Personal neoantigen vaccine for glioblastoma stimulates neoepitope-specific intra-tumoral T cell responses
Annabelle J. Anandappa1, Derin B. Keskin1, Itay Tirosh2, Jing Sun1, Nathan D. Mathewson1,3, Sachet A. Shukla1,2, Zhuting Hu1, Evisa Gjini1, Shuqiang Li2, Anita Giobbie-Hurder1, Oriol Olive1, Patrick Y. Wen1, E. Antonio Chiocca4, Gad Getz2,5, Donna Neuberg1, Eric S. Lander2, Kai Wucherpfennig1, Mario Suva2, Edward F. Fritsch1,2,6, Scott Rodig4, Keith L. Ligon4, Kenneth J. Livak1, Nir Hacohen2,5, Patrick A. Ott1,4, Catherine J. Wu1,2,4, David A. Reardon1,4
1Dana-Farber Cancer Institute; 2Broad Institute of MIT and Harvard; 3Harvard Medical School
4Brigham and Women's Hospital; 5Massachusetts General Hospital
6Current address: Neon Therapeutics, Inc.
We conducted a Phase 1/1b trial of personal neoantigen-targeting vaccines for newly diagnosed glioblastoma (GBM). Following standard of care surgery and radiation, 8 patients received vaccine consisting of up to 20 synthetic long peptides containing predicted neoepitopes, and poly-ICLC adjuvant. Changes in the tumor microenvironment were assessed in post-vaccination surgical resection specimens from 5 patients. Vaccination induced de novo circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses, and increased tumor-infiltrating lymphocytes (TILs) in 2 patients who did not receive dexamethasone during vaccine priming. We hypothesized that post-vaccination TILs were specific for immunizing neoantigens. Single cell T cell receptor (TCR) analysis of CD3+ TILs and peripheral T cells in vitro expanded against immunizing peptides was performed from one of the patients with circulating neoantigen-specific T cell responses. 4 CD4+ and 2 CD8+ T cell clonotypes in peripheral blood were identical to TILs. In order to probe their specificity, we applied a pipeline developed in our lab to clone and express TCR sequences of interest and screen them against candidate antigens. We identified a TCR shared in CD4+ T cells in peripheral blood and TILs specific for ARHGAP35, a neoantigen targeted by vaccination, and capable of discriminating between the mutant and wildtype peptide. Our observations demonstrate that neoantigen vaccines favorably alter the immune milieu of GBM, and that neoepitope-sensitized T cells can traffic from the periphery into intracranial tumors. These results are particularly promising in a tumor with relatively low mutation burden and low immune infiltrates at baseline.