Noriyuki Kasahara, MD, PhD
RRV for immunogenic suicide gene therapy and checkpoint inhibition in glioma.
Malignant brain tumors carry a dismal prognosis despite surgery, chemotherapy, and radiation, hence new therapeutic approaches are needed. New strategies are being investigated using modified viruses (termed “vectors”) to infect cancer cells and deliver genes that serve as blueprints to make therapeutic proteins inside the cancer cells themselves.
Until recently, most researchers used viral vectors that could deliver therapeutic genes to the initially infected tumor cells but are rendered incapable of infecting any additional cells. However, such ‘non-replicating’ vectors were found to have limited benefit, because not enough tumor cells could be reached.
A newer approach is to use virus vectors that actively replicate themselves and can spread forth from the initially infected cancer cells within tumors, but not in normal tissues, thereby continuing to infect more cancer cells even as the cells continue to proliferate. These tumor-selectively spreading viruses are used to deliver a “suicide gene,” which converts a non-toxic ‘trigger’ compound (“prodrug”) into a DNA synthesis-blocking chemotherapy drug. Because this virus causes the chemotherapy drug to be generated selectively and directly within the infected tumor itself, there are few adverse side effects.
The first version of this type of therapeutic virus has shown highly promising results in early-stage clinical trials and is currently being tested in an international Phase 2B/3 trial for recurrent brain cancer.
We recently discovered that this approach can also activate the immune system to attack tumors. Hence, in this Alliance for Cancer Gene Therapy funded study, we examine whether brain tumors that show a high rate of new mutations, which can be recognized by the immune system, may be correlated with better responses to this treatment.
We also propose to develop a new tumor-selectively spreading virus vector that delivers a different “suicide gene” which cross-links DNA and thereby generates new mutations for the immune system to attack, and we further propose to combine this mutagenic DNA cross-linking suicide gene therapy with strategies to overcome immune blockade (“checkpoint”) mechanisms within tumors.
Finally, we will conduct preclinical studies to evaluate the safety of this new virus vector for use in a future clinical trial. If the proposed preclinical studies are successful in validating the safety, efficacy, and mechanism of action for this new immunogenic suicide gene therapy, combined with immune checkpoint inhibition, we anticipate that this approach can be rapidly translated to the clinic in collaboration with a biotech partner that is already testing our previously developed virus vector in clinical trials.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.
Related Researcher Story:
Finding a better way.
“When I was a student in medical school, I watched my aunt lay in a coma for nearly a year, dying of glioblastoma. It was then that I realized that, as a physician, I’d likely be able to help at most a few thousand or so patients a year. As an educator, I could teach perhaps 100 students a year, who could each then go on to become physicians and collectively help hundreds of thousands of people a year. But as a researcher, by discovering the cause of an unexplained disease or by developing a new diagnostic test or a novel treatment, potential existed for me to impact the lives of millions of people, including those in generations not yet born.”