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Principal Investigators

Behnam Badie, City of Hope
Jana Portnow, City of Hope

Title

Development of Small Molecule Inhibitors and Biologic Agents for Treatment of Glioblastoma Using Intracerebral Microdialysis and Signatures of Vulnerability

Project Information

Project 1 - The combination of oncolytic virotherapy (OV) and monoclonal antibody (mAb) immunotherapy has great potential for the treatment of glioblastoma (GBM), the most common malignant brain tumor without a cure. An OV carrying a mAb-coding gene can produce and release the mAb drug specifically at the tumor site as a safe, effective, and innovative delivery system. Prior to our study, this approach has not been previously explored using herpes simplex virus 1-based OV (oHSV). CD47 is a transmembrane protein widely expressed on cancer cells including GBM. It acts as a “don’t eat me” signal by functioning as a ligand to signal regulatory protein-α (SIRPα) expressed on macrophages, resulting in inhibition of phagocytosis. We have generated an oHSV that expresses a full-length anti-CD47 mAb on an IgG1 scaffold (OV-αCD47-G1) that is capable of inducing antibody- dependent cellular phagocytosis (ADCP) by macrophages and antibody-dependent cellular cytotoxicity (ADCC) by natural killer cells to eradicate GBM cells in vitro and in vivo, in addition to blockade of the CD47-SIRPα “don’t eat me” signaling pathway in macrophages. We have demonstrated that our novel OV-αCD47-G1 significantly improves the survival of GBM-bearing mice in orthotopic, immunocompetent, and immunodeficient models. Our central hypothesis is that OV-αCD47-G1 will be safe and effective at improving GBM treatment and its anti- tumor activity in the brain will be reflected by markers in the peripheral blood. Importantly, we have optimized and manufactured GMP-grade OV-αCD47-G1 to conduct the proposed studies and will initiate a phase I clinical trial for adults with GBM. In this proposal, we will evaluate both the systemic and regional immune responses in vivo following clinical-grade OV-αCD47-G1 administration and identify markers in the circulation that correlate with anti-tumor activity in the brain in GBM animal models (Aim 1); we will perform Investigational New Drug (IND)-enabling in vivo safety and efficacy studies using clinical-grade OV-αCD47-G1 (Aim 2); and we will determine the safety of administering a single intracerebral infusion of OV-αCD47-G1 in adult patients with recurrent GBM (Aim 3). To accomplish these objectives, we will utilize immunocompetent and immunocompromised GBM mouse models for our correlative and preclinical studies evaluating OV-αCD47-G1 prior to the phase I clinical trial. Upon conclusion, we will understand how to optimize OV-αCD47-G1 therapy to cure GBM. Further insight into this process, as will result from the implementation and completion of this proposal, is impactful as it will ultimately lead to a reduction in mortality for adults suffering from GBM.

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.

Project 3 - The ubiquitin/proteasome system maintains intracellular homeostasis via degradation of unwanted proteins. Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in glioblastoma (GBM), and whose upregulation has been associated with glioma progression and worse survival. Pevonedistat is a first-in-class small-molecule neddylation inhibitor shown to impact protein degradation and inhibit growth of GBM cells in culture and orthotopic xenografts. Pevonedistat is in clinical trials and available through NCI’s Cancer Therapy Evaluation Program (CTEP). Because the molecular heterogeneity within and across GBM patients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials, we propose the use of molecular “signatures of vulnerability” to targeted agents in subsets of models, and to use these signatures to guide patient enrollment in early-stage clinical trials. Our preliminary data revealed molecular determinants of synergy against PTEN-deleted (PTENdel) and PTEN-mutated (PTENmt) GBM from combining pevonedistat with a TOP2A inhibitor, etoposide. We hypothesize that a specific “synergy signature” can be used to identify patients likely to respond to pevonedistat + etoposide and propose a signature-guided clinical trial to achieve synergy in patients with recurrent GBM (rGBM). We propose the following Aims: Aim 1. Discover and validate the mechanism underlying the antitumor synergy of pevonedistat + TOP2Ais in GBM. We will use GBM patient-derived xenograft (PDX) explant cultures and orthotopic tumors to pursue this aim and will validate the predictive performance of the “synergy signature” in patient tumor samples from the proposed clinical trial in Aim 3. Aim 2. Validate a “signature of vulnerability” to pevonedistat alone in GBM. We will use GBM PDX cultures and orthotopic models to refine and test the predictive accuracy of a “signature of vulnerability” to pevonedistat for future clinical trials. Aim 3. Determine the safety of pevonedistat + etoposide in “synergy signature” rGBM patients in a phase I clinical trial. We will enroll patients with “synergy signature” GBM to a phase I study of pevonedistat + etoposide to determine the maximum tolerated dose/recommended phase II dose of the combination therapy; obtain preliminary response data; define the neuropharmacokinetic (nPK) of pevonedistat using intracerebral microdialysis; and evaluate the neuropharmacodynamics (nPD) of pevonedistat using a window of opportunity design in subsets of study participants. This project relies on support from Core A for nPK analysis, Core B for exome and RNA Seq and bioinformatics, and the Admin Core for coordination and integration with Projects 1 and 2 for data sharing and comparison of signatures of vulnerability to OV-αCD47-G1 and tasquinimod. If successful, our project will advance drug development in the setting of a heretofore recalcitrant tumor by linking molecular subsets of GBM with both drug discovery/development and patient recruitment for highest likelihood of conveying precision medicine into the care stream.