Finding a better way.
Noriyuki Kasahara, MD, PhD
University of California San Francisco
When Noriyuki Kasahara, MD, PhD, was a student in medical school, he watched his aunt lay in a coma for nearly a year, dying of glioblastoma. It was then that he realized that, as a physician, he’d likely be able to help at most a few thousand or so patients a year. As an educator, he 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 him to impact the lives of millions of people, including those in generations not yet born.
Established approaches for treating cancer at that time (and today) included cutting it out with surgery, burning it with radiation or poisoning it with chemotherapy — all of which came with side effects that could cripple a person’s quality of life or be life-ending in themselves. Dr. Kasahara knew there had to be a better way… and finding a better way became his calling in life.
Dr. Kasahara’s “suicide gene” strategy began to take shape early in his 30-year career in gene therapy vector development. It was understood that cancer cells were very good at fighting off attacks by the body’s immune system, which made the cancer cells vulnerable to virus infections because they had suppressed the immune cells. Dr. Kasahara’s vision was to leverage this vulnerability and utilize the natural ability of viruses to break into tumors, replicate themselves and spread from one cancer cell to another.
These viruses would be genetically engineered to reprogram cancer cells to commit suicide by making them produce a chemotherapy drug directly inside the infected cell itself. Because the drug would be generated locally inside the tumor, it would eliminate the poisonous side effects of conventional, intravenously infused chemotherapy.
Initially, citing gene therapy safety concerns, the U.S. Food and Drug Administration (FDA) forbid the use of virus vectors that could replicate, and required that all virus vectors be disabled so they could no longer spread from cell to cell. However, cancer is a moving target that proliferates and constantly makes more cancer cells, so after over a decade of unsuccessful clinical trials, it became apparent that non-replicating single-shot virus vectors were just not efficient enough. After Dr. Kasahara and his team were able to validate the safety and tolerability of replicating virus vectors in preclinical studies, the FDA removed the replication hurdle and Dr. Kasahara and colleagues became the first investigators to employ genetically engineered retroviruses that retained the ability to replicate and spread from cancer cell to cancer cell selectively within tumors.
The first retroviral replicating vector to go into clinical trials was genetically engineered to carry the cytosine deaminase (CD) suicide gene. This virus successfully penetrated targeted tumors and delivered the CD gene, which caused the infected cancer cells to generate their own chemotherapy and self-destruct, which in turn enabled the patient’s natural immune system to access and destroy the rest of the cancer.
Dr. Kasahara’s preclinical results in uncovering this suicide gene therapy’s anti-tumor immune activation link were reported in the July 2017 issue of Neuro-Oncology and presented at the 2018 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting and the 2018 International Oncolytic Virus Conference (IOVC). Encouraging results in brain tumor patients from Dr. Kasahara’s clinical trials were reported in the June 2016 issue of Science Translational Medicine and September 2018 issue of Neuro-Oncology.
A grant from Alliance for Cancer Gene Therapy funded in part by Swim Across America Fairfield County is now allowing Dr. Kasahara to explore the potential of another genetically engineered replicating retrovirus vector with a more powerful suicide gene, nitroreductase (NTR), and combining this approach with immune checkpoint inhibitors that enhance the ability of a person’s natural immune cells to follow the virus into the tumor and do their job — which is to kill the cancer.
“I am extremely grateful to Alliance for Cancer Gene Therapy and Swim Across America for funding this next phase of our work,” says Dr. Kasahara. “At a time when federal funding has become scarce, it’s wonderful and inspiring to see foundations like Alliance for Cancer Gene Therapy step up to support the potential of innovative science. Together, we will continue our fight to find better ways to help cancer patients.”
This Alliance for Cancer Gene Therapy Research Fellow is funded by Swim Across America.
“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.”