Abstract

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 IfnarKO 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.

Patient 2Patient 2Patient 3
*copies per microgram RNA of cells derived from gargle sample at each time point: day +3, +8, +15, +22, and +29; no MV-N detected in urine or blood 
Anti-measles neutralizing Ab titer, pre-Rx / post Rx 1:10 / 1:160 < 1:10 / 1:20 < 1:10 / 1:10 
AEs possibly related Gr 2 plts Gr 1 plts, cough, fever, rigors Gr 2 Incr aPTT 
CD46 copies/cell CD138+ / CD138- BMPC 79,771 / 10,322 140,187 / 10,145 28,258 / 11,228 
MV-N QRT-PCR: d3/ d8/ d15/ d22/ d29 (cp/ug RNA)* −/ −/ −/ nd / nd −/ −/ 16,440 / 1405 / −  
123-I uptake on SPECT No Uptake day 8 No 
Patient 2Patient 2Patient 3
*copies per microgram RNA of cells derived from gargle sample at each time point: day +3, +8, +15, +22, and +29; no MV-N detected in urine or blood 
Anti-measles neutralizing Ab titer, pre-Rx / post Rx 1:10 / 1:160 < 1:10 / 1:20 < 1:10 / 1:10 
AEs possibly related Gr 2 plts Gr 1 plts, cough, fever, rigors Gr 2 Incr aPTT 
CD46 copies/cell CD138+ / CD138- BMPC 79,771 / 10,322 140,187 / 10,145 28,258 / 11,228 
MV-N QRT-PCR: d3/ d8/ d15/ d22/ d29 (cp/ug RNA)* −/ −/ −/ nd / nd −/ −/ 16,440 / 1405 / −  
123-I uptake on SPECT No Uptake day 8 No 

Author notes

Disclosure: No relevant conflicts of interest to declare.