SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.
Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.
Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.
“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”
“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”
Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.
They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.
The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.
The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.
Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.
For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.
When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.
The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.
Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.
