Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning

Blood - Tập 119 - Trang 4133-4141 - 2012
Hollie J. Pegram1, James C. Lee2, Erik G. Hayman2, Gavin H. Imperato2, Thomas F. Tedder3, Michel Sadelain2,4,5, Renier J. Brentjens2,6
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Immunology, Duke University, Durham, NC
4Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
5Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY
6Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY

Tóm tắt

Abstract Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)–modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4+ and CD8+ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR+ T cells. Importantly, IL-12–secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell–mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients.

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Blood

Tập 119

4133-4141

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