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A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity¹

Yangbing Zhao,^* Qiong J. Wang,^* Shicheng Yang,^* James N. Kochenderfer,^* Zhili Zheng,^* Xiaosong Zhong,^* Michel Sadelain, Zelig Eshhar, Steven A. Rosenberg,^* and Richard A. Morgan^2*

^*Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

To generate chimeric Ag receptors (CARs) for the adoptive immunotherapy of cancer patients with ErbB2-expressing tumors, a single-chain Ab derived from the humanized mAb 4D5 Herceptin (trastuzumab) was initially linked to T cell signaling domains derived from CD28 and the CD3 to generate a CAR against ErbB2. Human PBLs expressing the 4D5 CAR demonstrated Ag-specific activities against ErbB2⁺ tumors. However, a gradual loss of transgene expression was noted for PBLs transduced with this 4D5 CAR. When the CD3 signaling domain of the CAR was truncated or mutated, loss of CAR expression was not observed, suggesting that the CD3 signaling caused the transgene decrease, which was supported by the finding that T cells expressing 4D5 CARs with CD3 ITAM mutations were less prone to apoptosis. By adding 4-1BB cytoplasmic domains to the CD28-CD3 signaling moieties, we found increased transgene persistence in 4D5 CAR-transduced PBLs. Furthermore, constructs with 4-1BB sequences demonstrated increased cytokine secretion and lytic activity in 4D5 CAR-transduced T cells. More importantly, PBLs expressing this new version of the 4D5 CAR could not only efficiently lyse the autologous fresh tumor digests, but they could strongly suppress tumor growth in a xenogenic mouse model.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Z.E. was supported in part by and the Sixth Framework Programme of the European Commission consortium ATTACK.

² Address correspondence and reprint requests to Dr. Richard A. Morgan, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1201, Building 10, Room 3W5940, Bethesda, MD 20892. E-mail address: rmorgan{at}mail.nih.gov

³ Abbreviations used in this paper: ACT, adoptive cell therapy; AICD, activation-induced cell death; CAR, chimeric Ag receptor; PI, propidium iodide; TIL, tumor-infiltrating lymphocyte.

⁴ The online version of this article contains supplemental material.