1314 Immunostimulatory nanofilaments turn cancer cells into neoantigen agnostic cancer vaccines

<h3>Background</h3> Checkpoint immunotherapy revolutionized cancer treatment by potentiating antitumor immune responses. However, checkpoint inhibitor treatments fail in most patients, which is attributable in part to the lack of pre-existing antitumor immune cells. To circumvent this problem, personalized cancer vaccines have been used to mount immune responses against selected tumor antigens. This approach provided compelling efficacy data in the clinic, but also delays treatments and suffers from a high cost of production. Leveraging tumors as a direct source of neoantigens by turning cancer cells into immunogenic targets constitutes an attractive off-the-shelf alternative to overcome these limitations. <h3>Methods</h3> Using synthetic biology, we developed a new immunotherapy based on nanofilaments that bind to cancer cells and makes them more immunogenic. This approach leverages a bacteriophage engineered to display multiple therapeutic proteins simultaneously. The nanofilament candidate TAT003 combines PD-L1 blockade, interleukin-2 receptor stimulation, and a TLR9 agonistic activities. The biological activities of TAT003 were evaluated by ELISA and cellular assays. The therapeutic activity of TAT003 was then measured in syngeneic mouse models upon intratumoral administration in injected and non-injected lesions. Immune profiling of tumors was performed by flow cytometry. Cytokine paneling following TAT003 stimulation was also done <i>ex vivo</i> on micro-dissected tumor tissues on chip. <h3>Results</h3> TAT003 displayed biologically active anti-PD-L1 and IL-2 simultaneously (figure 1A-C). Upon intratumoral injection, TAT003 induced a potent antitumor response in several syngeneic cancer models, both locally and systemically (figure 1D). Injection of TAT003 in a tumor locally resulted in a strong infiltration and activation of myeloid cells (figure 1E), while it led to an increase in tumor infiltrating lymphocytes in non-injected lesions, as well as, an increase in the frequency of circulating tumor-cell specific CD8⁺ T-cells (figure 1F,G). TAT003 modulated the tumor micro-environment, inducing changes in the secretion of chemokines and cytokines from tumor associated immune cells, with some subsets being consistently induced or repressed across different tumor types (figure 1H). <h3>Conclusions</h3> TAT003, a nanofilament combining an anti-PD-L1, IL-2, and a TLR9 agonist promotes tumor clearance by (1) sparking intense infiltration and activation of myeloid cells in injected lesions, and (2) potentiating the activity of tumor cell specific CD8+ T cells through PD-L1/PD1 blockade and IL-2 stimulation. These compounding immune responses suggest TAT003-activated myeloid cells capture tumor neoantigens and help ignite a neoantigen specific T-cell immune response further potentiated by TAT003. Taken together, multimodal nanofilaments are a promising modality that stimulates antitumor immunity in novel ways. <h3>Acknowledgements</h3> The authors thank Prof. Jamie Scott, Dr. Gerald Baptiste, Dr. Howard Kaufman and Dr. Stéphane Champiat for their thoughtful advices. We are grateful to Émilie St-Pierre for her contributions to initial experiments that lead to the work presented in this article. Our collaborations with Eve technologies, the Plateforme d’histologie de l’Université de Sherbrooke, and the Plateforme de purification de protéine de l’Université de Sherbrooke are much appreciated; they have been instrumental to this work. We are especially grateful to Genome Québec, the Ministère de l’Économie et de l’Innovation du Québec and our private investors for funding the research reported here. <h3>Ethics Approval</h3> All mouse-related protocols were strictly evaluated to avoid animal suffering by the Université de Sherbrooke Animal Care Committee. The recommendations respect the guidelines of the Canadian Council on Animal Care.

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