The University of Alabama at Birmingham Archives

2019

Scholar Grant

Gregory Friedman

Birmingham, AL

Title: Overcoming Myeloid Cell-Mediated Immunosuppression to Enhance Immunovirotherapy

Executive Summary:
Pediatric high-grade gliomas (HGGs) are the leading cause of brain tumor-related death in children and countless studies have failed to improve survival rates. Inventive approaches are needed to improve outcomes for this terrible disease. Immunotherapy with a genetically altered cold-sore virus (HSV) offers an inventive, targeted, less-toxic approach for children with HGG; critically, our first-generation virus has shown promise thus far in an ongoing Phase 1 study. The altered virus does not harm normal cells but can infect and kill tumor cells while stimulating the child’s own immune system to attack the tumor. The primary challenge to achieving long-term responses is maximizing the immune system’s ability to attack the tumor. Unfortunately, immune cells called “myeloid-derived suppressor cells” have been shown to decrease the immune system’s ability to attack the tumor by producing an enzyme called “arginase”. Arginase deprives favorable immune cells (T cells) of a critical fuel needed to attack the tumor. Thus, we propose to maximize the anti-tumor immune response by combining a next-generation HSV with a drug that inhibits arginase. In addition to killing cells directly and initiating the immune system attack on the tumor, the new virus produces a protein (interleukin-12) that stimulates the favorable T cells to attack the tumor while preventing unfavorable immune cells (T regulatory cells) from limiting the immune system attack on the tumor. The arginase inhibitor will be given with the virus to improve the function of the favorable T cells. This will be the first study to test the benefit of this novel combination and to determine how the combination alters the immune cells in the tumor.

• Through previous Hyundai Hope on Wheels support, we translated our lab findings to a clinical trial using a first-generation altered HSV to treat pediatric brain tumors. Thus far the virus has been safe and tolerable with evidence of responses in many patients.

• Our goal with this lab project is to improve on the current therapy to achieve even better responses by developing a novel immunotherapy which combines our second-generation virus with a drug that inhibits an enzyme (arginase) and is designed to increase favorable immune cells needed to attack the tumor.

• Our aims are: 1) to determine expression and activity of the arginase enzyme in pediatric HGGs and establish how our virus alters expression of the enzyme. This will help us determine the ideal timing for combining the therapy; and 2) to establish the benefit of the combination therapy to target pediatric HGGs.

• Since the arginase inhibitor and next-generation virus are already in adult clinical trials, we have the ability to rapidly translate this state-of-the-art combination to clinical trials in children whom are in desperate need of novel, targeted therapies.

• If successful, the approach can be used to target other pediatric brain tumors and solid tumors.