First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells

Abstract

Background ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). Methods Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 10 6 plaque-forming units (PFU) to 1.8 × 10 7 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. Results No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients’ blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. Conclusions Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018.

Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms

“…As complement inhibition seems to play a crucial role in virus depletion following intravenous application [22], a new strategy is the application of an anti-C5-antibody (eculizumab) prior to virotherapy [NCT02714374]. Another recent approach to prevent intravascular virus clearance is to administer virus loaded cells as a carrier system for viral particles [23,24]. Reasonable options for NENs constitute intravenous administrations as well as direct virus injections into the hepatic artery in case of liver involvement (NCT02749331, [9];).…”

Oncolytic Viruses in Combination Therapeutic Approaches with Epigenetic Modulators: Past, Present, and Future Perspectives

“…The dose range for ACAM2000 was between 1.4 × 10 6 and 1.8 × 10 7 PFU/mL, administered via intravenous, intra-tumoral and intra-peritoneal injections. This study demonstrated that ACAM2000 was very safe and in some patients led to a substantial tumor size reduction at six months post-treatment, or complete eradication of the solid tumor after three months to treatment [197].…”

Current strategies of virotherapy in clinical trials for cancer treatment

“…Besides this, the evaluation of the antitumor effect for the solid tumor can be conducted more effectively and conveniently by the changes of lesions. However, virotherapy has begun to show its signals of antitumor effect in acute myeloid leukemia (AML) 152 and myeloma 153,154 . Interestingly, favorable results were able to be observed in tumors with different expression of endothelial growth factor receptor (EGFR) or the level of retinoblastoma phosphorylation.…”