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Cancer Res. 2015 Sep 1;75(17):3596-607. doi: 10.1158/0008-5472.CAN-15-0159.

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

Author information

1
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
2
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
3
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. yangbing@exchange.upenn.edu cjune@exchange.upenn.edu.

Abstract

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.

PMID:
26330166
PMCID:
PMC4560113
DOI:
10.1158/0008-5472.CAN-15-0159
[Indexed for MEDLINE]
Free PMC Article

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