Proteogenomic-based method for identifying tumor-specific antigens

Abstract

T cells, notably CD8 T cells, are known to be essential players in tumor eradication as the presence of tumor-infiltrating lymphocytes (TILs) in several cancers positively correlates with a good prognosis. To eliminate tumor cells, CD8 T cells recognize tumor antigens, which are MHC I-associated peptides present at the surface of tumor cells, with no or very low expression on normal cells. Described herein a proteogenomic approach using RNA-sequencing data from cancer and normal-matched mTEChi samples in order to identify non-tolerogenic tumor-specific antigens derived from (i) coding and non-coding regions of the genome, (ii) non-synonymous single-base mutations or short insertion / deletions and more complex rearrangements as well as (iii) endogenous retroelements, which works regardless of the sample's mutational load or complexity.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 724,760, filed August 30, 2018, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates generally to cancer, and more specifically to the identification of tumor antigens useful in T cell-based immunotherapy of cancer. Background technique [0004] As the presence of tumor-infiltrating lymphocytes (TILs) is positively associated with favorable prognosis in several cancers, CD8 T cells are considered essential players in tumor eradication and respond to immune checkpoint inhibitors 1,2 . To eliminate tumor cells, CD8 T cells recognize tumor antigens, which are abnormal MHC I-associated peptides (MAPs) presented by tumor cells. Since CD8 T cells recognize MHC I-associated peptides (MAPs), the most important unanswered question is the nature of the MAPs recognized by CD8 TILs 3 . The abun...

AI Technical Summary

Problems solved by technology

Presumably, exon mutation-based methods cannot identify TSA because they do not take into account two key factors

First, these methods only focus on mTSA and ignore aeTSA, essentially because there are currently no methods for high-throughput identification of aeTSA

This represents a major disadvantage because, while mTSA is a rare antigen, aeTSA would be a preferred target for vaccine development as they can be shared by multiple tumors 7,9

Second, the focus on the exome as the sole source of TSA is very limited

Despite improvements in the diagnosis and treatment of lung cancer over the past 25 years, the prognosis for patients remains unsatisfactory

Poor response to current standard of care in all but the most localized cancers

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