Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma

Abstract

Background: Gene-mediated cytotoxic immunotherapy (GMCI) is a tumor-specific immune stimulatory strategy implemented through local delivery of aglatimagene besadenovec (AdV-tk) followed by anti-herpetic prodrug. GMCI induces T-cell dependent tumor immunity and synergizes with radiotherapy. Clinical trials in adult malignant gliomas demonstrated safety and potential efficacy. This is the first trial of GMCI in pediatric brain tumors.

Methods: This phase I dose escalation study was conducted to evaluate GMCI in patients 3 years of age or older with malignant glioma or recurrent ependymoma. AdV-tk at doses of 1 × 1011 and 3 × 1011 vector particles (vp) was injected into the tumor bed at the time of surgery followed by 14 days of valacyclovir. Radiation started within 8 days of surgery, and if indicated, chemotherapy began after completion of valacyclovir.

Results: Eight patients (6 glioblastoma, 1 anaplastic astrocytoma, 1 recurrent ependymoma) were enrolled and completed therapy: 3 on dose level 1 and 5 on dose level 2. Median age was 12.5 years (range 7-17) and Lansky/Karnofsky performance scores were 60-100. Five patients had multifocal/extensive tumors that could not be resected completely and 3 had gross total resection. There were no dose-limiting toxicities. The most common possibly GMCI-related adverse events included Common Terminology Criteria for Adverse Events grade 1-2 fever, fatigue, and nausea/vomiting. Three patients, in dose level 2, lived more than 24 months, with 2 alive without progression 37.3 and 47.7 months after AdV-tk injection.

Conclusions: GMCI can be safely combined with radiation therapy with or without temozolomide in pediatric patients with brain tumors and the present results strongly support further investigation.

Clinical trial registry: ClinicalTrials.gov NCT00634231.

Keywords: gene therapy; glioblastoma; immuno-oncology; immunotherapy; viral therapy.

Fig. 1

Schematic of GMCI mechanism of action. GMCI synergizes with surgery and radiation, generating activated T cells that kill tumor cells left after tumor debulking by SOC. The GMCI mechanism includes 3 steps to induce an antitumor immune response: (1) AdV-tk (aglatimagene besadenovec) in tumor cells converts valacyclovir prodrug into nucleotide analogs that kill tumor cells, releasing tumor associated antigens; (2) the presence of the injected virions and the cell death through both necrosis and apoptosis generate “danger signals” which attract and stimulate antigen presenting cells (APCs) such as dendritic cells; and (3) the vector-expressed TK protein functions as a super-antigen that leads to a hyper-immunogenic microenvironment with STING pathway activation and production of proinflammatory cytokines, such as interleukin (IL)-2 and IL-12, with consequent antitumor T-cell stimulation and proliferation.

Fig. 2

Study design. AdV-tk was injected at the time of surgery into the surgical wall. Valacyclovir was administered for 14 days starting on days 1–3. Radiation was started 3–8 days after AdV-tk injection to overlap with AdV-tk activity and valacyclovir administration. If indicated, temozolomide was administered after completing valacyclovir.

Fig. 3

CONSORT diagram of patient enrollment. All 8 patients enrolled completed the study.

Fig. 4.

Kaplan‒Meier analysis of overall survival and progression-free survival. (A) Median OS was 8.9 months for dose level 1 and 25.3 months for dose level 2. (B) Median PFS was 5.8 months for dose level 1 and 8.9 months for dose level 2.