1315 A novel T cell engager targeting HLA-A*02:01 TP53-R175H for cancer immunotherapy

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Background The tumor suppressor protein p53 (TP53) plays a pivotal role in preventing tumor formation by inducing cell cycle arrest and apoptosis in response to DNA damage. However, TP53 mutations are prevalent across various cancer types, and these mutations not only result in loss of tumor suppressive functions but also confer gain-of-function properties that drive oncogenesis. Among these mutations, HLA-A*02:01 TP53-R175H represents the largest TP53 population with >34,000 cases per year in the US and EU across all solid tumor indications, with no therapies explicitly targeting this mutation in the clinic. Leveraging Affini-T’s TETHER platform, we present the development of a novel TCR-based T cell engager designed to redirect the cytotoxic potential of T cells against mutant TP53-expressing cancer cells. Methods A bispecific T cell engager was engineered to simultaneously engage T cells via CD3 and target TP53-R175H-expressing cancer cells by an affinity-matured specific TCR. Affinity maturation of the TCR was performed to increase its specificity and binding affinity towards the mutant peptide. Tumor co-culture assays were conducted to evaluate T cell-mediated cytotoxicity. T cell activation was assessed by measuring cytokine production, surface marker expression, and proliferation upon engagement with tumor cells. The tolerability profile of the engagers was established by X-scan, evaluating T cell activation by normal tissue, and identifying off-target binders in a yeast-displayed peptide library. Results The data demonstrate successful affinity maturation of the TCR, resulting in enhanced recognition of the HLA-A*02:01 TP53-R175H peptide with high specificity. Tumor co-culture assays revealed potent T cell-mediated killing of mutant TP53-R175H-expressing cancer cells by the engager, accompanied by robust T cell activation characterized by cytokine production, upregulation of CD25 and CD69, increased proliferation and degranulation. Importantly, the engager exhibited favorable tolerability profiles, demonstrated by minimal off-target activation via X-scan, minimal off-target binding in the yeast-displayed peptide library, and with minimal T cell activation towards normal tissue. Conclusions These findings highlight the promising activity and tolerability profile of a novel T cell engager targeting HLA-A*02 TP53-R175H for cancer immunotherapy. Harnessing the cytotoxic potential of T cells against mutant TP53-expressing tumors presents a promising approach for the development of innovative cancer treatments.

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