More Effective, Keeping It Safe: Repeat oHSV Treatment for Glioma
Abstract
Malignant gliomas are very aggressive cancers that affect adults, some young adults, and even children. These brain tumors have a bleak prognosis and are difficult to treat due in part to their location and their therapeutic resistance. Thus, there is an urgent need for alternative therapeutic approaches. We are investigating ways to improve the immune response against the tumor by using engineered viruses that selectively infect and lyse the tumor cells and trigger immune activity against the cancer. Our Translational Team Science Award (TTSA) group has worked together examining different engineered viruses and are finishing testing of a new virus called C134 that replicates in the tumor better than previous viruses. Initial clinical trial studies performed by Dr. Markert identified that we can safely dose the virus in people with recurrent malignant glioma tumors up to 1x10^6 pfu but that the biological activity and other markers of therapeutic response were similar for participants receiving between 1x10^5-1x10^6 in this study. During the clinical trial, a subset of patients underwent rebiopsy. These results showed in aggregate that the virus appeared to replicate well in the tumor leading to necrosis and that it recruited beneficial immune cells that persisted months after the initial treatment. Based upon our initial results, the U.S. Food and Drug Administration (FDA) amended our investigational study so that we can now offer a second dose of the C134 to other untreated regions of the tumor or inject in the margins after tumor resection to extend virotherapeutic activity. Dr. Markert will lead Project 1 and will examine the safety of repeated dosing in a phase 1b study. We anticipate that this will be safe and will improve the virus’s therapeutic activity based upon past studies that suggest that this is effective. Our second project for this TTSA examines whether there is a better way to retreat patients with a second dose of virus. Most repeat treatment studies use the same virus for the second dose (similar to Project 1). We have the luxury of having two different viruses available for clinical trials. Both are safe but stimulate the immune response in slightly different ways. We anticipate that, while retreatment with same virus will help patients, retreating with a second virus that triggers the immune response in a different way may be even better. We intend to study this in mouse brain tumor models and measure how these different treatment approaches alter the immune cell response (numbers of cells) and their functional activity against the tumor cells vs. the virus. The studies will also examine if there is a preferred sequence for the virus treatments in terms of their immune and therapeutic activity. If we are correct and this hybrid repeat dosing treatment is better, we have these two viruses ready and available for patients and can use these studies to discuss this possibility with the FDA. The third project in our TTSA involves analyzing the tumor materials from the treated clinical trial participants and from the animal studies using newer methods to identify immune response activity changes that are responsible for survival and the virus’s therapeutic activity. Dr. Mardis leads these studies and is in an expert in genomic analysis. Dr. Mardis analyzed tissue from our earlier virotherapy clinical trial and identified a gene expression response that correlated with patient survival. We anticipate that material from the C134 clinical trial (Project 1) and samples from our mouse studies (Project 2) can be analyzed using these newer better approaches to identify the viral and immune response changes responsible for the virotherapy efficacy. With this knowledge we can then go back and identify ways to improve these responses in our mouse models and then translate those to patients in clinical studies. Ultimately, we anticipate that by combining our unique talents, this integrati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310804
Entities
People
- Elaine Mardis
Organizations
- United States Army