Immunotherapy with Interleukin-12 Activated Gene Therapy for Glioblastoma
by Dr. C.H. Weaver M.D. 12/2019
Interleukin-12 (IL-12) immunotherapy is a potent anti-cancer medication that cannot be easily used to treat cancer because of its excessive side effects when administered systemically. Doctors from Dana Farber/Brigham and Women/s Cancer Center, Northwestern University, University of Chicago, Cedars-Sinai Medical Center and Ziopharm Oncology, Inc. applied a novel drug-inducible gene therapy for the first time in humans where they injected a gene therapy with a vector encoding for IL-12 into the tumor resection cavity of individuals with Glioblastoma Mulitforme (GBM) and then turned the gene on with an activator drug. This process allows the IL-2 to work where injected but not throughout the entire body.
The gene therapy approach combined immunotherapy with human IL-12 with an oral medication designed to control when the gene gets turned on known as an “activator”. During surgery for GBM, patients received an injection of a vector (Ad-RTS-hIL-12) that delivered an “inactive” IL-12 drug into the cavity that remains after the GBM was surgically removed. The IL-12 gene delivered in the vector is inactive when injected but can be switched on by the oral activator. Before surgery, patients received a dose of the activator and they continued taking the activator drug for 14 days after surgery.
The patients with recurrent GBM treated with the activator-IL-2 vector combination at the optimal dosing in the trial had a median overall survival of 18 months. The investigators were also able to evaluate the tissue from GBM’s in some patients that had been treated with the IL-12 gene therapy and they saw evidence that immune cells had infiltrated the cancer. They also saw evidence of increased checkpoint signaling, a trick that cancer cells use to turn off the immune system and avoid detection.
Checkpoint inhibitor medications are now widely available and can be used to reverse checkpoint signaling and ensure a cancer can’t evade detection by the immune system. The next step in evaluating this novel gene therapy approach is to combine the IL-12 gene therapy with an intravenous checkpoint inhibitor. The phase 1 clinical trial is currently underway.
- Sci. Transl. Med. 11, eaaw5680 (2019)