Lymphoma Immunotherapy Study Shows Why UW Carbone is a Leader in Cancer Virology
It may seem odd at first that there are researchers at the UW Carbone Cancer Center who study viruses, those tiny particles that do not develop cancer themselves because they are not even alive. But when they infect human cells, a subset of viruses can cause their host to develop cancer.
There are 12 Carbone Cancer Center faculty who study how viruses lead to cancer in humans and how those cancers can be prevented or treated. Even one small family of viruses known as the herpesviruses, some of which cause cancers, is studied by over half a dozen professors at the university, making UW a leader in the field. Reflecting this research strength, Madison was selected as the site for the 41st annual International Herpesvirus Workshop, to be held July 23-27.
"It is the meeting for herpesvirus researchers, and we were selected because we have many famous herpesvirologists here," said Shannon Kenney, MD, professor of medicine and oncology at the Cancer Center and the McArdle Laboratory for Cancer Research. "During this conference, one of the symposia will focus solely on the role of the viruses in cancer."
Kenney's research lab focuses on the Epstein-Barr virus (EBV) and how its infection of the immune system's B cells can lead to some blood cancers. Almost all adults have already been infected with EBV, a virus that is usually symptomless but can cause diseases such as mononucleosis. Like all herpesviruses, including chicken pox and herpes simplex viruses, EBV remains in cells permanently after infection and can reactivate, though most people's immune system T cells prevent the virus from causing disease symptoms.
Recently, Kenney and other UW colleagues investigated the role of immunotherapy in treating EBV-caused lymphomas. A type of therapy known as immune checkpoint inhibition has shown clinical success with some cancers, and mounting evidence suggests that the more mutations a cancer has, the better checkpoint inhibition works.
“Even in the absence of cellular mutations, virus-infected tumor cells produce a number of viral proteins that allow T cells to recognize these cancer cells as targets for destruction, and thus virally-infected cancers should be the best-case scenario for immune checkpoint therapy to work," Kenney said. "But for reasons that haven't been clear to us, immunocompetent people can develop cancers that have Epstein-Barr virus because their T cells are not working well."
Kenney's lab previously developed a mouse model of EBV-caused cancers to better understand the disease. Mice lacking any immune system are given newborn cord blood containing a competent but naive immune system. In some cases, the cord blood has been infected with EBV, and all those mice develop B cell lymphomas. The researchers found that the T cells were able to recognize the infected B cells, but something was preventing the T cells from killing off all the cancer cells.
"First, we showed in this model that the EBV-infected B cells were expressing immune checkpoint proteins that are known to inhibit the T cell response, " Kenney said. "Next, we showed that if the mice are given a class of FDA-approved drugs which block the action of the immune checkpoint inhibitors, then the T cells are much better at killing the tumor cells and the tumors are much smaller."
Because the T cells were attacking tumor cells, the mice given the checkpoint inhibitors did survive longer than non-treated mice, though all eventually succumbed to the disease. This one study, though, was asking if immunotherapy treatment could improve the T cell response to EBV cancers, not if it could singly cure B cell lymphomas.
"In a clinical setting, clinicians would usually try to decrease the size of the tumor with chemotherapy, surgery or other therapies in combination with the checkpoint therapy," Kenney said.
The study, published in the journal PLoS Pathogens, was conducted by members of Kenney's research group as well as that of Carbone Cancer Center faculty member Jenny Gumperz, PhD, associate professor of medical microbiology and immunology.
Date Published: 07/05/2016