Abstract 4254: ADT-010, a novel immunomodulatory antibody that harnesses the anti-tumor properties of tissue-resident Vδ1 γδ T cells

Abstract

Abstract Background: Recent studies have highlighted the contribution of gamma delta (γδ) T cells in the immune response to cancer, and their infiltration in tumors is a positive prognostic factor. Vδ1 T cells are the most abundant γδ T cells in epithelial tissues including the gut and skin and form a significant proportion of tumour infiltrating lymphocytes (TILs) in a number of solid tumour indications. Tissue-resident cytotoxic Vδ1 γδ T cells are of particular interest in immunotherapy approaches for their role in recognising and eradicating cancer cells, providing new avenues for antibody tissue-based immunological intervention. Vδ1 γδ T cells combine features of innate and adaptive immunity: in contrast to αβ T cells that rely on antigen-presentation via MHC, γδ T cells recognize and kill transformed cells by direct recognition of a pattern of stress associated ligands expressed on their surface, opening up a potential range of cold tumours with decreased or impaired tumour antigen presentation. Adaptate’s first-in-class approach is to harness the specific anti-tumour properties of Vδ1 T cells using activating immunomodulatory antibodies. Methods: Adaptate’s ADT-010 is a first-in-class, fully human, monoclonal antibody which selectively recognizes and binds to the Vδ1 TCR leading to Vδ1 T cell activation. ADT-010 was selected via high-stringency antigen binding using a human phage display library. To elucidate its mechanism of action, the binding and functional activity of ADT-010 was evaluated on expanded skin-derived Vδ1 T cells in vitro. Results: ADT-010 specifically enhanced the Vδ1 killing of cancer cells whilst sparing healthy non-diseased cells. The functional activity of ADT-010 on expanded skin-derived Vδ1 T cells was investigated in the presence or absence of tumour cells. ADT-010 mediated activation of Vδ1 T cells in the presence of target tumour cells was demonstrated through TCR downregulation, CD107a and CD25 upregulation, and enhanced anti-tumour cytotoxicity. Taken together the data indicates that Vδ1 TCR engagement on γδ T cells by ADT-010 results in their full activation and enhanced cytotoxicity only in the presence of target tumour cells. Conclusions: Despite recent advances in immune therapies in oncology, there currently remains a significant unmet need for effective and safe treatments for solid tumours. The challenges of treating such tumours which include infiltration into the tumour tissue and discrimination between healthy and tumour cells have the potential to be addressed by novel approaches such as Adaptate’s ADT-010 antibody. ADT-010 specifically activates a population of tumour-resident Vδ1 T cells that can then orchestrate a potent and highly selective anti-tumour response through direct killing.Adaptate’s first-in-class ADT-010 is being progressed to the clinic for the treatment of solid tumour indications. Citation Format: Jose Munoz-Olaya, Aoife McGinley, Daniel Foxler, Samuel Samuel, Tanguy Lechertier, Shefali Bhumbra, Robert Good, Luke Cave, Oxana Polyakova, Mark Uden, Mihriban Tuna, Natalie Mount. ADT-010, a novel immunomodulatory antibody that harnesses the anti-tumor properties of tissue-resident Vδ1 γδ T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4254.