Background: Neoantigens arise from DNA mutations and are critical targets that are presented on the surface of cancer cells for tumor-specific T cell responses. Vaccines targeting neoantigens have the potential to induce de novo and amplify pre-existing anti-tumor T cell responses. NEO-PV-01, a personal neoantigen vaccine that is designed based on a patient's tumor-specific mutations, is comprised of up to 20 long peptides, and administered with the immune adjuvant Poly-ICLC. Here we report a comprehensive immune and molecular analysis observed in two metastatic melanoma patients treated with NEO-PV-01 in combination with nivolumab (ClinicalTrials.gov: NCT02897765).
Methods: Immune monitoring was performed from peripheral blood and tumor biopsies collected i) prior to any treatment, ii) after 12-weeks of nivolumab monotherapy and, iii) after NEO-PV-01 vaccination. Peripheral blood samples were evaluated for the presence of antigen-specific T cell responses by IFNγ ELISPOT, intracellular cytokine staining, multi-parameter surface and functional phenotyping by FACS, and presence of cytolytic properties. Tumor biopsies were analyzed for multiple immune and tumor markers by immunohistochemistry, gene expression, and whole exome sequencing.
Results: IFNγ ELISPOT analysis with PBMCs revealed neoantigen-specific CD4 and CD8 T cell responses that were predominantly observed following vaccination. Vaccine-induced, neoantigen-specific CD8 T cells had an effector memory and central memory phenotype, secreted IFNγ, TNFα and IL2, and were cytolytic. Finally, induction of neoantigen-specific immunity by NEO-PV-01 led to epitope spreading of the immune response to neoantigens not included in the vaccine. Assessment of pre- and post-treatment tumor biopsies with repeat exome sequencing, gene expression, as well as immunohistochemistry and pathologic analysis will be presented.
Conclusions: NEO-PV-01 is immunogenic and leads to multiple de novo neoantigen-specific immune responses in the peripheral blood. Furthermore, the detection of epitope spreading to additional neoantigen targets suggests vaccine-induced broadening of the immune response.
Citation Format: Aung Naing, Patrick A. Ott, Samantha J. Gates, Jose G. Martinez, Riley R. Curran, Victoria L. Kohler, Meghan E. Bushway, Julian Scherer, Dominik Barthelme, Jesse Z. Dong, April Lamb, Lisa D. Cleary, Melissa Moles, Joel Greshock, Richard B. Gaynor, Matthew J. Goldstein, Lakshmi Srinivasan. Comprehensive immune and molecular analysis of two metastatic melanoma patients treated with a personal neoantigen vaccine, NEO-PV-01, in combination with anti-PD1: A case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-147.
