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Abstract
Background Preclinical combinations of CAR-T therapies with oncolytic viruses have shown promise,1 2 but thus far no clinical data are available. Here we report interim results for three patients with epithelial ovarian- and pancreatic cancer treated with an intravenous infusion of VCN-01, an investigational PH20 hyaluronidase-armed oncolytic virus3 followed by autologous T cells transduced to express a chimeric antigen receptor directed against mesothelin (huCART-meso) from an ongoing Phase I study.
Methods VCN-01 is a genetically modified, oncolytic adenovirus with tumor tropism enhanced by an integrin-binding motif and selective replication in pRB-defective cells.4 It encodes, PH20 hyaluronidase to degrade tumor hyaluronan and might thereby increase tumor penetrance of coadministered therapies.4–6 HuCART-meso are autologous T cells transduced with a fully humanized chimeric antigen receptor composed of anti-mesothelin ‘M5’ ScFv fused to 4–1BB and TCRzeta signaling domains.7 This is a phase I trial to establish safety and feasibility of the combination of VCN-01 and huCART-meso (table 1).
Results Three patients (table 2) received combination therapy at their assigned dose and no dose limiting toxicities observed. One subject experienced cytokine release syndrome (CRS), grade 2 in severity and lasting 2 days. No neurotoxicity was observed. Transient grade 3 anemia and lymphopenia were observed, and AST elevation, as expected from VCN-01. There was no grade 4 or higher adverse events. All three patients were retreated with huCART-meso cells via IV infusion post-Month 2. VCN-01 and huCART-meso were detected in the peripheral blood for extended periods (figure 1). The two patients with measurable disease (both with ovarian cancer) showed SD up to 150 and 300 days with the biggest decrease of disease volume 15% and 29.1% respectively by RECIST criteria (figure 2 and table 3).
Conclusions A regimen of IV delivery of 3.3 x 1012 VP VCN-01 followed 14 d later by 5 x 107 huCART-meso T cells is feasible and appears safe. Repeat dosing with huCART-meso post-Month 2 is also feasible. VCN-01 persistence suggests tumor infection and active replication. The peak and duration of huCART-meso T cells in the peripheral blood as well as duration of stable disease in evaluable patients show encouraging trends. The study will test higher doses of VCN-01 and will interrogate tumor biopsies to gain further insights. The results will inform and guide optimization of the combination of CAR T cells with oncolytic virus.
Acknowledgements We wish to acknowledge the clinical trial patients and their families, Theriva Biologics for providing VCN-01, and the members of the Clinical Trials Unit at the Abramson Cancer Center. Funding – UPenn private funds.
Trial Registration NCT05057715 (trial in progress)
References
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Ethics Approval University of Pennsylvania, Institutional Review Board, Federalwide Assurance: 00004028; Confirmation #: dgjegcid; Protocol Number: 849937\28-September 2022
Consent PC4b-03821-VCN-01=M5 Main IFC V3.12.03.2021
Pharmacokinetics of VCN-01 and huCART-meso in the peripheral blood.
Response to Combination Therapy. Change in tumor volume from baseline (%) is shown for the two patients with disease measurable by RECIST. Timepoints for infusion of VCN-01, huCART-meso (first dose) and huCART-meso retreatment are shown.
Study Design
Patient Demographics and Disease Characteristics
Response to Combination Therapy
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