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671 Phase 1 trial of human chimeric antigen receptor modified T cells (huCART-meso) administered in combination with oncolytic virus VCN-01 in patients with pancreatic and ovarian cancer
  1. Janos L Tanyi1,
  2. Mark H O’Hara2,
  3. Elizabeth Hexner2,
  4. Amy Marshall2,
  5. Julie Jadlowsky2,
  6. Matthew Ferrara2,
  7. Olivia Farrelly2,
  8. Adam Runkle2,
  9. Anne Chew2,
  10. Emily Dowd2,
  11. Vanessa Gonzalez2,
  12. Joseph A Fraietta2,
  13. Gabriela Plesa2,
  14. Neil C Sheppard2 and
  15. Carl H June3
  1. 1University of Pennsylvania, Media, PA, USA
  2. 2University of Pennsylvania, Philadelphia, PA, USA
  3. 3Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


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)


  1. Guedan S, Alemany R. CAR-T Cells and Oncolytic Viruses: Joining Forces to Overcome the Solid Tumor Challenge. Front Immunol. 2018;9:2460.

  2. McGrath K, Dotti G. Combining Oncolytic Viruses with Chimeric Antigen Receptor T Cell Therapy. Hum Gene Ther. 2021;32(3–4):150–157.

  3. Garcia-Carbonero R, Bazan-Peregrino M, Gil-Martin M, et al. Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors. J Immunother Cancer. 2022;10(3).

  4. Rodriguez-Garcia A, Gimenez-Alejandre M, Rojas JJ, et al. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res. 2015;21(6):1406–1418.

  5. Bazan-Peregrino M, Garcia-Carbonero R, Laquente B, et al. VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects. J Immunother Cancer. 2021;9(11).

  6. Farrera-Sal M, Moreno R, Mato-Berciano A, Maliandi MV, Bazan-Peregrino M, Alemany R. Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation. Mol Ther Oncolytics. 2021;22:27–35.

  7. Haas AR, Golden RJ, Litzky LA, et al. Two Cases of Severe Pulmonary Toxicity from Highly Active Mesothelin-Directed CAR T Cells. Mol Ther. 2023.

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

Abstract 671 Figure 1

Pharmacokinetics of VCN-01 and huCART-meso in the peripheral blood.

Abstract 671 Figure 2

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.

Abstract 671 Table 1

Study Design

Abstract 671 Table 2

Patient Demographics and Disease Characteristics

Abstract 671 Table 3

Response to Combination Therapy

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