Pre-Clinical Data and Preliminary Patient Results of Intravenous MV-NIS To Treat Relapsed, Refractory Multiple Myeloma.

Background: MV-NIS is an Edmonston-lineage measles virus that expresses the human sodium-iodide symporter (hNIS). The virus is oncolytic, and its activity can be monitored by noninvasive imaging of radioiodine uptake by hNIS. The receptor is CD46, a membrane regulator of complement activation that is overexpressed on myeloma cells.

Methods: Formal studies were done in collaboration with the RAID program to assess the efficacy, biodistribution and safety of MV-NIS in transgenic, measles susceptible mice and in non-human primates. The protocol therapy for the animal studies was modeled on the planned human clinical trial. Mouse efficacy studies were done in irradiated 6-week old female CB17 ICR SCID mice implanted subcutaneously with human KAS-6/1 cells. Mouse toxicity & biodistribution were done in 184 6–8 week Ifnar^KO x CD46 Ge mice treated with 10⁵–10⁷ TCID₅₀ MV-NIS. Squirrel monkey toxicity studies were done in 12 measles-naïve adults with 10⁸ TCID₅₀. The clinical trial is a 3 patient/cohort dose escalation study which allows for 1 dose of MV-NIS/patient. Once MTD of MV-NIS is reached, subsequent cohorts will be treated with CTX 10 mg/kg 2 days prior to MV-NIS at MTD/100. Immune response to measles is tested pre & post therapy. PK & biodistribution are tested by measurements of MV-N in blood, urine, & gargle samples and by serial nuclear imaging, respectively. BM myeloma cells are tested for CD46 expression and MV infectivity.

Results: Preclinical studies: The minimum effective dose in the mouse model was 4 x 10⁶ TCID₅₀ /kg. The MTD for MV-NIS with CTX was not reached in the mouse study. Pre-treatment with CTX changed the biodistribution of MV-NIS infected cells and the kinetics of virus elimination from infected tissues in mice and monkeys. In monkeys, MV-N mRNA was detected at day 1 in the buccal cavity with levels declining on day 2, then surging on day 8, suggesting viral replication. There were no unscheduled deaths or treatment related lesions on necropsy.

Patients: Three patients were treated with a dose of 10⁶ TCID₅₀ (Table). No DLT was observed. Two patients had MV-N amplified from their gargle specimen. Accrual to dose level 2 has begun.

Conclusions: IV administration of MV-NIS is feasible. The virus is capable of traveling to a distant site and replicating before being cleared by the immune system.