Abstract CT270: Immunogenicity of PGV_001 neoantigen vaccine in a Phase-I clinical trial, across various types of cancers in adjuvant setting
Authors: Saxena Mansi , Marron Thomas , Kodysh Julia , Rubinsteyn Alex , Finnigan John , Blasquez Ana , Meseck Marcia , O'Donnell Tim , Delbeau Daniela , Galsky Mathew , Doroshow Deborah , Miles Brett , Misiukiewicz Krzysztof , Irie Hanna , Tiersten Amy , Parekh Samir , Posner Marshall , Wolf Andrea , Mandeli John , Brody Rachel , Gnjatic Sacha , Schadt Eric , Friedlander Philip , Bhardwaj Nina 
Published: April 2023

Abstract
Introduction: Immunotherapies such as checkpoint blockade, have demonstrated remarkable clinical efficacy yet a large percentage of patients do not respond, potentially due to a paucity of pre-existing immune priming against neoantigens. We developed a personalized genome vaccine (PGV_001) platform to generate neoantigen vaccines targeting each patient’s unique mutanome. Primary objectives of the study were to determine 1) the safety and tolerability; 2) the feasibility of PGV_001 production and administration; and 3) the immunogenicity of PGV_001. Secondary objectives included immunophenotyping vaccine driven cellular and soluble immune milieu in peripheral blood. We previously reported on the clinical efficacy, and here we report, analysis of vaccine-driven immune responses in all treated patients.
Methods: The study (Trial Registration NCT02721043) enrolled patients with resected malignancies, including Head and neck squamous cell carcinomas, breast cancer and bladder cancer, or, in the case of multiple myeloma treated with autologous stem cell transplant; all patients determined to have a high risk of disease recurrence (&gt;30% over 5 years). Tumor-derived and germline RNA and DNA was sequenced to predict neoantigens utilizing our custom computation pipeline, OpenVax. Approximately 10 peptides were synthesized per patient, and a mixture of these peptides was administered as 10 subcutaneous and intradermal vaccines over 27 weeks in combination with poly-ICLC and helper Tetanus peptide as adjuvants. Immune responses were analyzed utilizing assays including IFN-gamma ELISPOT, antigen specific T cell expansion followed by flow cytometry, etc.
Results: In total 148 neoantigen peptides were manufactured for 15 patients. Overall, 136 PGV_001 doses were administered to 13 patients. Vaccine-specific T cell immunity was observed against multiple vaccine neoepitopes in all 13 subjects. Of the peptides administered, 45% of vaccine antigens (57/126) induced de novo immunity, starting as early as Week8 and often sustaining past last vaccination. Notably, while the vaccine driven T cell immunity was CD4 T cell dominant, most evaluated subjects also displayed vaccine induced polyfunctional CD8-T cell responses. Additional studies are ongoing to define qualities of reactive T cells, evaluate vaccine-induced humoral responses and probe the circulating inflammatory immune milieu. These will be presented.
Conclusions: We have established a platform for generating personalized neoantigen vaccines. 100% of the vaccinated patients developed an immune response specific to the vaccine neoantigens predicted by OpenVax. Subjects who received treatment experienced mild Grade 1 or 2 adverse reactions as per the CTEP v 4.0 NCI CTCAE. This vaccine trial reached the primary endpoint of safety, tolerability, feasibility and immunogenicity. Based on the PGV_001 platform two clinical trials, one in patients with glioblastoma multiforme (NCT03223103) in combination with TT fields and second in patients with urothelial carcinoma (NCT03359239) in combination with Atezolizumab have been performed. Data from these trials is under evaluation.
Citation Format: Mansi Saxena, Thomas Marron, Julia Kodysh, Alex Rubinsteyn, John Finnigan, Ana Blasquez, Marcia Meseck, Tim O'Donnell, Daniela Delbeau, Mathew Galsky, Deborah Doroshow, Brett Miles, Krzysztof Misiukiewicz, Hanna Irie, Amy Tiersten, Samir Parekh, Marshall Posner, Andrea Wolf, John Mandeli, Rachel Brody, Sacha Gnjatic, Eric Schadt, Philip Friedlander, Nina Bhardwaj. Immunogenicity of PGV_001 neoantigen vaccine in a Phase-I clinical trial, across various types of cancers in adjuvant setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT270.