Journal
BLOOD
Volume 119, Issue 18, Pages 4133-4141Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-12-400044
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Funding
- National Institutes of Health [CA95152, CA138738, CA059350, CA08748]
- Alliance for Cancer Gene Therapy
- Damon Runyon Clinical Investigator Award
- Annual Terry Fox Run for Cancer Research (New York, NY)
- Kate's Team
- Mr William H. Goodwin and Mrs Alice Goodwin and the Commonwealth Cancer Foundation for Research and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center
- Geoffrey Beene Cancer Foundation
- Howard Hughes Medical Institute
- [AI56363]
- [AI057157]
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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 IFN gamma 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. (Blood. 2012;119(18):4133-4141)
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