Alexandria P. Cogdill

Andreas Loew

Brentjens

Brian Granda

Carl H. June

Chongyun Fang

Devvora Olalere

Edward C. Pequignot

Li Zhou

Melissa Ramones

Na Li

Press

Regina M. Young

Robertson

Shiyu Yang

Shuguang Jiang

Szöllösi

Xiaojun Liu

Yangbing Zhao

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. Cancer Res; 75(17); 3596–607. ©2015 AACR.</jats:p

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Cancer Research

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

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

Abstract

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