In yet another nude mouse study, a single intraperitoneal injection of strain 73-T in mice bearing human neuroblastoma xenografts resulted in complete, durable tumor regressions in 9 of 12 (75%) of the treated mice.
Athymic, nude mice make small numbers of T cells, and they produce interferons, natural killer cells, and macrophages.[11,27,28] It is possible that these residual components of the immune system, which may be activated by the presence of NDV, contributed to the antitumor effects observed in the xenograft studies.
NDV and Cancer Immunotherapy
Other laboratory and animal studies have shown that NDV and NDV-infected cancer cells can stimulate a variety of immune system responses that are essential to the successful immunotherapy of cancer.[6,8,11,21,26,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] A few of these studies used human cells,[6,8,21,30,31,39,42,43,45,48] but most used animal cells and animal tumor models.[6,8,11,21,26,29,31,32,33,34,35,36,37,38,40,44,45,46,47]
Two of these in vitro studies demonstrated that infection of human immune cells with NDV causes the cells to produce and release cytokines interferon-alpha and tumor necrosis factor (TNF)-alpha.[6,8] In one of these studies, infection of human cancer cells with NDV made the cells more sensitive to the cytotoxic effects of TNF-alpha.
Some in vitro studies have shown that NDV-infected human cancer cells are better at activating human cytotoxic T cells, helper T cells, and natural killer cells than uninfected cancer cells.[8,30,31,49] The NDV protein hemagglutinin-neuraminidase, which is present in the plasma membrane of virus-infected cells, appears to play a role in the enhancement of T cell activation. There is evidence that this protein makes infected cells more adhesive, thereby promoting the interaction between virus-infected cells and immune system cells.[21,31]
Laboratory studies have shown that the interaction between NDV-infected cancer cells and T cells can be improved if monoclonal antibodies that bind the hemagglutinin-neuraminidase protein on the cancer cells and either the CD3 protein or the CD28 protein on T cells (i.e., bispecific monoclonal antibodies) are also used.[21,30,39,45,48,50,51] It has been reported that this improved interaction leads to better T cell activation.[21,30,39,45,48] T cells exposed to NDV-infected human colon cancer cells and bispecific monoclonal antibodies showed not only an increased ability to kill the virus-infected cells but also an ability to inhibit the proliferation of uninfected colon cancer cells.[21,30,39] On the basis of these and other in vitro findings, it has been proposed that vaccines consisting of NDV-infected cancer cells and bispecific monoclonal antibodies be tested in humans.[21,30,39,45,48]