Abstract 3624: CAR T cells targeting ICAM-1 trigger strong antitumor effects against advanced human thyroid tumors

Abstract

Abstract Introduction: Poorly differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet inherently lethal malignancies with limited treatment options. Many malignant tumors, including papillary thyroid cancer (PTC) and ATC, are associated with increased expression of intercellular adhesion molecule-1 (ICAM-1), providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive types of thyroid cancer. Therefore, we developed a third-generation chimeric antigen receptor (CAR) targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality against advanced thyroid cancer. Methods: We created a firefly luciferase-expressing human ATC model in mice that develops systemic metastases very rapidly. ATC engrafted mice were treated with human peripheral blood T cells modified with a lentivirus encoding an ICAM-1 specific CAR (ICAM-1-CAR) to investigate their therapeutic efficacy. Tumor burden was longitudinally measured by whole body bioluminescence imaging of luciferase-positive tumor cells. Effector:target assays consisting of ICAM-1-CAR T cells co-cultured with multiple malignant and non-malignant target cells were used to investigate specific target cell death and ‘off-tumor’ toxicity in vitro using luminescence and flow cytometry. Results: ICAM-1-CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Strikingly, despite heterogeneous expression of ICAM-1 in ATC cell lines, addition of cytotoxic CAR T cells induced increased ICAM-1 expression by T cell-derived interferon gamma such that all cell lines became targetable by ICAM-1-CAR T cells. Patient-derived, poorly differentiated PTC cells overexpressed ICAM-1 and were also mostly eliminated by autologous ICAM-1 CAR T cells in vitro. In mice with systemic ATC, a single administration of ICAM-1-CAR-T cells at a clinical dose mediated significant tumor killing with a 100-fold reduction in primary tumor burden compared to pre-treatment. Reductions in tumor burden persisted for over 80 days and treated mice demonstrated significantly improved survival without toxicity. Conclusion: Our findings are the first demonstration of the potential for CAR-T cell therapy for metastatic, advanced thyroid cancers. ICAM-1-CAR T cells demonstrated significant therapeutic efficacy in vitro and in vivo and extended survival benefits in animal models. Citation Format: Irene M. Min, Yogindra Vedvyas, Enda Shevlin, Marjan Zaman, Brian Wyrwas, Weibin Wang, Susan Park, Maureen Moore, Theresa Scognamiglio, Rasa Zarnegar, Thomas J. Fahey, Moonsoo M. Jin. CAR T cells targeting ICAM-1 trigger strong antitumor effects against advanced human thyroid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3624. doi:10.1158/1538-7445.AM2017-3624