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Lancet Oncology, The

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Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial - 30/08/23

Doi : 10.1016/S1470-2045(23)00347-9 
Yoshie Umemura, MD a, Daniel Orringer, MD b, Larry Junck, ProfMD a, Maria L Varela, PhD b, c, d, Molly E J West, MS b, c, d, Syed M Faisal, PhD b, c, d, Andrea Comba, PhD b, c, d, Jason Heth, ProfMD b, Oren Sagher, ProfMD b, Denise Leung, MD a, Aaron Mammoser, MD a, Shawn Hervey-Jumper, MD b, Daniel Zamler, BS b, Viveka N Yadav, PhD b, Patrick Dunn, BS b, Wajd Al-Holou, MD b, Todd Hollon, MD b, Michelle M Kim, MD e, Daniel R Wahl, MD e, Sandra Camelo-Piragua, ProfMD f, Andrew P Lieberman, ProfMD f, Sriram Venneti, MD f, Paul McKeever, ProfMD f, Theodore Lawrence, ProfMD e, Ryo Kurokawa, MD g, Karen Sagher, BS b, David Altshuler, MD b, Lili Zhao, PhD i, Karin Muraszko, ProfMD b, Maria G Castro, ProfPhD b, c, d, Pedro R Lowenstein, ProfMD PhD b, c, d, h, ⁎
a Department of Neurology, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
b Department of Neurosurgery, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
c Department of Cell and Developmental Biology, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
d The Rogel Cancer Center, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
e Department of Radiation Oncology, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
f Department of Pathology, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
g Department of Radiology, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA 
h Department of Biomedical Engineering, University of Michigan School of Engineering, University of Michigan, Ann Arbor, MI, USA 
i Department of Biostatistics, The University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA 

* Correspondence to Prof Pedro R Lowenstein, Department of Neurosurgery, The University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109-0650, USA Department of Neurosurgery The University of Michigan Medical School University of Michigan Ann Arbor MI 48109-0650 USA

Summary

Background

High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma.

Methods

In this dose-finding, first-in-human trial, treatment-naive adults aged 18–75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1–3 days and 10–12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992.

Findings

Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3–4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1–26·1).

Interpretation

The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial.

Funding:

Funded in part by Phase One Foundation, Los Angeles, CA; The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA; The Rogel Cancer Center at The University of Michigan; and the National Cancer Institute, National Institutes of Health.

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Vol 24 - N° 9

P. 1042-1052 - septembre 2023 Retour au numéro
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