First clinical trial of drug-inducible gene therapy yields encouraging preliminary results

August 14, 2019

Immunotherapeutic drugs are a potent way of transforming the immune system into a ferocious guard dog that can sniff out and destroy tumor cells. But for some therapies, it helps to have a leash. Without one, immunotherapies can do their job too well, stimulating the immune system to overreact, causing systemic toxicity. A new clinical trial by investigators from Brigham and Women's Hospital and Dana-Farber Cancer Institute set out to test the safety and effectiveness of controlling a powerful immunotherapy, known as human interleukin-12 (hIL-12), by using an oral activator -- a drug that can give finer control over when a gene gets turned on -- in patients with recurrent glioblastoma. The protein hIL-12 can stimulate many branches of the immune system, but previous clinical trials that leveraged it were halted because of toxicity. Results from the new clinical trial, sponsored by Ziopharm Oncology, Inc., are more promising: the drug-inducible gene therapy approach showed anti-tumor effects, with tolerable and reversible side effects. The study lays groundwork for more robust clinical trials of this therapy, with potential applications for glioblastoma and beyond. Results are published in Science Translational Medicine.

"In a phase 1 trial, we're always trying to find a glimmer: Is there any evidence of efficacy? These results give us that glimmer of hope," said corresponding author Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at the Brigham. "We believe it is now possible to do regulatable immunotherapy via genes. It's well-tolerated in patients with glioblastoma, with some encouraging evidence that the drug is having its intended effect."

Glioblastoma is an aggressive, incurable cancer with a median overall survival of 15 months. Patients with glioblastoma receive surgery, radiation and chemotherapy, but in almost all cases, tumors return within months. When glioblastoma recurs, median overall survival is only a few months. In the current, multi-center study, 31 patients with recurrent glioblastoma received a dose of veledimex, the oral activator, before surgery to remove brain tumors. They received an injection of an hIL-12 vector (Ad-RTS-hIL-12), which delivered an IL-12 drug, at the time of surgery. They then continued taking veledimex for 14 days.

Patients received 10-40 mg of veledimex, and the researchers reported dose-related increases of veledimex, IL-12, and other measures of immune activity in the blood of patients. Frequency and severity of adverse events, including cytokine release syndrome, correlated with the veledimex dose, reversing promptly upon discontinuation. Patients taking the 20 mg dose of veledimex had a median overall survival rate of 12.7 months.

The team found that taking corticosteroids while on the IL-12 gene therapy negatively impacted survival. Corticosteroids are prescribed to relieve brain swelling but are also immunosuppressive, potentially dampening the effectiveness of the therapy. Overall, Patients taking 20 mg of veledimex with minimal corticosteroids had a median overall survival of 17.8 months (6.4 months for those on corticosteroids).

While these median overall survival times are favorable compared to recurrent glioblastoma historical controls (numbers reported in previous studies), more advanced studies with more patients will need to be performed to confirm if the treatment is truly efficacious.

When Chiocca and colleagues had access to tissue from tumors that had been treated with the IL-12 gene therapy, they saw evidence that immune cells had infiltrated the tumor -- a good sign -- but also saw evidence of increased checkpoint signaling, a trick that cancer cells use to stop the immune system. As a next step, the team is combining IL-12 gene therapy with intravenous checkpoint inhibitors. A phase 1 clinical trial is now underway.
-end-
The current clinical trial and correlative studies were funded by Ziopharm Oncology, Inc. and by 2P01CA163205 and CA069246-20 from the National Institutes of Health. Seven co-authors are employees and own equity interest in Ziopharm Oncology, Inc. Chiocca has advised Ziopharm Oncology. He also is a named inventor on patents related to oncolytic HSV1. A co-author has served on the advisory board of Ziopharm. A co-author reports royalties from intellectual property led by or licensed to Ziopharm Oncology Inc. A full list of disclosures, please see the paper.

About Dana-Farber/Brigham and Women's Cancer Center

Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) brings together specialists from two world-class medical centers. Our team has deep experience in treating various cancers and includes experts from a wide span of disciplines, such as medical and radiation oncologists, cancer surgeons and many others. We offer access to the latest treatments, many of which were pioneered at DF/BWCC, along with clinical trials of promising new therapies.

Brigham and Women's Hospital

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.