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 journalArticle

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
Externally publishedYes

Fingerprint

Interleukin-12
T-Lymphocytes
Neoplasms
Interleukin-2
Adoptive Transfer
T-Cell Antigen Receptor
Immunotherapy
Vaccines
Natural Killer T-Cells
Tumor Microenvironment
Therapeutic Uses
Regulatory T-Lymphocytes
Genes
Vaccination
Cell Count

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Kerkar, S. P., Muranski, P., Kaiser, A., Boni, A., Sanchez-Perez, L., Yu, Z., ... Restifo, N. P. (2010). Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Research, 70(17), 6725-6734. https://doi.org/10.1158/0008-5472.CAN-10-0735

Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. / Kerkar, Sid P.; Muranski, Pawel; Kaiser, Andrew; Boni, Andrea; Sanchez-Perez, Luis; Yu, Zhiya; Palmer, Douglas C.; Reger, Robert N.; Borman, Zachary A.; Zhang, Ling; Morgan, Richard A.; Gattinoni, Luca; Rosenberg, Steven A.; Trinchieri, Giorgio; Restifo, Nicholas P.

In: Cancer Research, Vol. 70, No. 17, 01.09.2010, p. 6725-6734.

Research output: Contribution to journalArticle

Kerkar, SP, Muranski, P, Kaiser, A, Boni, A, Sanchez-Perez, L, Yu, Z, Palmer, DC, Reger, RN, Borman, ZA, Zhang, L, Morgan, RA, Gattinoni, L, Rosenberg, SA, Trinchieri, G & Restifo, NP 2010, 'Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts', Cancer Research, vol. 70, no. 17, pp. 6725-6734. https://doi.org/10.1158/0008-5472.CAN-10-0735
Kerkar, Sid P. ; Muranski, Pawel ; Kaiser, Andrew ; Boni, Andrea ; Sanchez-Perez, Luis ; Yu, Zhiya ; Palmer, Douglas C. ; Reger, Robert N. ; Borman, Zachary A. ; Zhang, Ling ; Morgan, Richard A. ; Gattinoni, Luca ; Rosenberg, Steven A. ; Trinchieri, Giorgio ; Restifo, Nicholas P. / Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. In: Cancer Research. 2010 ; Vol. 70, No. 17. pp. 6725-6734.
@article{94d9c4440c5e4f1ebef4a0395f6d9330,
title = "Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts",
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.",
author = "Kerkar, {Sid P.} and Pawel Muranski and Andrew Kaiser and Andrea Boni and Luis Sanchez-Perez and Zhiya Yu and Palmer, {Douglas C.} and Reger, {Robert N.} and Borman, {Zachary A.} and Ling Zhang and Morgan, {Richard A.} and Luca Gattinoni and Rosenberg, {Steven A.} and Giorgio Trinchieri and Restifo, {Nicholas P.}",
year = "2010",
month = "9",
day = "1",
doi = "10.1158/0008-5472.CAN-10-0735",
language = "English (US)",
volume = "70",
pages = "6725--6734",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=77956280888&partnerID=8YFLogxK

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

VL - 70

SP - 6725

EP - 6734

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 17

ER -