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

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 × 10(9) NFAT.IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10(9) 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 IFNγ 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 10 Pg. 2278-88 (May 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25695689 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Interleukin-12

Topics

• Adult
• Aged
• Cells, Cultured
• Female
• Genetic Engineering
• Humans
• Immunotherapy
• Interleukin-12 (biosynthesis, genetics)
• Lymphocytes, Tumor-Infiltrating (physiology, transplantation)
• Male
• Melanoma (immunology, secondary, therapy)
• Middle Aged
• Skin Neoplasms (immunology, pathology, therapy)
• Transcriptional Activation
• Treatment Outcome
• Young Adult