Title | Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Park S, Shevlin E, Vedvyas Y, Zaman M, Park S, Hsu Y-MS, Min IM, Jin MM |
Journal | Sci Rep |
Volume | 7 |
Issue | 1 |
Pagination | 14366 |
Date Published | 2017 10 30 |
ISSN | 2045-2322 |
Keywords | Animals, Antibody Affinity, Cell Line, Cell Line, Tumor, Hematologic Neoplasms, Humans, Immunotherapy, Adoptive, Intercellular Adhesion Molecule-1, Lentivirus, Ligands, Mice, Mice, Nude, Positron Emission Tomography Computed Tomography, Receptors, Antigen, T-Cell, Receptors, Chimeric Antigen, T-Lymphocytes, Xenograft Model Antitumor Assays |
Abstract | Adoptive transfer of high-affinity chimeric antigen receptor (CAR) T cells targeting hematological cancers has yielded impressive clinical results. However, safety concerns regarding target expression on healthy tissue and poor efficacy have hampered application to solid tumors. Here, a panel of affinity-variant CARs were constructed targeting overexpressed ICAM-1, a broad tumor biomarker, using its physiological ligand, LFA-1. Anti-tumor T cell potency in vitro was directly proportional to CAR affinity and ICAM-1 density. In a solid tumor mouse model allowing simultaneous monitoring of anti-tumor potency and systemic off-tumor toxicity, micromolar affinity CAR T cells demonstrated superior anti-tumor efficacy and safety compared to their nanomolar counterparts. Longitudinal T cell tracking by PET/CT and concurrent cytokine measurement revealed superior expansion and contraction kinetics of micromolar affinity CAR T cells. Therefore, we developed an ICAM-1 specific CAR with broad anti-tumor applicability that utilized a reduced affinity targeting strategy to significantly boost efficacy and safety. |
DOI | 10.1038/s41598-017-14749-3 |
Alternate Journal | Sci Rep |
PubMed ID | 29085043 |
PubMed Central ID | PMC5662687 |
Grant List | P50 CA172012 / CA / NCI NIH HHS / United States R01 CA178007 / CA / NCI NIH HHS / United States |
Related Institute:
Molecular Imaging Innovations Institute (MI3)