FROM LEUKEMIA
Reovirus, a naturally occurring oncolytic virus, appears to exert direct cytotoxic activity against chronic lymphocytic leukemia (CLL) and “phenotypically and functionally” activates patient natural killer cells using a monocyte-derived interferon alpha–dependent mechanism, according to preclinical data published in Leukemia.
Reovirus also enhances antibody-dependent cellular cytotoxicity – mediated killing of CLL cells in combination with anti-CD20 antibodies.
“Reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL … and now warrants clinical evaluation,” wrote Christopher Parrish, Ph.D., of the Leeds (England) Institute of Cancer and Pathology and his colleagues (Leukemia. 2015;29:1799-1810. doi: 10.1038/leu.2015.88).Reovirus is a naturally occurring double-stranded RNA virus, and it exerts its effects against cancer cells by direct oncolysis and activation of antitumor immunity. The researchers investigated the efficacy of reovirus for the treatment of CLL, both as a direct cytotoxic agent and as an immunomodulator, using CLL cell lines and primary CLL cells from 24 patients.
Dr. Parrish and his team treated human CLL cells with live or UV-inactivated reovirus for 7 days. They assessed the ability of reovirus to stimulate immune-mediated killing of CLL using peripheral blood mononuclear cells from healthy volunteers and CLL patients. Reovirus activated natural killer (NK) cells from CLL patients, as well as stimulating innate antitumor immunity.
Rituximab, which is believed to act in part via NK cell–mediated antibody-dependent cellular cytotoxicity, was added to peripheral blood mononuclear cells that were treated with reovirus. Compared with rituximab alone, reovirus treatment significantly increased NK-cell CD107a/b degranulation. Reovirus was then paired with ofatumumab and GA101 to see if the effects observed with reovirus/rituximab could be translated to other anti-CD20 antibodies in which NK cells also play a role. The results were similar.
Absolute monocyte count and the type 1 interferon-alpha response could be used to predict the generation of antitumor innate immunity by reovirus. In cells from 24 CLL patients, about 75% responded to reovirus, with NK-cell activation. Further, NK-cell activation correlated with absolute monocyte count. The role of interferon-alpha is further supported by identification of an interferon gene signature within NK cells from reovirus-treated patients, the researchers said.
The study was supported by Yorkshire Cancer Research and Cancer Research UK. One of the investigators is an employee of Oncolytics Biotech and holds company stock and options. All the other authors declared no conflicts of interest.
