Research Project
10306305
PROJECT SUMMARY ? PROJECT 2 Although immunotherapy has significantly improved patient survival for many types of cancers, to date no immunotherapeutic agent has shown consistent efficacy against glioblastoma (GBM). Many promising immunotherapy approaches for GBM are administered in the peri-operative period, but, unfortunately, for GBM patients two surgery-related factors work against the success of these immunotherapies: 1) Most GBM patients are treated peri-operatively with high doses of dexamethasone, which suppresses the immune system, and 2) surgical brain injury from tumor resection results in a substantial release of cytokines and chemokines that alter the tumor milieu and support tumor regrowth. Our preclinical data demonstrate the significant role that the receptor for advanced glycation end products (RAGE) pathway plays in the brain?s inflammatory response to surgical brain injury and that the RAGE ligand S100A9 is a key intermediary. The overall goal of this research project is to repurpose tasquinimod, an anti-inflammatory small molecule inhibitor of S100A9, by developing it as an immunotherapy adjunct that will control cerebral edema while diminishing post-surgery activation of the pro-tumor inflammatory response, thus creating a tumor microenvironment that enhances the efficacy of immunotherapies administered in the peri-operative period for the treatment of GBM. We will begin by performing a phase I safety and feasibility study to determine the maximum tolerated dose of tasquinimod when administered in combination with relatively low doses of dexamethasone peri-operatively in GBM patients who undergo tumor resection (Aim 1). We will assess the ability of tasquinimod to reverse myeloid-induced immunosuppression in the tumor microenvironment (Aim 2) by measuring changes in concentrations of cytokines and RAGE ligands in the peritumoral brain interstitium with intracerebral microdialysis and evaluating changes in levels of these inflammatory markers as well as immune cell populations in resection cavity fluid. To determine the immune-modulatory effect of tasquinimod when used in combination with immunotherapy approaches that are administered during the peri-operative period (Aim 3), we will perform preclinical in vivo studies to assess the efficacy of tasquinimod in combination with PD-1 inhibitors, oncolytic viruses, and CAR T cells. By inhibiting the activity of myeloid-derived suppressor cells, tasquinimod could enhance the anti-tumor activity of these emerging immunotherapy technologies, leading to increased efficacy against GBM. Successful completion of these aims would provide a strong foundation to support development of future clinical trials to assess use of tasquinimod alone for controlling cerebral edema and to evaluate tasquinimod in combination with the most promising immunotherapy approach determined in Aim 3 with the goal of improving outcomes for patients with GBM.
