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Combined Cytotoxic and Immune Therapy for Primary Adult High-Grade Glioma

BACKGROUND: High-grade gliomas are fatal with universally poor prognosis. Initiation of effective cancer immune responses requires functional immune cells, especially afferent antigen presenting cells, which are absent from the brain parenchyma.1,2 To address this requirement, two adenoviral vectors expressing HSV1-TK and Flt3L were combined to target human gliomas. This first in human trial assessed safety, cytotoxicity, and immune recruitment to the tumor. METHODS: Eighteen treatment-naive adults with high-grade glioma received injections of HSV1-TK- and Flt3L-expressing adenoviral vectors to the tumor bed after maximal safe resection, at six escalating doses (total 1.1x1010-2x1011 vp), followed by two 14-day courses of valacyclovir, and standard upfront chemoradiation. Key inclusion criteria were: age 18-75, KPS [≥]70, and treatment-naive high-grade glioma amenable to gross total resection. Patients were consented pre-operatively. Enrollment occurred intraoperatively, upon pathology confirmation. RESULTS: The treatment was well tolerated without dose-limiting toxicity in patients with glioblastoma (n=17) (3 of the gliosarcoma variant), or anaplastic ependymoma (n=1). The maximal-tolerated dose was not reached. The median overall-survival was 21.3 months (95%CI: 11.1, 26.1). Tissues from subsequent resections from 8 subjects showed elevated markers for CD3+ and CD8+ T cells indicating potential successful anti-glioma immunity recruitment. Multiplex immunohistochemistry on two patients indicated a change in the intratumoral redistribution of CD8+ T cells and microglia/macrophages. CONCLUSIONS: Use of two adenoviral vectors expressing HSV1-TK and Flt3L is safe and well tolerated in newly diagnosed high-grade glioma patients. Promising multiplex immunocytochemical evidence of immune infiltration warrants further efficacy studies, possibly in combination with blockade of the inhibitory tumor microenvironment. (Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, and The Rogel Cancer Center at The University of Michigan; clinicaltrials.gov: NCT01811992)