Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma

Ling Zhang, Richard A. Morgan, Joal D. Beane, Zhili Zheng, Mark E. Dudley, Sadik H. Kassim, Azam V. Nahvi, Lien T. Ngo, Richard M. Sherry, Giao Q. Phan, Marybeth S. Hughes, Udai S. Kammula, Steven A. Feldman, Mary Ann Toomey, Sid P. Kerkar, Nicholas P. Restifo, James C. Yang, Steven A. Rosenberg

Research output: Contribution to journalArticle

Abstract

Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT. IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 109 NFAT.IL12 transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNg as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100- fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.

Original languageEnglish (US)
Pages (from-to)2278-2288
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number10
DOIs
StatePublished - May 15 2015
Externally publishedYes

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Tumor-Infiltrating Lymphocytes
Interleukin-12
Immunotherapy
Melanoma
Genes
Interleukin-2
Neoplasms
NFATC Transcription Factors
Liver Diseases
Immunity
Research Design
Fever
Animal Models
Hemodynamics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. / Zhang, Ling; Morgan, Richard A.; Beane, Joal D.; Zheng, Zhili; Dudley, Mark E.; Kassim, Sadik H.; Nahvi, Azam V.; Ngo, Lien T.; Sherry, Richard M.; Phan, Giao Q.; Hughes, Marybeth S.; Kammula, Udai S.; Feldman, Steven A.; Toomey, Mary Ann; Kerkar, Sid P.; Restifo, Nicholas P.; Yang, James C.; Rosenberg, Steven A.

In: Clinical Cancer Research, Vol. 21, No. 10, 15.05.2015, p. 2278-2288.

Research output: Contribution to journalArticle

Zhang, L, Morgan, RA, Beane, JD, Zheng, Z, Dudley, ME, Kassim, SH, Nahvi, AV, Ngo, LT, Sherry, RM, Phan, GQ, Hughes, MS, Kammula, US, Feldman, SA, Toomey, MA, Kerkar, SP, Restifo, NP, Yang, JC & Rosenberg, SA 2015, 'Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma', Clinical Cancer Research, vol. 21, no. 10, pp. 2278-2288. https://doi.org/10.1158/1078-0432.CCR-14-2085
Zhang, Ling ; Morgan, Richard A. ; Beane, Joal D. ; Zheng, Zhili ; Dudley, Mark E. ; Kassim, Sadik H. ; Nahvi, Azam V. ; Ngo, Lien T. ; Sherry, Richard M. ; Phan, Giao Q. ; Hughes, Marybeth S. ; Kammula, Udai S. ; Feldman, Steven A. ; Toomey, Mary Ann ; Kerkar, Sid P. ; Restifo, Nicholas P. ; Yang, James C. ; Rosenberg, Steven A. / Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 10. pp. 2278-2288.
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abstract = "Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT. IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 109 NFAT.IL12 transduced TILs to 17 patients resulted in a single, objective response (5.9{\%}). However, at doses between 0.3 and 3 × 109 cells, 10 of 16 patients (63{\%}) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNg as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100- fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.",
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T1 - Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma

AU - Zhang, Ling

AU - Morgan, Richard A.

AU - Beane, Joal D.

AU - Zheng, Zhili

AU - Dudley, Mark E.

AU - Kassim, Sadik H.

AU - Nahvi, Azam V.

AU - Ngo, Lien T.

AU - Sherry, Richard M.

AU - Phan, Giao Q.

AU - Hughes, Marybeth S.

AU - Kammula, Udai S.

AU - Feldman, Steven A.

AU - Toomey, Mary Ann

AU - Kerkar, Sid P.

AU - Restifo, Nicholas P.

AU - Yang, James C.

AU - Rosenberg, Steven A.

PY - 2015/5/15

Y1 - 2015/5/15

N2 - Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT. IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 109 NFAT.IL12 transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNg as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100- fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.

AB - Purpose: Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site. Experimental Design: Thirty-three patients with metastatic melanoma were treated in a cell dose escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT. IL12). No IL2 was administered. Results: The administration of 0.001 to 0.1 × 109 NFAT.IL12 transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNg as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability. Conclusions: In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100- fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.

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