Tuesday, March 25, 2025
3/25/2025
PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) provide durable clinical responses in about 20% of cancer patients, but have minimal effects in cancers lacking intra–tumoral T cells. Approaches that turn T–cell–deplete cancers into ones that attract high–quality T cells are needed to sensitize these unresponsive cancers to ICIs. Tumors contain somatic mutations that encode for mutant proteins that are tumor–specific and not expressed on normal cells (termed neoantigens). Cancers, such as melanoma, with the highest mutational burdens are more likely to respond to single agent ICIs. However, most cancers, including pancreatic ductal adenocarcinoma (PDAC), have lower mutational loads, resulting in lower antigenicity, weaker endogenous T cell repertoires, and fewer T cells infiltrating the tumor. PDACs also have an immunosuppressive tumor microenvironment (TME) consisting of monocytes, B cells and T cells that express T cell inhibitory signals. Preclinical studies show that a mutated KRAS (mKRAS) vaccine given with ICIs to genetically–engineered mice overexpressing mKRASG12D (KPC mice) inhibits premalignant lesions from progressing to PDAC (PMID: 24607504). My work with Panc02 cells showed that a neoantigen–targeted vaccine, PancVAX, a mixture of twelve 20–mer neoantigen peptides, when paired with IC modulators cleared tumors in Panc02–bearing mice with a survival benefit (PMID: 30333318). In this proposal we will test the hypothesis that peptide vaccines targeting ‘shared’ mKRAS neoantigens, or ‘personalized’ patient–tumor–specific neoantigens will trigger high–quality neoantigen–specific effector and effector memory T cells, which will then become available for further activation by ICIs and result in tumor rejection. We will thus conduct two early clinical trials to test vaccines targeting mKRAS (Specific Aim 1) or patient–tumor–specific neoantigens (Specific Aim 2) in combination with the ICIs ipilimumab and nivolumab in patients with resected and metastatic PDAC, respectively. In both instances, we will assess safety of the triple combinations, perform in–depth immune phenotyping of peripheral blood to include T cell number, quality and repertoire, and study the cellular architecture of the TME. A complement of state–of–the–art technologies including single cell RNA–Seq and TCR–Seq, and multispectral immunofluorescence will be utilized. In the long term, these studies should inform future combination immunotherapy approaches in PDAC patients, and, in the short term, will provide me with vital new skillsets in bioinformatics, human immunology, and early clinical trial design. The outstanding mentorship of my Advisory Team, the rich scientific environment at Johns Hopkins, and the vast array of available resources should poise me to achieve my goal of becoming a funded, independent investigator in translational oncology by the end of this grant period.
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