Chemoprotection & Immune Remodeling after Hematopoietic Progenitor Cell Gene Therapy for Glioblastoma

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ABSTRACT Glioblastoma (GBM) remains a devastating diagnosis with a median survival of 12-14 months. Although radio-chemotherapy improves outcomes, benefit is primarily in the subset of patients bearing tumors with low expression of the MGMT gene, which comprises less than 45% of all patients. Initial studies demonstrated that the MGMT inhibitor, O-6benzylguanine (BG) depletes AGT and sensitized GBM to TMZ. However, toxicity was high and this was abandoned. To reduce the hematopoietic toxicity of adding BG to chemoradiation, hematopoietic progenitor cells (HPCs) were genetically engineered to express an MGMT mutant (P140K) first identified by PI Gerson, which has low affinity to BG, but removes O-6 methyl adducts with similar efficacy as AGT. This innovative approach protects the hematopoietic progenitor cells (HPC) from BG/TMZ treatment in both in vitro and in vivo preclinical studies and early clinical trials suggest clinical efficacy. Although our original hypothesis was that this treatment strategy would improve survival by improving tolerance to dose-escalated chemotherapy, the emerging recognition of the importance of the immune system in controlling cancer has raised additional important questions not anticipated during initial trial design. Is the observed improved survival due simply to chemoprotecton of the hematopoietic compartment resulting in increased tolerance to cytotoxic chemotherapy as originally hypothesized? Alternatively, does this strategy alter the balance between anti-tumor immune immunosuppressive subpopulations? Which immune subpopulations might be rendered chemo-resistant by transduced P140K-MGMT, and does this contribute to treatment response or resistance? To address these questions, we propose a collaborative project between the Case Comprehensive Cancer Center (CCCC) and the NIH Clinical Center (NIHCC) to expand an ongoing active IND phase I trial and incorporate additional analysis of biospecimens from patients with newly diagnosed GBM. The improved patient access, clinical expertise, and unique, cutting edge immunological monitoring capabilities at the NCICC will speed up accrual, help assess the feasibility of this complex trial, and help quantify the changes in quantity and function of various immune subpopulations, which will markedly enhance the impact of this innovative treatment approach. The overall goal of this proposal is to define the longitudinal changes in both the quantity and function of immune cell subtypes in blood, marrow and the tumor microenvironment, while documenting treatment tolerance to chemotherapy, the persistence of the transduced gene, integration site safety, and changes in tumor mutation profile after treatment. Our hypothesis is that GBM patients treated with MGMT-P140K transduced HPC followed by BG/TMZ, will: A). tolerate treatment better, maintain improved hematopoietic and immune function, and demonstrate increased progression-free and overall survival; and B). demonstrate altered proportions of effector and suppressor immune subpopulations before and after treatment. The collaboration with NIHCC and intramural investigators is essential to these to these ongoing studies given the complementary expertise in genetically engineered HPCs at CCCC; the increased access for patient accrual and the unique immunological monitoring and clinical expertise at NIHCC. This project also synergizes with the ongoing collaboration between the PIs.