(MD Anderson Cancer Center)
13 February 2018. A clinical trial testing a common virus modified to generate a specific immune response dramatically reduced deadly brain tumors in a small group of patients and extended their survival for years, but most other patients had only limited success. Results of the trial by researchers at MD Anderson Cancer Center in Houston, part of the University of Texas system, appear in yesterday’s issue of Journal of Clinical Oncology (paid subscription required).
The team led by MD Anderson neurosurgeon Frederick Lang is seeking effective and reliable treatments for glioblastoma, an aggressive brain cancer that affects astrocyte or glial cells supporting neurons or nerve cells in the brain. Glioblastoma is often difficult to treat, where usually the best hope is to slow progression of the disease with radiation or chemotherapy. The cancer generally grows and spreads quickly, often resulting death within 15 months of diagnosis. American Association of Neurological Surgeons estimates glioblastoma occurs in 2 to 3 out of 100,000 adults per year, and accounts for 52 percent of all primary brain tumors.
Lang, along with neuro-oncology colleagues Juan Fueyo and Candelaria Gomez-Manzano, are developing a therapy that enlists the immune system to fight glioblastoma. Their treatment uses a genetically modified adenovirus, a type of virus benign to most people, but may cause the common cold and other viral diseases. In this case, the engineered adenovirus, code-named DNX-2401, is made to attack glioblastoma cells both directly and with the immune system.
“We designed DNX-2401 to specifically infect cancer cells,” says Fueyo in an MD Anderson statement, “replicate inside those cells to kill them, and spread from cell to cell in a destructive wave throughout the tumor.” The authors say preclinical studies show their approach could work with this type of brain cancer, with the clinical study its first test in humans.
The clinical trial recruited 37 patients with glioblastoma to test the safety and response of tumor cells to DNX-2401. Of the 37 participants, 25 received a single injection of DNX-2401 by catheter into their tumors at various dosage levels, while the other 12 patients received a DNX-2401 injection, followed by surgical removal of the tumor 2 weeks later to study the therapy’s mechanism of action in the brain. The primary measure of efficacy in the trial was reduction of tumor size.
The findings show dramatic outcomes for some patients, but only limited results for most. Of the 25 participants receiving DNX-2401 injections, 5 of the patients survived for more than 3 years. In addition, 3 of those patients showed 95 percent or more reduction in tumor size. “In the case of these long-term complete responders,” says Gomez-Manzano, “the virus breaks the tumor’s shield against immune response by killing cells, creating multiple antigen targets for the immune system. These tumors are then completely destroyed.”
After 3 years, however, beneficial effects of the treatments appear to wear off. The researchers say all 3 of the longer-term survivors experienced recurrences of cancer that proved fatal. Two of the survivors developed gliosarcoma, a different type of brain cancer. All 3 of the long-term survivors lived for nearly 5 years after their treatments.
Of the remaining patients, 18 experienced some reduction in their brain tumors, with a median overall survival time of 9.5 months. Among the 12 patients receiving DNX-2401 to study its activity in the brain, the authors say the virus replicates and spreads within the tumors as designed. In addition, the researchers report little toxicity and low-grade reactions to the treatments among 2 participants.
The trial’s results indicate the team has more work to expand the effectiveness of DNX-2401 to a larger percentage of glioblastoma patients. The researchers are studying the addition of new factors to the treatments to cover a broader range of people with the disease.
Fueyo and Gomez-Candelaria founded the company DNAtrix Inc. in Houston to take DNX-2401 to market. The company licenses the rights to the intellectual property owned by MD Anderson, with MD Anderson also holding an equity stake in the company. The company plans to further develop DNX-2401 as a treatment for solid tumor and blood-related cancers, both alone and with other therapies.
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