Background: The prognosis for patients (pts) with recurrent (r) glioblastoma (GBM) is poor, with no highly effective approved therapies. Treatment failure may result from poor penetration of drugs through the blood-brain barrier and the immunosuppressive nature of the tumor microenvironment (TME). PVSRIPO, a recombinant poliovirus (PV):rhinovirus chimera, is a novel, non-neurovirulent, intratumoral immunotherapy. Trial results in rGBM pts showed greater long-term survival with PVSRIPO monotherapy (21%, 36-60 months [mos]) vs. criteria-matched external controls (4%, 36 mos; 2%, 60 mos; Desjardins 2018 NEJM). PVSRIPO targets CD155 (PV receptor), expressed on solid tumors and APC. PVSRIPO IT infection results in inflammatory-mediated destruction of tumor cells but non-lethal lingering infection in TME APC. This leads to a type-I/III interferon-dominant inflammation and ultimately, tumor antigen-specific T cell activation and recruitment (Brown 2017 Sci Transl Med), which is potentiated by immunologic recall to intratumoral replicating virus via prior vaccination. Induction of type-1 IFN dominant inflammation and compensatory activation of the PD-1:PD-L1 immune checkpoint (IC) pathway support investigation of PVSRIPO in combination with PD-1/L1 IC inhibitors. Immunologically cold mouse glioma models showed PVSRIPO+anti-PD-1 therapy resulted in greater anti-tumor response than either agent. Trial design/objectives: LUMINOS-101 (NCT04479241) is a phase 2, multicenter, open-label, single-arm study of intratumoral infusion of PVSRIPO (day 1: 5×107 TCID50) followed by the anti-PD-1 monoclonal antibody pembrolizumab (200mg IV q3w) in adult pts with rGBM. The trial objective is to evaluate the anti-tumor activity, safety, and tolerability of the combination. Eligibility criteria: Pts ≥18 years who had prior PV and boost IPOL® immunizations, histologically confirmed supratentorial rGBM, infusible 1 to ≤5.5cm enhancing disease, confirmed disease progression following prior therapies, and KPS ≥70 will be enrolled. Key exclusion criteria include multifocal disease; discontinuation of prior anti-PD-1/L1 agent for toxicity; prior intratumoral therapy, immunotherapy, or radiotherapy within 12 weeks; high-dose systemic corticosteroids; chemotherapy, anti-VEGF, or TTF therapy ≤1-6 weeks depending on the therapy; serious cerebral herniation syndrome; extensive leptomeningeal, subependymal, or ≥1cm enhancing disease crossing the midline; and severe active comorbidities. Endpoints: Primary endpoints are objective response rate, duration of response, and safety. Secondary endpoints include overall and progression-free survival and disease control rate and duration. Exploratory endpoints include assessment of tumor and blood for biomarkers of response. The study is currently enrolling in the US, and results will inform the design of a randomized phase 3 trial.

Citation Format: Andrea True Kelly, Prakash Ambady, Michael Brown, Nicholas Butowski, Robert Cavaliere, William Curry, Annick Desjardins, Lisa Franklin, Henry Friedman, Matthias Gromeier, LeAnn Jackson, Lori Mixson, Shirley Ong, Dina Randazzo, Andrew Sloan, Patrick Wen, Garrett Nichols. LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT240.