For patients with Merkel cell carcinoma (MCC), outcomes are typically poor and therapeutic options are limited, but advances in understanding MCC’s biology and in the emergence of cutting-edge treatments are expected to improve the outlook in this tumor type, according to speakers at the 3rd Annual World Cutaneous Malignancies Congress (San Francisco, 2014).
Isaac Brownell, M.D., Ph.D., head of the cutaneous development and carcinogenesis section at the National Cancer Institute, described exciting work being done in understanding the polyomavirus (MCPyV) in MCC.
At least 10% of all cancers are driven by viruses, and in 2008 MCC joined this list when approximately 80% of MCC tumors were found to harbor the MCPyV. According to Dr. Brownell, genes in the polyomavirus family express T antigens that allow the virus to co-opt the machinery of the cell, make new viral DNA, and potentially cause cancers.
“We thought we had this nailed down, that MCPyV infection equals MCC, but it’s not that simple,” he says.
Most MCPyV infections are subclinical and not oncogenic, and most adults have circulating antibodies that indicate prior infection. For cancer to develop, however, two other things must occur: Virus DNA must become integrated into the genome of the tumor, and a mutation in the large T antigen must make the virus replication deficient. Interaction with the immune system seals the deal when the host has a loss of protective immunity, for example, because of advanced age. This potentially allows the virus to expand, integrate, mutate, and spur the uncontrolled growth of the tumor, he explains.
While 80% of tumors are virus-positive, the prognostic implications of MCPyV status remain “questionable,” he says. Some studies have found that virus-positive tumors fare better than negative ones, but other studies have contradicted this.
“The jury is still out on this,” he notes. It is not necessary, therefore, to test for the presence of the virus.
On the other hand, a serological assay for antibodies against the small T antigen of MCPyV could help detect recurrence and allow for prompt treatment of progressive disease. Up to 50% of newly diagnosed MCC patients have antibodies that recognize the T-antigen, but such oncoprotein antibodies are virtually never present in healthy individuals — despite the fact that most people harbor the virus on their skin. Titers are stable or reduced in MCC patients after treatment, but they increase by 20% or more in patients who progress.
The determination of MCPyV status may also, someday, become relevant in terms of treatment. About half of MCC patients have circulating T-cells that are MCPyV-reactive. This could be leveraged for autologous T-cell therapy.