Clinical Activity of Single Dose Systemic Oncolytic VSV Virotherapy in Patients with Relapsed Refractory T-Cell Lymphoma
Joselle Cook, Kah Whye Peng, Thomas E. Witzig, Stephen M. Broski, José C. Villasboas, Jonas Paludo, Mrinal M. Patnaik, S. Vincent Rajkumar, Angela Dispenzieri, Nelson Leung, Francis K. Buadi, N. Nora Bennani, Stephen M. Ansell, Lianwen Zhang, Nandakumar Packiriswamy, Baskar Balakrishnan, Bethany Brunton, Marissa Giers, Brenda Ginos, Amylou C. Dueck, Susan M. Geyer, Morie A. Gertz, Rahma Warsame, Ronald S. Go, Suzanne R. Hayman, David Dingli, Shaji Kumar, P. Leif Bergsagel, Javier Muñoz, Wilson I. Gonsalves, Taxiarchis Kourelis, Eli Muchtar, Prashant Kapoor, Robert A. Kyle, Yi Lin, Mustaqeem Siddiqui, Amie Fonder, Miriam Hobbs, Yi L. Hwa, Shruthi Naik, Stephen J. Russell, Martha Q. Lacy
Abstract
Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-β (IFN-β) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNβ-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 × 1011 TCID50), and 6 were treated at DL4 (1.7 × 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-β, a biomarker of VSV-IFNβ-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-β of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL, resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. This trial is registered at www.clinicaltrials.gov as #NCT03017820.