Decoding the Resistance Mechanisms to Oncolytic Virotherapy in Muscle-Invasive Bladder Cancer
Abstract
Scientific Objective and Rationale: Chemotherapy is typically used to eliminate cancer cells spread outside of the bladder in patients with muscle invasive bladder cancer 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 postsurgically. To address this unmet need, we have launched a first-in-human clinical trial at Moffitt Cancer Center, investigating the safety and efficacy of combined treatment using a novel drug called oncolytic virus (which directly infects cancer cells and incites a cancer-specific immune reaction) and immune checkpoint therapy (which 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. (For more information: https://moffitt.org/endeavor/archive/novel-bladder-cancer-trial- showing-promising-results/) However, this treatment combination is still far from perfect – three of the first six patients treated had residual disease at the time of surgery. We have thus begun a series of studies to understand why some patients respond while others do not. From our preliminary results, we found that predictors for treatment response can be gleaned from the pre-treatment 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. We found that in one of the patients who did not respond to therapy, E2F1 was not found in the pre-treatment sample, rendering the virus unable to replicate and perform its anti-tumor activities. In the first part of the study, 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. 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 immune checkpoint, eradicated the tumor by creating a strong anti-tumor immune response. In the second part of our study, we will explore how the 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. Principal Investigator’s Career Goals: My long-term career goals include understanding the mechanisms of disease progression and drug resistance in bladder cancer, to personalize treatment rendered according to the tumor biology, and to develop new bladder sparing immunotherapies. The proposed project will help to further my understanding of immuno-oncology, cancer genetics, and clinical trial methodology as well as to gain invaluable experience both as a benchtop cancer immunologist and clinical investigator. Applicability/Overarching Challenge: The proposed study may help to establish combination oncolytic virus and immune checkpoint blockade as a neoadjuvant treatment option of choice for chemo-ineligible patie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210395
Entities
People
- Roger Li
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army