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 chimeric antigen receptor (CAR) targeting ICAM-1 to leverage adoptive T-cell therapy as a new treatment modality.Experimental Design: ICAM-1 CAR T cells were applied to multiple malignant and nonmalignant target cells to investigate specific target cell death and "off-tumor" toxicity in vitroIn 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 against both a metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies. Clin Cancer Res; 23(24); 7569-83. ©2017 AACR.

• Authors: Irene M Min, Enda Shevlin, Yogindra Vedvyas, Marjan Zaman, Brian Wyrwas, Theresa Scognamiglio, Maureen D Moore, Weibin Wang, Susan Park, Spencer Park, Suraj Panjwani, Katherine D Gray, Andrew B Tassler, Rasa Zarnegar, Thomas J Fahey 3rd, Moonsoo M Jin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 24 Pg. 7569-7583 (Dec 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 29025766 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Receptors, Antigen, T-Cell
• Intercellular Adhesion Molecule-1

Topics

• Animals
• Carcinoma, Papillary (immunology, pathology, therapy)
• Cell Line, Tumor
• Cell- and Tissue-Based Therapy (methods)
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, immunology)
• Mice
• Neoplasm Metastasis
• Receptors, Antigen, T-Cell (administration & dosage, immunology)
• T-Lymphocytes (immunology)
• Thyroid Cancer, Papillary
• Thyroid Carcinoma, Anaplastic (immunology, pathology, therapy)
• Thyroid Neoplasms (immunology, pathology, therapy)
• Xenograft Model Antitumor Assays