With JUAN FUEYO, MD, at MD Anderson Cancer Center
By Sarah DiGiulio
Recurrent glioblastoma is a tough cancer to treat. Glioma cancer cells at the outset are very resistant to treatments, such as chemotherapy and radiation therapy that tend to traditionally work in fighting and killing other types of cancer cells. "The FDA has only approved three drugs to treat malignant gliomas and one of them does not improve survival," explained Juan Fueyo, MD, Professor in the Department of Neuro-Oncology at MD Anderson Cancer Center, Houston. "Other therapies, including biological therapies, needed to be developed."
So Fueyo and other investigators developed the "smart bomb" virus or Delta-24, an adenovirus that is genetically engineered to replicate selectively in tumor cells. "The fact that the virus will identify a pathway abnormal in cancer cells to replicate and kill is the 'smart' component of the strategy," he told Oncology Times.
The team has published results of a phase I clinical trial that evaluated the therapy in 37 patients with malignant brain tumors (J Clin Oncol 2018; doi:10.1200/JCO.2017.75.8219). The trial was designed to assess toxicity and help determine an appropriate dose, not test efficacy, Fueyo said.
Twelve patients were treated with the virus and subsequently had their tumors removed surgically (patients in this arm had to have tumors that were manageable by surgery, which would have been standard treatment for these patients had they not be part of the study). The other 25 patients in the second arm of the study were treated with the virus and followed (and did not have their tumors surgically removed). The first group that underwent surgery gave the researchers the opportunity to observe how the virus had infected the tumor cells after the tumors were removed, Fueyo explained.
More than half of the patients receiving the therapy had some response and, of the group who did not have their tumors removed surgically, five patients survived more than 3 years with three patients showing a complete response (meaning they had clear radiological images and survival of more than 3 years). Toxicities among all patients on the trial were minimal, with two patients experiencing low-grade side effects related to treatment.
From the resected tumors, researchers observed that the virus could replicate in human tumors, noted Frederick Lang, MD, Professor and Chairman in the Department of Neurosurgery at MD Anderson. "Our trial was unique for brain tumor trials because of this arm. We didn't just look at clinical and radiographic outcomes. We actually looked at the biological effects of the virus on the tumor."
"And the patients eligible for this trial had already failed surgery, radiotherapy, and chemotherapy," Fueyo added.
More testing in a larger group of patients is needed before the therapy is ready for primetime, Fueyo said. Here's what else he told Oncology Times about the new treatment.
1. Why were you so surprised by the findings from this research?
"First, we did not expect to have long-term survivors—that a patient whose survival was statistically measured in weeks was capable to live for 5 years with great quality of life was a wonderful surprise.
"The second surprise came after the realization that the pathology and radiologic evidence pointed out that infection of the tumor with Delta-24 elicited an anti-tumor immune response that was probably responsible for the elimination of the tumors. This is a paradigm shift in virotherapy. As a result, virotherapy is now considered one of the strongest forms of immunotherapy for solid tumors.
"The trial also showed that Delta-24 is not toxic and can be safely administered by injection into solid tumors. The fact that the response to the therapy is not accompanied by the common and serious side effects of the chemo and radiotherapy is a big plus."
2. What's next for this therapy?
"We are now focused in improving the immune arm of the therapy. To this end, we have modified the Delta-24 to express immunomodulators. This new generation virus, called Delta-24-RGDOX, should be more powerful than the parental virus in the awakening of the immune system. Our lab published these results a few months ago in Cancer Research. In addition, the combination of Delta-24 with antibodies against anti-PD-1 is currently being tested in a multi-center clinical trial (the CAPTIVE trial). In 1 year, we should be able to know if the combination of these two treatments increases the percentage of long-term survivors [thanks to the use of] Delta-24 as single treatment.
"Also, the Delta-24 virus is now in a phase II clinical study and, if this trial is successful, that pathway for commercialization should be very fast.
"The virus is easily produced and vialed. It can be used in any hospital with a department of neurosurgery. [It's] a sophisticated treatment because its inception required knowledge of fundamental cancer biology and virology. But the process for the clinical grade manufacture is not complex—and the administration requires technology that is available in the majority of the hospitals.
"In a matter of few years the 'smart bomb' virus would be available to cancer patients. Delta-24 is targeted to a pathway that is abnormal in the vast majority of cancers and, therefore, the treatment can be applied to the majority of patients with solid tumors, including melanoma, breast, and lung cancers. The new generation Delta-24-RGDOX induces not only local anti-tumor effect, but it is also useful to treat metastases."
3. What's the takeaway for this new therapy?
"We should probably accept that, in addition to conventional therapies, new biological therapies including CAR-T cells, immune checkpoint antibodies, and oncolytic viruses are knocking on the door to be included in the current armamentarium of cancer therapies. Clinical studies are demonstrating these therapies work [based on] the new and more complete knowledge that we have of the immune system and the immune characteristics of the tumor. Immunotherapy is currently leading a revolution in cancer therapy that results in long-term survivors and should be kept in mind at the moment of planning any treatment regimen for cancer patients."