video: Clinical trial of regulated IL-12 gene immunotherapy for cancer. This material relates to a paper that appeared in the August 14, 2019, issue of Science Translational Medicine, published by AAAS. The paper, by E.A. Chiocca at Brigham and Women's Hospital in Boston, MA; and colleagues was titled, "Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial." view more
Credit: Steven Kyriadis, Christopher J. Fenton, Dominic U. Udoakang, Mark Murphy, E.A. Chiocca (Brigham and Women's Hospital); Nathan Demars (Ziophram Oncology, Inc.)
A phase 1 clinical trial has demonstrated that a two-step gene therapy treatment was safe and effective in 31 patients with recurrent glioblastoma - a stubborn form of brain cancer - potentially overcoming a major hurdle that has hindered the use of systemically administered interleukin 12 (IL-12)-based regimens. The therapy boosted the infiltration of immune cells into tumors and showed encouraging preliminary benefits, indicating it has promise as a treatment for patients with this usually fatal disease. Glioblastoma has several approved treatments, but there are currently no curative options. Studies have found that interleukin 12 (IL-12) - an antitumor molecule - has beneficial effects against cancer, but IL-12 cannot be administered systemically due to its unfavorable safety profile. In search of a much-needed treatment alternative, E. Antonio Chiocca and colleagues developed an approach that leverages the anticancer benefits of IL-12, while limiting its toxicity. Their two-step approach (conducted after surgical removal of the tumor) involves injecting the tumor site with a viral vector that delivers the gene for IL-12, followed by oral administration of a drug candidate named veledimex that triggers the production of IL-12. In a multicenter phase 1 trial, the regimen boosted IL-12 production in the brains of 31 patients with recurrent glioblastoma while limiting the amount of IL-12 that entered systemic circulation. Although some patients exhibited serious side effects, they were easily reversed after discontinuing the treatment and were less severe in patients receiving lower doses of veledimex. Antitumor immune cells penetrated the tumor more effectively after treatment, and the scientists saw signs that the therapy may have boosted overall survival. Patients who received restricted doses of the corticosteroid dexamethasone throughout IL-12 treatment showed greater survival benefits, hinting that limiting corticosteroid use could maximize the benefits of IL-12 treatment and similar immunotherapies.
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Journal
Science Translational Medicine