Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice

Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from n...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-09, Vol.75 (17), p.3596-3607
Main Authors: Liu, Xiaojun, Jiang, Shuguang, Fang, Chongyun, Yang, Shiyu, Olalere, Devvora, Pequignot, Edward C, Cogdill, Alexandria P, Li, Na, Ramones, Melissa, Granda, Brian, Zhou, Li, Loew, Andreas, Young, Regina M, June, Carl H, Zhao, Yangbing
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Gene Expression Regulation, Neoplastic - immunology
Humans
Immunotherapy, Adoptive
Mice
Neoplasms - drug therapy
Neoplasms - immunology
Neoplasms - pathology
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - immunology
Receptor, ErbB-2 - antagonists & inhibitors
Receptor, ErbB-2 - immunology
Receptors, Antigen - antagonists & inhibitors
Receptors, Antigen - immunology
Single-Chain Antibodies - administration & dosage
Single-Chain Antibodies - immunology
T-Lymphocytes - immunology
Xenograft Model Antitumor Assays
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Summary:Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from normal tissues that express it at physiologic levels. A CAR-expressing T-cell panel was generated with target antigen affinities varying over three orders of magnitude. High-affinity cells recognized target expressed at any level, including at levels in normal cells that were undetectable by flow cytometry. Affinity-tuned cells exhibited robust antitumor efficacy similar to high-affinity cells, but spared normal cells expressing physiologic target levels. The use of affinity-tuned scFvs offers a strategy to empower wider use of CAR T cells against validated targets widely overexpressed on solid tumors, including those considered undruggable by this approach.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-15-0159