Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), and T-Cell Neoplasms (TCL)

Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluati