CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors. Academic Article uri icon

Overview

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.

publication date

  • October 12, 2017

Research

keywords

  • Carcinoma, Papillary
  • Intercellular Adhesion Molecule-1
  • Receptors, Antigen, T-Cell
  • Thyroid Carcinoma, Anaplastic
  • Thyroid Neoplasms

Identity

PubMed Central ID

  • PMC5732861

Scopus Document Identifier

  • 85038423141

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-17-2008

PubMed ID

  • 29025766

Additional Document Info

volume

  • 23

issue

  • 24