On January 28, 2021 Genocea Biosciences, Inc. (NASDAQ: GNCA), a biopharmaceutical company developing next-generation neoantigen immunotherapies, reported a milestone publication in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Genocea Biosciences, JAN 28, 2021, View Source [SID1234574439]). The paper, titled, "An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor T cell responses or drive tumor growth," builds on years of preclinical research and clinical experience. It shows that ATLAS zeroes in on tumor mutations that are either neoantigens that activate anti-tumor responses or inhibitory antigens (Inhibigens) that are targets of pro-tumor responses, in both CD8+ (killer) and CD4+ (helper) T cells. This breakthrough improves neoantigen immunotherapies by potentially ensuring they are targeting the right neoantigens and excluding Inhibigens.
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ATLAS profiling of neoantigen-specific T cell responses in a cohort of lung cancer patients revealed three critical observations. First, many of these tumor-specific helper and killer T cells were inhibitory and shut off neighboring beneficial T cell responses. Second, none of the common features used for in silico predictions, currently in use for identifying neoantigens for vaccine or cell therapy targeting, accurately identify either Inhibigens or neoantigens. Third, patients have existing T cell responses to a much greater proportion of neoantigens than previously reported by others using epitope prediction algorithms.
Preclinical results demonstrate the biological relevance of Inhibigens. In the B16F10 mouse melanoma model, T cell responses to Inhibigens stifle protective anti-tumor immune responses in vivo. ATLAS-identified Inhibigens on their own, or more importantly, when combined in an otherwise protective vaccine formulation and administered to tumor-bearing mice, led to tumor growth that was comparable to, or in some cases surpassed, tumor growth in control animals. In contrast, when an ATLAS-identified anti-tumor neoantigen was added to the same formulation, tumor growth was either significantly delayed or completely abrogated, an effect that was durable and protected animals upon tumor re-challenge.
"To effectively treat cancer patients with neoantigen-targeted therapies, it is essential to identify the correct tumor antigens, both presented by the tumor and recognized by the immune system, against which to direct T cell responses," said Jessica Baker Flechtner, Chief Scientific Officer of Genocea. "Our research in both humans and mice has consistently shown that Inhibigens are negatively associated with responses to tumor immunotherapy and must be excluded from treatments because of their tendency to completely undermine efficacy. In this way, Genocea’s ATLAS platform is proving to be an invaluable tool in identifying what does – and what does not – belong in an immunotherapy."
More evidence of the relevance of ATLAS is emerging from Genocea’s GEN-009 neoantigen vaccine Phase1/2a trial evaluating its safety, immunogenicity and efficacy. The study authors found that participants immunized with GEN-009 generated broad CD4+ and CD8+ T cell responses to 99% of the vaccinated peptide neoantigens. Importantly, CD8+ killer T cell responses were measurable directly from the blood without any requirement for specialized amplification in the laboratory – a remarkable and unprecedented result based on peer-reviewed neoantigen vaccine clinical trial publications to date.
"Our ongoing Phase 1/2a study evaluates the GEN-009 vaccine in combination with standard-of-care immunotherapy regimens," said Thomas Davis, M.D., Chief Medical Officer of Genocea. "The ability to selectively elicit a T cell response against relevant personalized targets, those presented by the tumor and recognized by the T cells, while avoiding specific suppression of immunity by Inhibigens, is a novel and fundamental concept that can drive the development of safer and more effective vaccines and cell therapies for patients. The results to date suggest that GEN-011, a personalized cell therapy targeting up to 30 neoantigens, should have broad and potent anti-tumor effects in the ongoing phase 1 TITAN study."