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.
Patients with pancreatic cancer have few therapeutic options and immune-based therapies have largely been ineffective due in part to the absence of T cells recognizing immunogenic targets. We have developed a method to identify several new T cell targets for cancer. While scanning for these targets, we identified targets in some tumors that share the same genetic code as the COVID19 virus (yet are not infected with the COVID19 virus). In genetic evolution, tumors and some viruses can share the same sequence and using this information, we believe these same tumor-associated virus-associated targets can be used to generate T cells that not only target tumors that express these viral sequences, but also can be used to generate T cells to treat patients with COVID19 disease. We propose to identify these unique tumor-associated COVID19 virual targets.
