Anticancer Virotherapy May Be Better If Backed by Natural Killer Overkill

They did the math and then checked their work – not on paper or in a computer program, but in preclinical tests – to confirm that their immunotherapy proposal added up. The proposal, offered by scientists based at UTHealth, the University of Texas Health Science Center at Houston, was that oncolytic viruses and externally supplied natural killer (NK) cells won’t necessarily work at cross-purposes, as other studies have suggested. Instead, NK cells can improve the cancer-fighting efficiency of virotherapy.

NK cells, which comprise part of the innate immune system and help protect the body from cancer, tend to stick to their main function – fighting infections such as viruses – even if those viruses preferentially infect and kill cancer cells. Consequently, virotherapy may be expected to become more effective if NK cells are depleted. Yet the math done by the UTHealth scientists suggested that virotherapy could also get a boost if NK cells were superabundant.

This counterintuitive idea was developed through mathematical modeling that unlocked the complex interactive relationship between externally introduced viruses and NK cells and the immune system’s existing NK cells to calculate cancer cell-killing potency. The mathematical modeling predicted how a virus-treated tumor would respond to NK cell therapy, depending on the number of NK cells introduced.

Results appeared in the Proceedings of the National Academy of Sciences (PNAS) article entitled “Complex Role of NK Cells in Regulation of Oncolytic Virus-Bortezomib Therapy.” This article showed that when the number of externally introduced NK cells is increased, the ability to fight cancer is strengthened.

“…we investigated the role of natural killer (NK) cells in combination therapy with an oncolytic virus (OV) and bortezomib, a proteasome inhibitor,” the article’s authors wrote. “We developed a mathematical model to address the question of how the density of NK cells affects the growth of the tumor. We found that the antitumor efficacy increases when the endogenous NKs are depleted and when exogenous NK cells are injected into the tumor.”

While the patient’s own NK cells, present in smaller numbers, concentrate on clearing the virus and therefore hurt virotherapy by limiting the virus’s cancer-busting power, this impact can be reversed to destroy more of the tumor by introducing greater numbers of external NK cells. These NK cells display rapid and potent immunity to metastatic and hematological cancers, and they overcome the immunosuppressive effects of the tumor microenvironment.

The theory behind scientists’ equations was subsequently confirmed in practice by experiments on mice with brain tumors, paving the way for further work.

“This research is very exciting because it helps unravel the complex yin and yang relationship between the natural cancer-fighting power intrinsic to our immune system and externally added cancer-killing cells that are given as a therapy,” said the study’s corresponding author Balveen Kaur, Ph.D., professor and vice chair of research in the Vivian L. Smith Department of Neurosurgery at McGovern Medical School at UTHealth. “It’s significant because it shows, contrary to recent scientific claims, that virotherapy can be combined with cell therapy for a positive effect.”

“Natural NK cells sense and kill infected cancer cells, thus clearing viruses. But by adding exogenous NK cells in sufficient quantities, they can also destroy the residual tumor. Our tests showed when you get this ratio right; there’s a significant improvement in cancer-fighting efficacy. So, it’s a big step forward, which should create more opportunities for further research and development of clinical trials for treating cancer in humans and animals.”