Abstract CT018: Phase I immunovirotherapy trial of oncolytic HSV-1 G207 alone or combined with radiation in pediatric high-grade glioma

Abstract

Introduction: Pediatric high-grade gliomas (pHGGs) are routinely fatal with a median overall survival (OS) at recurrence of 5.6 months (mos). A safe, effective immunotherapy for pHGG has eluded investigators. Oncolytic HSV-1 G207 contains mutations that prevent a productive infection of normal cells but permit replication in tumor cells. In addition to direct tumor cell lysis, G207 activates innate/adaptive immune cells and promotes cross-presentation of tumor antigens to generate an anti-tumor immune response. A 5 Gy radiation dose increases viral replication and spread. We evaluated the safety and efficacy of G207 alone and combined with radiation in children with progressive supratentorial HGG (NCT02457845). Methods: We employed a 3 + 3 design with 4 cohorts. Children 3-18 years old with biopsy-confirmed HGG underwent stereotactic placement of up to four intratumoral catheters. The next day, we administered 107 or 108 plaque-forming units (pfu) of G207 by controlled rate infusion over 6 hours. Within 24 hours of G207, patients in dose level 3 and 4 received 5 Gy to the gross tumor volume. The primary objective was safety/tolerability. We assessed secondary objectives of virus shedding in blood, saliva and conjunctiva by PCR, response by MRI and evaluation of matched pre- and post-G207 tissue for tumor-infiltrating lymphocytes (TILs), and seroconversion by immunofluorescence assay. Results: 12 patients (age range 7-18) with progressive, IDH wild-type pHGG received G207. At screening, 10 patients had tumors with a bi-perpendicular sum ≥ 5.5 cm, 3 had multi-focal disease, 8 had failed ≥ 2 prior treatment regimens, and 4 had failed ≥ 3 regimens. 3-4 catheters (44 total) were placed safely throughout the cerebrum and resulted in no neurologic sequelae. G207 alone or with radiation was safe and tolerable in all patients with no dose-limiting toxicities, attributable grade 3 or 4 toxicities/serious adverse events, or evidence of virus shedding. 11 participants had radiographic, neuropathologic, and/or clinical responses. Median OS was 12.2 mos (95% CI 8.0, 16.4). Thus far, 36% of patients have lived >18 mos, the median OS for newly diagnosed pHGG. Compared to patients who seroconverted post-G207 (n=3), patients with baseline HSV-1 antibodies (n=3) had a shorter median survival: 5.1 mos (3.0, 7.2) vs 18.3 mos (9.2, 27.4). G207 significantly increased CD4+ and CD8+ TILs. Conclusions: G207 alone and combined with radiation was tolerable and safe with evidence of responses in children with pHGG. The promising median OS (12.2 mos) compares favorably with historical data (5.6 mos). Baseline HSV-1 seropositivity and seroconversion are potential biomarkers of treatment response that require further investigation. Importantly, G207 converted ‘cold' tumors to ‘hot' with a dramatic increase in TILs. A multi-institutional Phase II clinical trial of G207 in pHGG is forthcoming (NCT04482933). Citation Format: Gregory K. Friedman, James M. Johnston, Asim K. Bag, Joshua D. Bernstock, Rong Li, Inmaculada Aban, Kara Kachurak, Li Nan, Kyung-Don Kang, Stacie Totsch, Charles Schlappi, Allison M. Martin, Devang Pastakia, Sameer Farouk Sait, Yasmin Khakoo, Matthias A. Karajannis, Karina Woodling, Joshua D. Palmer, Diana S. Osorio, Jeffrey Leonard, Mohamed S. Abdelbaki, Avi Madan-Swain, T. Prescott Atkinson, Richard J. Whitley, John B. Fiveash, James M. Markert, G. Yancey Gillespie. Phase I immunovirotherapy trial of oncolytic HSV-1 G207 alone or combined with radiation in pediatric high-grade glioma [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 CT018.

Oncolytic virotherapy: Potentially a game-changing tumor treatment

“…Four patients, one from each treatment group, underwent post-treatment surgery, and this allowed for the comparison of post-treatment tissue with the tissue of the initial treatment-naive tissue, which demonstrated a robust increase in CD3+, CD4+, and CD8+ lymphocytes, mainly from a very low baseline level, and no evidence for active HSV-1 G207 infection. The immunological response, as the clinical response, was not associated with either virus titers or radiotherapy; however, OS negatively correlated with baseline HSV-1 antibodies as a result of prior HSV infections, and serum conversion after HSV-1 G207 local administration, in oftentimes negative younger patients, was positively correlated with OS (Friedman et al, 2021).…”

“…Non-hypermutated tumors are deemed immunologically ''mute'' or ''cold,'' i.e., they have hardly any mutations or neo-antigens as targets, and accordingly only a few lymphocytes migrate into the tumor tissue. On the tumor cell level, factors enhancing the likelihood of CPI efficacy include the presence of immunogenic mutations, which may be created by infection of the tumor cells with an oncolytic HSV-1 (Friedman et al, 2021) or vaccines against tumor-specific or mutated antigens (Hilf et al, 2019); in the TME, type I interferons (IFNs) are key to establish an antitumor response (Zitvogel et al, 2015). Because systemic type I IFNs have unwanted effects, local stimulation of type I IFNs by agonists of viral nucleic acid cellular sensors, such as RIG-1, STING, or TLR3, or the direct use of replicating viruses (Friedman et al, 2021) triggers immunogenic cell death and thereby ''heats up'' the TME.…”

“…On the tumor cell level, factors enhancing the likelihood of CPI efficacy include the presence of immunogenic mutations, which may be created by infection of the tumor cells with an oncolytic HSV-1 (Friedman et al, 2021) or vaccines against tumor-specific or mutated antigens (Hilf et al, 2019); in the TME, type I interferons (IFNs) are key to establish an antitumor response (Zitvogel et al, 2015). Because systemic type I IFNs have unwanted effects, local stimulation of type I IFNs by agonists of viral nucleic acid cellular sensors, such as RIG-1, STING, or TLR3, or the direct use of replicating viruses (Friedman et al, 2021) triggers immunogenic cell death and thereby ''heats up'' the TME. Nectin-1, which binds HSV-1 glycoprotein D and thereby is thought to facilitate viral cell entry, is more highly expressed in pHGG compared to adult high-grade gliomas, making children and adolescents a suitable target population for the HSV-1 virotherapy, but also demanding assessment as biological inclusion factor.…”

“…As in this trial, concepts in early development, such as HSV-1 virotherapy (Friedman et al, 2021), are likely to be tested in intensively pretreated patients. Their tumors show features of the natural course of progression as well as features of the prior genotoxic treatments.…”

Translational landscape of glioblastoma immunotherapy for physicians: guiding clinical practice with basic scientific evidence

“…G207 has also been studied in pediatric high-grade gliomas, as recently published by Friedman and colleagues as a phase I clinical trial. They treated 12 patients, with or without radiation, via intratumoral infusion with G207, and found clinical responses in 11 of 12 patients, with median overall survival of 12.2 months and 4 of 11 patients still alive at 18-month follow-up [ 216 , 217 ]. The data from this trial informed a larger phase II clinical trial currently ongoing [NCT04482933].…”