CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

Abstract

Purpose Poorly-differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors including papillary thyroid cancer (PTC) and ATC are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation CAR targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality. Experimental Design ICAM-1 CAR T cells were applied on multiple malignant and non-malignant target cells to investigate specific target cell death and ‘off-tumor’ toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases. Results ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR-T cells mediated profound tumor killing that resulted in long term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models. Conclusions Our findings are the first demonstration of CAR T therapy for metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies.

Intercellular Adhesion Molecule-1 as Target for CAR-T-Cell Therapy of Triple-Negative Breast Cancer

“…Intercellular adhesion molecule-1 is an important transporter that is upregulated in several types of cancers. ICAM1-targeting therapy has potential application values in the treatment of some malignancies, including thyroid cancer, pancreatic cancer, and gastric carcinoma (20,33,34). In this study, we analyzed the expression of ICAM1 in TNBC based on the UALCAN database.…”

Differences in gene expression profiling and biomarkers between histological colorectal carcinoma subsets from the serrated pathway

“…An important histological–molecular correlation is that ICAM1 expression was previously associated with poorly differentiated tumours such as hmMSI‐H . Recent findings demonstrate the antitumour effect of chimeric antigen receptor T cells targeting ICAM1, thus paving the way for targeted therapy for this CRC subtype.…”

“…The results confirm, at the mRNA and protein levels, that ICAM1 is overexpressed in hmMSI-H as compared with SAC, this being the first study to report higher expression of ICAM1 in MSI-H CRCs. An important histological-molecular correlation is that ICAM1 expression was previously associated with poorly differentiated tumours such as hmMSI-H. 24,25 Recent findings demonstrate the antitumour effect of chimeric antigen receptor T cells targeting ICAM1, 26 thus paving the way for targeted therapy for this CRC subtype.…”

ICAM-1-LFA-1 Dependent CD8+ T-Lymphocyte Aggregation in Tumor Tissue Prevents Recirculation to Draining Lymph Nodes

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