TMIC-05. ABSCOPAL IMMUNE RESPONSE IN GLIOBLASTOMA ELICITED BY MIR124-ATTENUATED ONCOLYTIC HERPES SIMPLEX VIRUS 1 ARMED WITH UL16 BINDING PROTEIN 3

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2018-11, Vol.20 (suppl_6), p.vi256-vi257
• Main Authors: Wirsching, Hans-Georg, Zhang, Huajia, Grandi, Paola, Arora, Sonali, Cimino, Patrick J, Campbell, Jean S, Szulzewsky, Frank, Pattwell, Siobhan S, Ene, Chibawanye, Kumasaka, Debrah, Pierce, Robert H, Finer, Mitchell, Queva, Christophe, Houghton, A McGarry, Holland, Eric
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy148.1065

Abstract Glioblastoma is a deadly disease with median survival ranging below one year. T-cell-based immunotherapy approaches failed to prolong survival of glioblastoma patients in two phase III clinical trials, thus reflecting the immunologically inert features of glioblastoma. Pre-clinical efficacy of oncolytic virus therapy in combination with immune checkpoint inhibition was demonstrated in syngeneic glioblastoma models. However, given the extensive spreading of glioblastoma cells throughout the brain, we hypothesized that efficacious immunotherapy approaches in patients will need to elicit abscopal responses, i.e. the secondary targeting of tumor cells at sites distant from treated lesions. We addressed this issue in an immune competent RCAS/tv-a-based genetic glioblastoma model that recapitulates the genotype, gene expression, histology and immune phenotype of human glioblastomas. Spatial distance of virus-treated and untreated glioblastoma lesions was modeled by generating two tumors in both hemispheres of N/tv-a;Ink4a/Arf-/-;PTENfl/fl;LucLSL/LSLmice. One tumor was generated by transduction with RCAS-Pdgfb and RCAS-shPTEN. A second, contralateral tumor was generated with RCAS-Pdgfb and RCAS-Cre, thus enabling additional monitoring of tumor growth through luciferase activity. We infected luciferase-negative tumor lesions with a miR-124-attenuated oncolytic herpes simplex virus 1 (oHSV) armed with the NKG2D ligand ULBP3. oHSV-ULBP3 infection slowed the growth of distant, non-infected glioblastoma lesions and prolonged survival. oHSV-ULBP3 led to influx and activation of T-cells in both, treated and untreated glioblastoma lesions. Massive influx of monocytes yielded an increase of mostly PD1+ macrophages in both tumors. Neutrophils were also increased ubiquitously, whereas NK-cells were suppressed. Treatment with an anti-PD1 antibody alone had no effect, but combination with oHSV-ULBP3 counteracted macrophage and neutrophil influx and enhanced abscopal anti-tumor responses. We conclude that oHSV-ULBP3 in combination with anti-PD-1 is a feasible approach to induce abscopal T-cell-mediated immune responses in glioblastoma. Unraveling the role of myeloid components of the tumor microenvironment may be critical to overcome resistance to such treatment.