Clinical Activity Of Systemic Vsv-Ifn Beta-Nis Oncolytic Virotherapy In Patients With Relapsed Refractory Hematologic Malignancies

Context This is the first in human Phase 1 dose escalation trial of oncolytic Vesicular Stomatitis Virus (VSV) incorporating interferon beta and sodium iodine symporter transgenes (VSV-IFNβ-NIS) to be administered intravenously in patients with relapsed and refractory hematologic malignancies. Objective The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. The secondary objectives were to determine safety and efficacy of VSV-IFNβ-NIS. Correlative objectives included monitoring viremia and virus shedding. Design This was a 3+3 phase 1 clinical trial from April 2017 to August 2020 including adult patients (pts) with relapsed refractory multiple myeloma (MM), T-cell lymphoma (TCL), or acute myeloid leukemia (AML). Results Fifteen patients received VSV-IFNβ-NIS: MM (7), TCL (7), and AML (1); median age was 64 years, 60% male, and median prior lines of systemic cancer therapies was 5 (range, 2 to 11). Three patients were treated at each dose level (DL) 1 through 3 (respectively 0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL 4 (1.7x1011 TCID50). There were no dose-limiting toxicities. Hematologic AEs, particularly lymphopenia (73%) were the predominant grade 3 and 4 AEs. Non-hematologic AE of interest were grade 1 (6.7%) and 2 (46.6%) cytokine release syndrome, of which only 1 patient required transient norepinephrine support. Objective responses were seen in patients with TCL. There was a 3-month partial response (PR) in a patient treated at DL 2 after 11 prior systemic therapies. However, compelling responses were seen at DL 4 with a deepening 6-month PR in a patient with PTCL and ongoing CR, even 14 months after VSV in another patient with cutaneous relapse of PTCL; both patients received 5 prior lines of therapy. Viremia rapidly declined after infusion, and there was no significant viral shedding. Neutralizing anti-VSV antibodies developed by day 29. IFNβ appeared to indicate intratumoral amplification with TCL patients mounting the highest levels. Conclusions A single intravenous dose of VSV-IFNβ-NIS up to 1.7x1011 is safe in heavily pre-treated patients with hematologic malignancies and appears to be most effective as a single agent at DL 4, especially in patients with TCL. Future trials of combination strategies with immune-modulatory drugs are currently being planned. Grant Acknowledgements Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE), Grohne gifts, Phillips gift, and Liu gift.