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

BackgroundHigh-grade gliomas are fatal with universally poor prognosis. Initiation of effective cancer immune responses requires functional immune cells, particularly afferent antigen-presenting cells, which are typically absent from the brain parenchyma. To overcome this limitation, two adenoviral vectors expressing HSV1-TK and Flt3L were combined to target human gliomas. This first-in-human trial assessed safety, cytotoxicity, and recruitment of immune cells to the brain, in support of a future phase 1b/2 clinical trial. MethodsTreatment-naive high-grade glioma adult patients received injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumor bed, following maximal safe resection, at six escalating doses ranging from a total of 1.1x1010 to a maximum of 2x1011 viral particles. This was followed by two 14-day courses of Valacyclovir and standard upfront chemoradiation. Key inclusion criteria were age between 18 to 75, KPS[≥]70, and treatment-naive possible high-grade glioma amenable to gross total resection. Patients were consented pre-operatively, and definitive enrollment occurred intraoperatively upon pathology confirmation of malignant glioma. FindingsThe treatment was well-tolerated without dose-limiting toxicity in patients with high grade glioma (n=17) (including 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) compared to 14.6 months with standard-of-care, with seven patients surviving for >2 years, three patients surviving for >3 years, and one patient still alive 57 months after enrollment. Tissue from subsequent re-resections from eight subjects showed elevated markers for CD3+, CD8+ T cells, and plasmacytoid dendritic cells (pDCs), suggesting the potential stimulation of anti-glioma immunity. Additionally, we detected biological activity from both viral vectors: (i) an increase in serum levels of Flt3L two weeks after vector administration, and (ii) expression of HSV1-TK in neurons, astrocytes, and SOX2+ cells in brain tumor samples up to 17 months post-vector injection into the brain. InterpretationUse of two adenoviral vectors expressing HSV1-TK and Flt3L appears to be both safe and feasible. Promising evidence from multiplex immunocytochemical analyses shows the presence of the expected immune infiltration, i.e., pDCs, along with persistent vector expression lasting up to 17 months post-injection. Moreover, the two-year survival rate of 38.8% compared to 19.6% with standard-of-care is promising, suggesting that this approach warrants further investigation in a phase 1b/2 clinical trial. FundingFunded 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.