#TIL's Genetically #Engineered w/Inducible Gene Encoding IL-12 for #Immunotherapy of Metastatic #Melanoma http://t.co/ABuiy4QodT #health
Abstract
Purpose: Infusion of interleukin-12 (IL-12) can mediate anti-tumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the anti-tumor activity of adoptively transferred human tumor infiltrating lymphocytes (TIL) genetically engineered to secrete single-chain IL-12 selectively at the tumor site. Experimental Design:Thirty-three patients with metastatic melanoma were treated in a cell-dose escalation trial of autologous TIL transduced with a gene encoding a single chain IL-12 driven by a nuclear factor of activated T cells promoter (NFAT.IL12). No IL-2 was administered. Results:The administration of 0.001-0.1 X 109 NFAT.IL12 transduced TIL to 17 patients resulted in a single objective response (5.9%). However, at doses between 0.3-3 X 109 cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short and the administered IL-12 producing cells rarely persisted at one month. Increasing cell doses were associated with high serum levels of IL-12 and gamma-interferon 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 TIL transduced with an inducible IL-12 gene mediated tumor responses in the absence of IL-2 administration using cell doses 10-100 fold lower than conventional TIL. However, due to toxicities, likely attributable to the secreted IL-12, further refinement will be necessary before this approach can be safely utilized in the treatment of cancer patients.
Via Krishan Maggon
+Author Affiliations
1Surgery ranch, Center for Cancer Research, National Cancer Institute,National Institutes of Health2Surgery Branch, Center for Cancer Research, National Cancer Institute,National Institutes of Health3Surgery Branch/NCI, National Cancer Institute4Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health5Surgery Branch, National Cancer Institute, NIH6Surgery Branch, National Cancer Institute7Laboratory of Pathology, National Institutes of Health8Surgery Branch, Center for Cancer Research, National Institutes of Health, National Cancer Institute9National Cancer Institute, Surgery Branch, NCI10Surgery Branch, Center for Cancer Research, National Cancer Institute↵* Corresponding Author:Steven A. Rosenberg, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bldg 10-CRC, Rm 3W-3940, 10 Center Dr, MSC 1201, Bethesda, 20892, United States sar@mail.nih.gov