Abstract CT541A: Oncolytic viral reshaping of the tumor microenvironment to promote CAR T cell therapy for glioblastoma
Authors: Brown Christine E. , Xella Agata , Hibbard Jonathan C. , Salvary Vanessa , Aguilar Brenda , Wagner Jamie , Dezube Bruce , Niss Knut , Bayless Lynn , Edinger James , Leavenworth Jianmei , Forman Stephen J. , Badie Behnam , Markert James M. , Cassady Kevin A. 
Published: June 2022

Abstract
The combination of chimeric antigen receptor (CAR) T cell therapy, which delivers large numbers of tumor reactive T cells, and oncolytic viral therapy, causing activation of host immune responses, is an attractive approach for improving outcomes for patients with glioblastoma (GBM). Here we present data from two independent phase I clinical trials evaluating IL13Rα2-targeted CAR therapy (NCT02208362) and C134 oncolytic viral (OV) therapy (NCT03657576) for the treatment of recurrent GBM (rGBM), along with preclinical studies supporting the utility of combining these two therapies. For NCT02208362, locoregional delivery of IL13Rα2-targeted CAR T cells were evaluated in heavily pretreated patients with rGBM. Interrogating biomarkers of clinical response revealed that levels of intratumoral T cells prior to treatment were positively associated with overall survival; furthermore, two patients who achieved a complete response had the highest levels of intratumoral CD3+ T cells pre-therapy. These findings suggest that therapeutic strategies which increase endogenous immune infiltrates could augment CAR T cell mediated responses. For NCT03657576, intratumoral delivery of C134, a herpes simplex virus (HSV-1) that has been genetically engineered to safely replicate and kill glioma tumor cells, is also being evaluated for treatment of rGBM. We report findings from a patient treated intratumorally with 1 × 106 pfu of C134. At 6-7 weeks post treatment this patient had MRI changes that suggested possible recurrence or pseudoprogression, and therefore underwent resection with biopsy assessment. Evaluation of virus-treated areas showed increased immune infiltrates as compared to untreated tumor sites, suggesting that C134 activated host immune responses. These clinical findings provide the rationale for evaluating a combination therapy of C134 OV and IL13Rα2-CAR T cells to potentially reshape the tumor microenvironment (TME) and enhance CAR therapy. In orthotopic GBM models in nude mice, we show that co-treatment with the two agents gave no adverse reaction, and more notably pre-treatment with C134 re-shaped the TME by increasing immune cell infiltrates and enhanced the efficacy of sub-therapeutic doses of CAR T cell therapy delivered either intraventricularly or intratumorally. Ongoing preclinical studies aim to provide detailed phenotypic analysis, as well as a mechanistic understanding of this combination approach to support the potential benefit of a soon to be opened combination trial evaluating C134 and IL13Rα2-CAR T cells. In this clinical trial in patients with IL13Rα2+ rGBM and anaplastic astrocytoma, increasing doses of intratumorally administered C134 will be followed by dual intracranial intratumoral and intraventricular administration of IL13Rα2-targeted CAR T cell therapy.
Citation Format: Christine E. Brown, Agata Xella, Jonathan C. Hibbard, Vanessa Salvary, Brenda Aguilar, Jamie Wagner, Bruce Dezube, Knut Niss, Lynn Bayless, James Edinger, Jianmei Leavenworth, Stephen J. Forman, Behnam Badie, James M. Markert, Kevin A. Cassady. Oncolytic viral reshaping of the tumor microenvironment to promote CAR T cell therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT541A.