Abstract SY45-02: Engineering strategies based on receptors derived from gdT cells

Abstract

Abstract Gamma delta T (γδT) cells are a unique subset of T cells that play a crucial role in the body's immune response to infection, cancer, and cellular stress. Unlike their alpha-beta T cell counterparts, γδT cells can recognize and respond to a wide range of antigens without the need for antigen presentation by Major Histocompatibility Complex (MHC) molecules, allowing them to act swiftly in recognizing and eliminating abnormal cells. Clinical translation of γδT cell-based therapies, however, has faced significant challenges. Despite the safety profile of γδT cell infusions being well-established in cancer patients, the clinical outcomes have often been underwhelming (1). These results have raised questions about the efficacy of γδT cells in cancer treatment and the mechanisms through which they can be effectively harnessed. Despite these challenges, there have been encouraging developments that suggest the potential for γδT cell therapies. One notable advancement is the discovery of γδT cells carrying Chimeric Antigen Receptors (CARs) in long-term cancer survivors (2). These cells persist many years after treatment, indicating their long-lasting immune memory and surveillance capabilities. Another significant observation is the role of γδT cells as effective agents in immunotherapy that lack MHC class I molecules. This suggests that γδT cells can overcome the limitations of traditional immunotherapies that rely on MHC-mediated antigen presentation (3). Additionally, the successful use of engineered αβT cells expressing a high-affinity γδT Cell Receptor (TEG) in achieving complete remission in acute myeloid leukemia highlights the potential of redirecting T cell specificity to enhance anti-tumor responses (4). The exploration of Butyrophilin (BTN) and BTN-like (BTNL) molecules is a frontier in the understanding and enhancement of γδT cell therapies. BTN and BTNL molecules are implicated in the regulation of γδT cell responses through their interactions with γδT Cell Receptors (TCRs), particularly influencing the recognition of antigens and the subsequent immune response. Recent research focusing on BTN2 and BTN3 has aimed to delineate their roles in the activation and function of γδT cells, especially through γ9δ2TCRs (5). This research is crucial for unraveling the complexities of γδT cell antigen recognition and for developing strategies to enhance their therapeutic potential. Moreover, the diversity of the αβT cells, which are central to the TEG concept, presents another layer of complexity and opportunity in the design of T cell-based therapies. By engineering T cells to express specific, high-affinity γδTCRs, it is possible to harness the unique antigen-recognition capabilities of γδT cells while leveraging the proliferative and functional advantages of αβT cells. However detailed studies revealed a huge diversity in cell individual cell behavior (6). Finally, the role of costimulation in augmenting the activity of TEGs represents a promising area of investigation. Costimulatory signals are crucial for the full activation and sustained response of T cells. Enhancing costimulation in the context of TEGs could amplify their therapeutic efficacy, leading to improved outcomes in preclinical cancer treatment models by shaping the transcriptomic heterogeneity (7). In summary, while the clinical translation of γδT cell-based therapies has encountered challenges, recent discoveries and ongoing research offer hope for their future success. By understanding and manipulating the interactions between γδTCRs and BTN/BTNL molecules, diversifying TCR repertoires, and optimizing costimulatory signals, there is potential to unlock the full therapeutic promise of γδT cells in cancer immunotherapy. 1. Sebestyen Z, Prinz I, Dechanet-Merville J, Silva-Santos B, Kuball J. Translating gammadelta (gammadelta) T cells and their receptors into cancer cell therapies. Nat Rev Drug Discov. 2020;19(3):169-84. 2. Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, et al. Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells. Nature. 2022;602(7897):503-9. 3. Dart RJ, Zlatareva I, Vantourout P, Theodoridis E, Amar A, Kannambath S, et al. Conserved gammadelta T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science. 2023;381(6663):eadh0301. 4. de Witte MAS, J.; 1, Weertman, N.; Daudeij, A.;, van der Wagen, L.; Oostvogels, R.; de Haar, C.; Prins, H.J.; Dohmen, W.W.C; Bartels-Wilmer,C.M.; Johanna, I; Sebestyen, Z.; Kuball, J.; Straetemans, T. First in human clinical responses and persistence data on TEG001: a next generation of engineered αβ T cells targeting AML and MM with a high affinity γ9δ2TCR. ASH confidential and under embargo until 04 11 2022 2022. 5. Mamedov MR, Vedova S, Freimer JW, Sahu AD, Ramesh A, Arce MM, et al. CRISPR screens decode cancer cell pathways that trigger gammadelta T cell detection. Nature. 2023;621(7977):188-95. 6. Dekkers JF, Alieva M, Cleven A, Keramati F, Wezenaar AKL, van Vliet EJ, et al. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat Biotechnol. 2023;41(1):60-9. 7. Hernandez-Lopez P, van Diest E, Brazda P, Heijhuurs S, Meringa A, Hoorens van Heyningen L, et al. Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells. Nat Immunol. 2024;25(1):88-101. Citation Format: Jürgen Kuball. Engineering strategies based on receptors derived from gdT cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY45-02.