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Background Tumor neoantigens arise from somatic mutations and can be recognized by the T cells of cancer patients. Personalized cancer vaccines target tumor neoantigens by inducing de novo neoantigen-specific T cells and/or boosting pre-existing ones. Different personalized cancer vaccines have shown preliminary efficacy in clinical trials with diverse tumor types. InnoPCV (INV002) is a mRNA/lipid nanoparticle based polyepitope vaccine being developed by Innovac Therapeutics, Inc that encodes up to 50 neoantigens per patient. It is designed to elicit diverse and robust neoantigen-specific T cells to drive anti-tumor immunity.Methods The Phase Ia dose escalation study evaluates the safety, tolerability and immunogenicity of InnoPCV when administered in combination with a fixed dose of an Anti-PD-1 monoclonal antibody. Individuals with locally advanced or advanced non-small cell lung cancer were enrolled with treatment intended for patients who have achieved at least stable disease (CR/PR/SD) according to RECIST 1.1 criteria. Enrolled patients must also have an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients received tislelizumab (200 mg, IV Q3W) or sintilimab (200 mg, IV Q3W) for a lead-in period of one to three cycles. Subsequently, they receive up to nine cycles of combination therapy of InnoPCV (0.06 – 1 mg, IM, Q3W) with the anti-PD-1 antibody. The study employs an accelerated titration design combined with a ‘3+3’ dose-escalation of InnoPCV (0.06 mg (n=1), 0.3 mg (n=1), and 1.0 mg (n=3-6)). Peripheral blood mononuclear cells are collected at different timepoints (Pre-vaccine, post-2, post-4, and post-9 cycles of InnoPCV). Immunogenicity evaluations include the detection of neoantigen-specific T cell responses after ex vivo restimulation and in vitro culture of patient PBMC with peptide epitopes corresponding to their personalized vaccine design.Results Dose limiting toxicity was not reached and InnoPCV related adverse events were mild to moderate. InnoPCV induced robust neoantigen specific T cell responses in 3/3 evaluable patients to multiple neoantigens. Combining ex vivo and in vitro expansion ELISpot results, showed 80-100% response rates to peptide pools (n=5 pools) corresponding to the vaccine neoantigens. These responses were observed despite the dysfunctional immune status of the patients’ CD8+ T cells which contained very low frequencies of naïve cells (Median: 7.1%, n=5) and a preponderance of T effector-memory cells (Median: 76%, n=5).Conclusions InnoPCV was well tolerated at all dose levels and induced neoantigen-specific T cells to multiple neoantigens encoded in the vaccine after 4 or less immunizations at the 0.3 and 1 mg doses.Acknowledgements We’d like to thank the patients who participated in this Phase 1a trial.Trial Registration NCT06497010Ethics Approval Ethical Approval: The study was approved by Affiliated Hospital of Guizhou Medical University’s Ethics Board, approval number 2024072K.