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.
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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.
Reference:
- Sci. Transl. Med. 11, eaaw5680 (2019)
