with an initial immunotherapeutic composition that is different from the immunotherapeutic composition.
13 . The method of claim 1 wherein the patient was previously treated with chemotherapy.
14 . A method of treating a tumor with an immunotherapeutic composition, the method comprising:
preparing the immunotherapeutic composition by the steps of:
obtaining and storing, from a patient, in a computer-readable memory, digital omics data from a tumor tissue and a matched normal tissue, wherein the digital omics data comprise whole genome data, whole transcriptome data and/or whole proteome data;
comparing, via at least one processor, the digital omics data of the tumor tissue with the omics data of the normal tissue to identify neoepitopes and RNA sequences having a cancer- and patient-specific mutation;
determining, via at least one processor, the level of expression for identified RNA sequences; and
generating an immunotherapeutic composition comprising the expressed RNA and/or neoepitopes having the cancer- and patient-specific mutation;
treating the tumor by administering to a patient in need thereof the immunotherapeutic composition.
15 . The method of claim 14 further comprising a step of administering a new round of immunotherapy or chemotherapy subsequent to the step of administering the immunotherapeutic composition to the patient.
16 . The method of claim 14 wherein the new round of immunotherapy or chemotherapy is informed by identification of treatment relevant neoepitopes.
17 . The method of claim 14 further comprising a step of administering chemotherapy using a low-dose regime.
18 . The method of claim 14 , wherein the RNA comprises mRNA, hnRNA, polyA + RNA, non-polyadenylated RNA, siRNA, and/or miRNA.
19 . The method of claim 14 , wherein the RNA is a specific modRNA translation (SMRT) RNA.
20 . The method of claim 14 , wherein the immunotherapeutic composition comprises a recombinant adenoviral vaccine engineered to express the RNA sequences and/or the neoepitopes having the cancer- and patient-specific mutation.