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Blood. 2012 May 3;119(18):4133-41. doi: 10.1182/blood-2011-12-400044. Epub 2012 Feb 21.

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

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1
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.

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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PMID:
22354001
PMCID:
PMC3359735
DOI:
10.1182/blood-2011-12-400044
[Indexed for MEDLINE]
Free PMC Article

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