Abstract 5579: First-in-human study of ICAM-1-specific affinity tuned CAR T cells against advanced thyroid cancer

Abstract Background: The use of chimeric antigen receptor (CAR) T cells for solid tumors has a number of challenges, such as lack of tumor-specific targets, CAR T cell exhaustion, and the immunosuppressive tumor microenvironment. To address these challenges, AffyImmune has developed technologies to affinity tune and track CAR T cells in patients. The targeting moiety is affinity tuned to preferentially bind to tumor cells overexpressing the target while leaving normal cells with low basal levels untouched, thereby increasing the therapeutic window and allowing for more physiological T cell killing. The CAR T cells are engineered to co-express somatostatin receptor 2 (SSTR2), which allows for the tracking of CAR T cells in vivo via PET/CT scan using FDA-approved DOTATATE. Methods: AIC100 was generated by affinity tuning the I-domain of LFA-1, the physiological ligand to ICAM-1. Various mutants with 106-fold difference in affinity were evaluated for structure activity relationships using targets with varying antigen densities. The AIC100 with micromolar affinity was clearly the most effective in non-clinical animal models. AIC100 is currently being evaluated to assess safety, CAR T expansion, tumor localization, and preliminary activity in patients with advanced thyroid cancer (ATC) in a phase I study (NCT04420754). Our study uses a modified toxicity probability interval design with three dosage groups of 10 × 106, 100 × 106, and 500 × 106 cells. Results: Preclinical studies demonstrated greater in vivo anti-tumor activity and safety with micromolar affinity CAR T cells. A single dose of AIC100 resulted in tumor elimination and significantly improved survival of animals bearing ATC xenografts. AIC100 activity was confirmed in other high ICAM-1 tumor models including breast cancer, gastric cancer, and multiple myeloma. In a Phase I patient given 10 × 106 CAR T cells, near synchronous imaging of FDG and DOTATATE revealed preliminary evidence of transient CAR T expansion and tumor reduction at multiple tumor lesions, with the peak of CAR T cell density coinciding with the spike in CAR T cell numbers in blood. Conclusion: We have developed affinity tuned CAR T cells designed to selectively target ICAM-1 overexpressing tumor cells and to spatiotemporally image CAR T cells. Near-synchronous FDG and DOTATATE scans will enhance patient safety by early detection of off-tumor CAR T activity and validation of tumor response. We anticipate that our “tune and track” technology will be widely applicable to developing potent yet safe CAR T cells against hard-to-treat solid cancers. Citation Format: Jingmei Hsu, Yen-Michael Hsu, Koen van Besien, Thomas J. Fahey, Jana Ivanidze, Janusz Puc, Karrie Du, Yanping Yang, Yogindra Vedvyas, Irene M. Min, Eric von Hofe, Moonsoo M. Jin. First-in-human study of ICAM-1-specific affinity tuned CAR T cells against advanced thyroid cancer [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 5579.