Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma.

Abstract Personalized cancer vaccines can generate circulating immune responses against predicted neoantigen targets, but whether such responses lead to actual immune recognition of a patient’s tumor and consequent clinical activity is largely unknown. To investigate this, we conducted a phase I clinical trial of a personalized neoantigen vaccine as adjuvant therapy in high-risk, completely surgically resected, stage III/IV clear cell renal cell carcinoma (RCC; NCT02950766). This first-in-disease study included several modifications from prior neoantigen vaccine studies, including: (i) the use of an improved antigen prediction tool (HLAthena), a neural network model that was trained on a large HLA class I immunopeptidome dataset; (ii) the subcutaneous and intradermal administration of the vaccine to engage a broader repertoire of antigen-presenting cells in the skin; and (iii) the inclusion of ipilimumab administered subcutaneously next to the vaccination site (for pre-specified cohorts) intended to improve T cell priming and activation at the local draining lymph node. Across all nine patients, a median of 15 vaccinating peptides (range: 8 – 19) were successfully manufactured and administered per study subject, targeting a median of 13 unique mutations (range: 7 – 17). Six of nine patients were vaccinated against a neoantigen formed through a mutation in at least one known RCC driver gene (VHL, PBRM1, BAP1, KDM5C, or PIK3CA). Single-cell transcriptomic and T cell receptor (TCR) sequencing analysis of vaccine site immune populations in the skin revealed a substantial increase in the number of T cells (p = 0.003) and T cell clonotypes (p < 0.001) following vaccination. No patient had a pre-existing ex vivo peripheral T cell response against any of the neoantigen peptides in the vaccine. Following vaccination, all nine patients developed detectable ex vivo peripheral T cell response (by IFN-gamma ELISPOT) against neoantigen peptides in the vaccine. Nearly all detectable ex vivo responses were derived from CD4+ T cells as assessed by flow cytometry analysis, and a substantial proportion of responses (27.4% - 99.8% of total responses for an individual pool of vaccine peptides) were polyfunctional (with T cells producing at least 2 of the following cytokines: IFN-gamma, IL-2, or TNF-alpha). Among peripheral immune responses, there were no observable differences in the quantity or phenotype of T cells responding to vaccine alone versus the vaccine co-administered with ipilimumab. In seven of nine patients, neoantigen vaccine-specific T cells exhibited in vitro anti-tumor reactivity against autologous RCC cells. Clinically, there were no dose limiting toxicities, and no disease recurrences were observed in this high-risk population (median follow-up of 23.9 months at time of data cutoff). Overall, these data suggest that personalized neoantigen vaccines (with or without co-administered subcutaneous CTLA-4 blockade) can induce anti-tumor immune responses in patients with RCC. Citation Format: David A. Braun, Derin B. Keskin, Sachet A. Shukla, Bradley A. McGregor, Nicholas R. Schindler, Eryn Blass, Susan Klaeger, Lucas Pomerance, Siranush Sarkizova, Shuqiang Li, Jackson Southard, Giorgia Moranzoni, Christina B. Pedersen, Yiwen Liu, Steven L. Chang, Michelle S. Hirsch, Nicole R. LeBoeuf, Matthew Mossanen, Vipheaviny Chea, Isabel Carulli, Oriol Olive, Ambica Mehndiratta, Haley Greenslade, Giacomo Oliveira, J. Bryan Iorgulescu, Sabina Signoretti, Jon C. Aster, Liudmila Elagina, Ignaty Leshchiner, Gad Getz, Maegan Harden, Stacey Gabriel, Lars R. Olsen, Donna S. Neuberg, Edward F. Fritsch, Nir Hacohen, Kenneth J. Livak, Steven Carr, Patrick A. Ott, Catherine J. Wu, Toni K. Choueiri. Tumor-specific immunity generated by a personalized neoantigen vaccination incorporating locally delivered ipilimumab in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR015.