William C Timmer
UNIVERSITY OF TX MD ANDERSON CAN CTR
National Cancer Institute (NCI)
Pancreatic ductal adenocarcinoma (PDAC) in its advanced stages, is refractory to conventional therapy, with a median patient survival rate of 6-7 months and 1-year survival rate of 10-15%. Adoptively transfer of antigen- specific T cells represents a potentially effective strategy in combination with immune checkpoint blockade. In this proposal we address two major challenges to advancing the use of adoptive cellular therapy (ACT) for pancreatic cancers: 1. a paucity of proven immunogenic targets for pancreatic cancer and, 2. a means of rapidly deploying antigen-specific cellular therapy targeting such antigens. Our scientific premise is that strategies that address the lack of tumor-reactive T cells in pancreatic cancer, where the mutational burden and immunogenicity is significantly lower, would be desirable and achievable by the adoptive transfer of tumor-reactive T cells recognizing pancreatic cancer-associated antigens. To address the challenge of identifying immunogenic targets for pancreatic cancer, we implemented an epitope discovery workflow to analyze peptides eluted from tumor MHC by LC-tandem mass spectrometry. In the course of performing these studies, we cross-indexed predicted epitopes against the virus Uni-Prot database to identify potential tumor-associated epitopes representing human endogenous viral sequences, and discovered that segments of the SARS-CoV2 viral genome are processed and presented by tumor MHC. Analysis of the genomic sequences of K562 revealed that several regions of the of the SARS-CoV2 gene are present in intron sequences and we propose in this supplement to interrogate additional tumor genomic and RNA sequencing databases to identify additional epitopes associated with SARS-CoV2 and other viruses to determine 1) their immunogenicity (ability to elicit high affinity virus- and tumor-specific T cells) 2) prevalence among tumor types. We believe this to be an unprecedented source of immunogenic epitopes that can be used to develop predictive/ prognostic algorithms (TCR clustering) and for therapeutic intervention (antigen-specific adoptive T cell therapy and vaccination) for malignancies as well as for the treatment of SARS-CoV2 and other coronoviral diseases. This supplement proposes to identify these novel epitopes in alignment with the objective proposed in Aim 3 of the original R01 application.