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 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.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Xiaojun
X
Liu
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Shuguang
S
Jiang
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Chongyun
C
Fang
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Shiyu
S
Yang
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Devvora
D
Olalere
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Edward C
EC
Pequignot
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Alexandria P
AP
Cogdill
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Na
N
Li
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Melissa
M
Ramones
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Brian
B
Granda
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Li
L
Zhou
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Andreas
A
Loew
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Regina M
RM
Young
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.
Carl H
CH
June
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.
Yangbing
Y
Zhao
D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D011946:Receptors, Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011946:Receptors, Antigen; D057127:Single-Chain Antibodies; C512478:EGFR protein, human; C508053:ERBB2 protein, human