Abstract 4869: Chimeric costimulatory receptor targeting ICAM1 augments functional efficacy of antitumor T cell

Abstract Background: Adoptive T cell therapy has evolved with innovations such as chimeric antigen receptor (CAR)- and engineered T cell receptor (TCR)-T cell therapies that target tumor surface antigens or tumor-associated antigens, respectively. Although remarkable antitumor response has been demonstrated in engineered T cell therapy, tumor recurrence still occurs partly due to tumor antigen escape. Low affinity of endogenous TCR for tumor antigens has been an obstacle to the success of TCR-therapy. We hypothesized that tumor-specific T cell function in an immunosuppressive tumor microenvironment could be enhanced by an expression of ICAM1-specific chimeric costimulatory receptor (ICCR). ICAM1 is overexpressed in many solid tumor cell membranes and is greatly induced by T cell cytokine IFNγ, which may enable reinforcement of specificity and efficacy of those TCRs engaged with the target tumor antigens. Methods: We genetically engineered primary T cells with an ICCR, comprised of a single chain fragment variable sequence fused to a costimulatory molecule CD137. We first tested an ICCR in combination with CTL16, an HLA-A2-restricted, MAGE-C2-specific TCR, in cocultures with A375-MA2 melanoma cells. We measured levels of cytotoxicity and cytokine secretion when the antigen density is low or high. Next, we genetically modified allogeneic and autologous T cells with an ICCR and tested their functional efficacy in xenograft models of anaplastic thyroid cancer. Finally, TCR sequencing, signaling reporter assay, and gene expression analysis were performed to gain insights into the ICCR activity. Results: Jurkat T cell line expressing both ICCR and CTL16 showed elevated NFκB and NFAT activities following TCR engagement when compared to cells expressing CTL16 alone. Cytotoxicity induced by the ICCR/CTL16 primary T cells were specific to target tumor cells, and functional efficacy was augmented even when antigen presentation is at a subthreshold level. The ICCR expression increased allogeneic TCR activity, leading to improved control of anaplastic thyroid cancer growth. When autologous peripheral T cells were genetically modified with the ICCR, PD1+ T cells showed a superior response in controlling the growth of anaplastic thyroid cancer patient-derived tumor. ICCR expression promoted selective clonal expansion, enabling isolation of tumor-specific TCRs. Conclusion: ICCR improves functional efficacy of the TCR activated at a subthreshold level, facilitating a robust activation of polyclonal tumor-specific T cells that may have been restricted in an immunosuppressive tumor microenvironment. Citation Format: Yanping Yang, Dessislava Stefanova, Yogindra Vedvyas, Diella S. Babu, Yago Alcaina, Maria Cristina Riascos, Janusz Puc, Kevin Chen, Juan Gonzalez, Jose Thaiparambil, Thomas J. Fahey, Rasa Zarnegar, Moonsoo M. Jin, Irene M. Min. Chimeric costimulatory receptor targeting ICAM1 augments functional efficacy of antitumor T cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4869.