Human t cell receptors targeting tumor-enhanced splicing epitopes on hla-a*02:01 for small cell carcinoma

Abstract

We utilized a newly developed computational method, Isoform peptides from RNA splicing for Immunotherapy target Screening methodology (IRIS), to process and capture small cell carcinoma-specific RNA splicing events. Candidate epitopes were used to stimulate peripheral mononuclear cells (PBMCs) from healthy donors. Reactive T cells were then isolated by either surface activation marker (CD137) or intracellular activation markers (IFNγ and TNFα). T cell receptors (TCRs) from recovered cells were retrieved by 10X Genomics single cell V(D)J sequencing. Paired TCR alpha and beta chain were engineered and introduced into normal human PBMCs and tested for functionality. We were able to define a group of TCRs targeting 7 distinct small cell cancer-enhanced splicing epitopes that predicted by our in-silico platform. Those TCRs specifically and efficiently recognize their cognate targets on HLA-A*02:01. These inventions can be used to develop new treatment for pan-small cell cancer treatments.

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