Tumor-Specific CD8+ T Cells Expressing Interleukin-12 Eradicate Established Cancers in Lymphodepleted Hosts
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- Sid P. Kerkar
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Pawel Muranski
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Andrew Kaiser
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Andrea Boni
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Luis Sanchez-Perez
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Zhiya Yu
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Douglas C. Palmer
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Robert N. Reger
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Zachary A. Borman
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Ling Zhang
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Richard A. Morgan
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Luca Gattinoni
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Steven A. Rosenberg
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Giorgio Trinchieri
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
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- Nicholas P. Restifo
- Authors' Affiliations: 1Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick, Maryland
Description
<jats:title>Abstract</jats:title><jats:p>T-cell–based immunotherapies can be effective in the treatment of large vascularized tumors, but they rely on adoptive transfer of substantial numbers (∼20 million) of tumor-specific T cells administered together with vaccination and high-dose interleukin (IL)-2. In this study, we report that ∼10,000 T cells gene-engineered to express a single-chain IL-12 molecule can be therapeutically effective against established tumors in the absence of exogenous IL-2 and vaccine. Although IL-12–engineered cells did not perist long-term in hosts, they exhibited enhanced functionality and were detected in higher numbers intratumorally along with increased numbers of endogenous natural killer and CD8+ T cells just before regression. Importantly, transferred T cells isolated from tumors stably overproduced supraphysiologic amounts of IL-12, and the therapeutic effect of IL-12 produced within the tumor microenvironment could not be mimicked with high doses of exogenously provided IL-12. Furthermore, antitumor effects could be recapitulated by engineering wild-type open-repertoire splenocytes to express both the single-chain IL-12 and a recombinant tumor-specific T-cell receptor (TCR), but only when individual cells expressed both the TCR and IL-12, indicating that arrested migration of T cells at the tumor site was required for their activities. Successful tumor eradication was dependent on a lymphodepleting preconditioning regimen that reduced the number of intratumoral CD4+ Foxp3+ T regulatory cells. Our findings reveal an approach to genetically modify T cells to reduce the cell number needed, eliminate the need for vaccines or systemic IL-2, and improve immunotherapy efficacy based on adoptive transfer of gene-engineered T cells. Cancer Res; 70(17); 6725–34. ©2010 AACR.</jats:p>
Journal
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- Cancer Research
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Cancer Research 70 (17), 6725-6734, 2010-08-31
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1361699994973959552
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- ISSN
- 15387445
- 00085472
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- Data Source
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- Crossref