Boosting the Systemic and In Situ CD4+ T-Cell Responses to Malignant Glioma by Oncolytic HSV Virotherapy
Abstract
Objective and Rationale: This application proposes studies combining two Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: brain cancer and immunotherapy. Malignant gliomas are high-grade primary brain tumors with a dismal prognosis, evincing the unmet need for more effective therapies. We have developed herpes simplex virus (HSV) type 1 based vectors for the treatment of patients with malignant gliomas. These HSV viruses are specifically replicating in the tumor cells and can directly destroy tumor cells through oncolysis (termed “oHSV”). We have then constructed oHSV that expresses either human version or murine version of interleukin-12 (IL-12-oHSV) to enhance antitumor effects. These oHSVs are injected into the tumor, appear to be safe, and produce antitumor responses in both mouse models and patients. However, the variation in patient outcomes has justified the need of better understanding their impact on immune responses with the goal of improving this approach. This project will use samples from patients in our ongoing IL-12-oHSV trials to identify subsets of T lymphocytes as biomarkers to predict which patients with brain tumors are likely to benefit from IL-12-oHSV immunotherapy and which are not. We will then use mouse glioma models to understand the mechanisms of enhanced antitumor responses by these subsets after IL-12-oHSV treatment. These studies will help dissect the precise nature of the antitumor immune responses to IL-12-oHSV therapy and will help inform clinical trial design for future oHSV studies and direct the overall field of oncolytic virus research. Applicability and Military Relevance: The identified subsets and associated molecules as new biomarkers would potentially lead to better strategies for patient stratification for selecting the patients with better response outcomes for future trials with IL-12-oHSV immunotherapy. This can be readily applied to the clinical practice. Results from the proposed study may also form the foundation of developing the best combinatorial immunotherapeutic approaches – IL-12-oHSV therapy and targeting these candidate cells or molecules – that would improve dramatically the survival benefit to both the general population and the military personnel, particularly Gulf War Veterans who are vulnerable to brain cancers. Ultimately, these therapies would enhance the natural function of the immune system to fight malignant gliomas. Career Goals in Cancer Research: My career vision is to perform multidisciplinary, high-impact translational research focused on cancer immunotherapy. My 5-year career goal is to develop an independent research program that is based on the findings of the research in this application. Since the proposed study cuts across multiple fields – immunology, brain tumor biology, and oHSV-based immunotherapy – I am developing a line of independent research that integrates all three areas. I have already trained in immunology and immunotherapy, I will use the PRCRP Career Development Award to acquire training in brain tumor biology and oHSV-based research, and to generate pilot data on this study, and finally to improve professional skills needed to succeed in an academic research career. Combining these areas of expertise will enable me to compete successfully for independent R-type funding and to develop a novel translational research program bridging brain tumor and oHSV immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810315
Entities
People
- Jianmei W Leavenworth
Organizations
- United States Army
- University of Alabama at Birmingham