Design and Delivery of Neoantigen-based Tumor Vaccines Neoantigens are a class of cancer antigen derived from mutations occurring within the genome of the tumor, and they present an attractive target for therapeutic tumor vaccines. Despite advancements in the development of neoantigen tumor vaccines, extensive challenges impede clinical translation. These challenges include how to optimally deliver neoantigenic peptides for vaccination and how to select for immunogenic epitopes from a set of computationally-predicted neoantigens. To address the challenges associated with neoantigen delivery (Aim 1), we will develop a poly(lactic-co- glycolic acid) (PLGA)-based neoantigen-delivering nanoparticle (ndNP) platform as a vehicle for vaccination in B16F10 melanoma and BBN963 basal bladder cancer models. We will study the interactions of these ndNPs with dual checkpoint-inhibitor/co-stimulator immunotherapy, measuring efficacy through tumor growth and survival studies. Immune monitoring through flow cytometry, RNA-sequencing, and IFN-? ELISpot of tumor and draining lymph nodes will be used to study how therapeutic combinations differentially affect immune cell activation and phenotypic distributions. To address optimal selection of neoantigens for therapeutic vaccination (Aim 2), we will develop a predictive algorithm based on correlative analysis of intrinsic neoantigen features with their immunogenicity. Current neoantigen prediction methods have high false-positive rates, with no robust methods to predict for therapeutic efficacy of these predicted neoantigens. From the literature and preliminary studies, we believe five intrinsic neoantigen features correlate with immunogenicity: 1) predicted peptide/MHC binding affinity, 2) amino acid physicochemical characteristics, 3) mutational position, 4) gene expression, and 5) derivative gene function. Using B16F10 and BBN963 neoantigens that we previously predicted and validated with IFN-? ELISpot, we will correlate these five intrinsic neoantigen features with ability to elicit IFN-? production. Correlative analysis will include univariable and multivariable elastic net regression, and the predictive algorithm derived from these analyses will be validated using neoantigens predicted from the MC-38 colon adenocarcinoma tumor model. Pursuit of these aims could provide beneficial knowledge for the translation of neoantigen tumor vaccine strategies.
The aims of this proposal will provide training in a unique skillset of immuno-oncology, nanotechnology, and computational biology. The training provided under this award will facilitate my development toward my career goal of leading an independently funded immuno-oncology laboratory focused on therapy development.

Public Health Relevance

Conventional treatment methods for metastatic cancers are, by and large, unable to cure patients of their disease and are often associated with dangerous and distressing side effects. Therapeutic vaccines designed from tumor-specific mutations (neoantigens) may offer an immunologically driven approach to provide patients with long-term cure. Development of superior predictive tools for identifying these neoantigens and sophisticated delivery platforms for vaccination could result in extensive advancements for the future of cancer therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Panda, Anshuman; de Cubas, Aguirre A; Stein, Mark et al. (2018) Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. JCI Insight 3:
Smith, Christof C; Beckermann, Kathryn E; Bortone, Dante S et al. (2018) Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J Clin Invest 128:4804-4820