It’s a story of targeted chemotherapy, immune system changes, and the possibility of prolonged survival for people with gliomas.
Noriyuki Kasahara, M.D., Ph.D., a gene therapy expert at Sylvester Comprehensive Cancer Center and professor of cell biology and pathology at the Miller School of Medicine, and colleagues developed a unique technology to deliver chemotherapy exclusively to tumors. They deploy retroviral replicating vectors (RRVs) that deliver a prodrug activator (“suicide”) gene into the DNA of cancer cells. When later exposed to the prodrug, these infected cancer cells convert it into a chemotherapy drug within their own cell walls, and self-destruct.
Kasahara’s new findings were published in Neuro-Oncology, the leading journal in the field of brain tumor research, and featured on the cover of the July issue. These studies provide new insights into how RRV prodrug activator gene therapy activates the immune system to fight tumors, and may help to devise new strategies to combine gene therapy and immunotherapy. “Identifying the roles of these particular cell types … now allows us to focus our efforts on augmenting immune mechanisms of action against tumors,” Kasahara said.
Their first clinical target has been recurrent high-grade glioma, a type of brain cancer that has relapsed after becoming resistant to standard treatments. In previous trials, including multicenter Phase I studies with 126 glioma patients, “it proved to be highly effective in destroying the tumors locally, but without any adverse side effects — such as those caused by conventional systemic chemotherapy to normal tissues in the rest of the body,” Kasahara said. “In particular, there is no collateral damage to the patient’s immune system, so the immune cells can remain healthy and mount a secondary attack on the tumor.”
Improved disease symptoms and neurological function, beneficial radiographic tumor responses, and increased survival compared to historical benchmarks were observed. “Some of these patients showed radiographic responses that became apparent many months after the initial virus treatment, while continuing to take just the prodrug as an oral pill,” Kasahara said.
The therapeutic benefit of prodrug activator gene therapy may also be durable. “In some of our clinical trial patients, we have seen late-stage responses that were reported to occur well past the historical median survival time of seven months, and these patients are still alive at the time of the most recent follow-up, in some cases almost four years later.”
Insight into Immune Alterations
Encouraged by these late-stage responses in clinical trial patients, Kasahara is taking the research a step further, now going back from the bedside to the bench, using preclinical glioma models to delve deeper into the immune mechanisms triggered by this treatment. “We hypothesized that our RRV-mediated prodrug activator gene therapy may somehow be activating anti-tumor immune responses.”
“In our preclinical glioma model, as a ‘bystander effect’ of the prodrug activator gene causing the infected cancer cells to locally generate their own chemotherapy drug, we found that adjacent immune suppressor cells were also killed,” Kasahara said. “This reversed the local immunosuppression within the tumor environment, and enabled incoming immune cells such as T cells to mount a more effective attack and reject the tumor. T ‘helper’ cells turned out to play a critical role in immune-mediated rejection of the glioma cells.”
“Even within the field of virotherapy, our strategy is unique in taking advantage of the ability of RRV to spread selectively within tumors without immediate destruction of the infected cells, enabling the virus to fly under the radar of the immune system, while permanently integrating its prodrug activator gene into the DNA of the cancer cells,” Kasahara said. “This enables long-term persistence of the virus and its prodrug activator gene within the tumor, and the trigger can be pulled at any time, in all of the infected cancer cells simultaneously, by administering the prodrug to the patient.”
Although recent advances in immunotherapy have generated a great deal of excitement in cancer treatment, immunotherapy tends to work better in tumors with more genetic mutations, known as “hot tumors.” These genetic alterations create mutated proteins that become targets for the immune system. In contrast, immunotherapy effectiveness tends to be lower in “cold tumors” with fewer mutations. “So a major effort in the field is how to make cold tumors turn hot,” Kasahara said. This could be another potential advantage of the RRV prodrug activator gene therapy – that this highly targeted, locally generated chemotherapy converts cold tumors to hot tumors, which will be more sensitive to immunotherapy.
Kasahara and team have completed enrollment and are awaiting results of an international Phase IIB/III clinical trial of Toca 511, their clinical RRV for prodrug activator gene therapy in recurrent high-grade glioma patients. This trial has completed enrollment in more than 60 sites in the U.S., Canada, Israel, and Korea, and will compare this innovative gene therapy approach to standard chemotherapy.
Miller School of Medicine