Dr. Roger Li, a genitourinary oncology surgeon and researcher at Moffitt Cancer Center, received a grant from the Department of Defense to study the immunogenic actions of the oncolytic virus and immune checkpoint blockade.
For patients with muscle-invasive bladder cancer, chemotherapy is typically used to eliminate cancer cells spread outside of the bladder before surgical bladder removal. The implementation of such treatments has led to significant increases in patient survival following surgery and represents one of the major breakthroughs in bladder cancer treatment over the last 20 years.
Unfortunately, up to 50% of the patients with muscle-invasive bladder cancer cannot receive chemotherapy due to other medical illnesses (e.g., kidney dysfunction). These patients are left with no alternative option than upfront surgery, but often quickly develop cancer recurrence post-surgically. To address this unmet need, Dr. Li's team launched a first-in-human clinical trial at Moffitt, investigating the safety and efficacy of combined treatment using a novel oncolytic virus called CG0070. It directly infects cancer cells and incites a cancer-specific immune reaction. In conjunction, the patient will also receive immune checkpoint therapy that boosts the pre-existing cancer-specific immunity.
The early results from this clinical trial are very promising and show that the efficacy of the combination is even better than chemotherapy given to healthier patients with similar stages of bladder cancer. Furthermore, the drug combination is safe and very well tolerated by patients. Read more about this trial in Dr. William Sanders’ story.
However, this treatment combination is still far from perfect. For example, three of the first six patients treated had residual disease at the time of surgery. Dr. Li's team has thus begun a series of studies to understand why some patients respond while others do not. From their preliminary results, predictors for treatment response can be gleaned from the pretreatment tumor samples. For instance, E2F1, a protein expressed in most bladder tumors, is a known driver for the replication and propagation of the oncolytic virus within the cancer cells. It was discovered that in one of the patients who did not respond to therapy, E2F1 was not present in the pre-treatment sample, rendering the virus unable to replicate and perform its anti-tumor activities.
"In the first part of the correlative studies, we plan to investigate whether there is a direct correlation between features of the pre-treatment tumor samples (called biomarkers) and the ability of the virus to infect tumor cells leading to treatment response," said Dr. Li. "Secondly, we also found that in those patients who responded to therapy, their post-treatment biopsy samples showed evidence of a robust immune response occurring at the previous tumor site. This led us to believe that the viral infection, along with the immune checkpoint, eradicated the tumor by creating a strong anti-tumor immune response.
In the second part of our study, we will explore how viral infection leads to immune activation. We hypothesize that as the virus causes accumulating tumor cell lysis, more of the proteins present only within the tumor cells (called neoantigens) are released into the microenvironment surrounding the tumor. These neoantigens are subsequently recognized as foreign by the body's immune system, which in turn leads to a tumor-specific immune response."
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