Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts

Sid P. Kerkar, Pawel Muranski, Andrew Kaiser, Andrea Boni, Luis Sanchez-Perez, Zhiya Yu, Douglas C. Palmer, Robert N. Reger, Zachary A. Borman, Ling Zhang, Richard A. Morgan, Luca Gattinoni, Steven A. Rosenberg, Giorgio Trinchieri, Nicholas P. Restifo

Research output: Contribution to journalArticlepeer-review

Abstract

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 lympho-depleting 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.

Original languageEnglish (US)
Pages (from-to)6725-6734
Number of pages10
JournalCancer Research
Volume70
Issue number17
DOIs
StatePublished - Sep 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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