Neoantigens: Friend or foe? New insights into tumor mutations that both betray and protect cancer
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Identification and optimization of the best tumor antigens has been a consistent focus for cancer immunotherapy development, but Genocea has identified a new immune off-switch that may be critical in tumor survival and antigen selection.
While conventional wisdom holds that tumor targets are either beneficial or neutral, the discovery that specific antigens can also be deleterious suggests that a cancer immunotherapy’s success might equally hinge on what must be excluded. Genocea has found that tumors express inhibitory antigens (or InhibigensTM) that can be detrimental to a cancer-fighting immune response. Responses to these antigens may explain some of the disappointing efficacy with other candidate immunotherapies.
This breakthrough discovery was identified by Genocea’s unique and proprietary ATLASTM bioassay, the only technology of its kind able to comprehensively identify neoantigens that trigger anti-tumor T cell responses while unmasking pro-tumor Inhibigens that can be actively excluded from immunotherapies. By harnessing a patient’s own immune system, it is also the only technology that can be applied to patients of all races and ethnicities and avoids the inherent inaccuracies of in silico predictions.
ATLAS has powered a growing body of preclinical and clinical data that has revealed the mere presence of Inhibigens can impair protective immunity, undermining otherwise effective immunotherapies and enhancing tumor growth. Reporting on their continued efforts to characterize and better understand the function of Inhibigens, Genocea published the data behind this important new immune mechanism in Cancer Discovery, a prominent journal of the American Association for Cancer Research, on January 27th.
The paper, titled, “An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor T cell responses or drive tumor growth,” highlights ATLAS as an invaluable tool to identify what does — and what does not — belong in an immunotherapy. Read more about the findings of the study here. While further investigation is ongoing, Genocea’s results have the power to transform the immuno-oncology therapeutic landscape.
“Armed with a rapidly expanding database of Inhibigens, Genocea’s discoveries could power new biomarkers and prognostic indicators to inform treatment choices — ensuring the right patients are served by the right drugs.” said Hubert Lam, the study’s lead author. “We are working to further characterize the mechanism of action of Inhibigen-specific responses, including building collaborations to accelerate our efforts.”
To treat cancer patients more effectively 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. Inhibigen-specific T cell responses have been identified in nearly every cancer patient that has been screened with ATLAS to date, and their dominance may be an explanation for why some patients fail checkpoint inhibition therapy (CPI), which non-specifically potentiates existing T cell responses.
Genocea scientists have observed that when responses to Inhibigens are present, otherwise potent, anti-tumor immune responses are stifled, turning tumors “cold,” devoid of the army of macrophages, dendritic cells, and T cells — the arsenal of players needed to attack and eliminate cancer cells. The team has consistently shown this effect in mice and is currently working to understand how Inhibigen-specific responses shut down anti-tumor immune responses.
Their latest findings presented at the most recent Society for Immunotherapy of Cancer meeting demonstrated that Inhibigen-mediated suppression of anti-tumor T cell responses cannot be overcome by CPI. The data highlight the importance of identifying and excluding Inhibigens since the inclusion of even just one could completely override a potentially life-saving cancer immunotherapy.
“Inhibigens may in fact be the best targets to overcome tumors, because they are covert, yet highly disruptive and in most screening platforms unrecognizable to the immune system,” said Pamela Carroll, Chief Business Officer of Silicon Therapeutics. “If they can be made visible in a therapeutically positive way, then this may open up entirely new avenues for developing treatments that work for a broader range of cancer patients.”
More evidence of the importance of selecting the right targets is emerging from Genocea’s GEN-009 neoantigen vaccine Phase1/2a clinical trial. The study authors found that participants immunized with GEN-009 generated broad CD4+ and CD8+ T cell responses to 99% of the vaccinated neoantigens — a remarkable and unprecedented result based on peer-reviewed neoantigen vaccine clinical trial publications to date.
“The prompt and durable immune responses and favorable patient outcomes in Part A of the trial are encouraging.” said Roger Cohen, M.D. Associate Director of Clinical Research, Abramson Cancer Center. “The results reported in this manuscript describe the utility of ATLAS in immune targeting and suggest that GEN-009 can have a role in the immunotherapy of multiple tumor types.”
To learn more about Inhibigens and Genocea’s ATLAS platform, visit www.genocea.com.