TY - JOUR
T1 - Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts
AU - Kerkar, Sid P.
AU - Muranski, Pawel
AU - Kaiser, Andrew
AU - Boni, Andrea
AU - Sanchez-Perez, Luis
AU - Yu, Zhiya
AU - Palmer, Douglas C.
AU - Reger, Robert N.
AU - Borman, Zachary A.
AU - Zhang, Ling
AU - Morgan, Richard A.
AU - Gattinoni, Luca
AU - Rosenberg, Steven A.
AU - Trinchieri, Giorgio
AU - Restifo, Nicholas P.
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=77956280888&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-0735
DO - 10.1158/0008-5472.CAN-10-0735
M3 - Article
C2 - 20647327
AN - SCOPUS:77956280888
SN - 0008-5472
VL - 70
SP - 6725
EP - 6734
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -