Affecting about 1,500 Americans per annum, Merkel cell carcinoma is a rare yet aggressive type of skin cancer. Experts from the University of Washington, Emory University, Atlanta and Johns Hopkins University in collaboration with various cancer research centers have found a potential treatment for Merkel cell carcinoma. The proposed first-line treatment is through the use of humanized monoclonal immunoglobulin G4 antibody ‘pembrolizumab’ which has a response rate of 56%, as opposed to the less effective chemotherapy modality. The results of this significant study were also recently published in The New England Journal of Medicine (NEJM).
In the phase 2 study, 26 Merkel cell cancer patients were enrolled who had not received a prior systematic treatment for their tumor. These patients were treated with Pembrolizumab at a dose of 2 milligrams per 1 kilogram of body weight for every 3 weeks. Amongst these patients, the response rate of the therapy was recorded according to the Response Evaluation Criteria in Solid Tumors, Version 1.1.
The tumor appears as a flesh-colored or bluish red nodule on a skin. These nodules often appear on face, head or neck and the likelihood of the cancer increased with age. The likelihood of developing Merkel cell carcinoma is increased by exposure to UV radiations of sun and a weak immune system. The presence of Merkel cell polyomavirus in the person’s bloodstream is also closely linked to the Merkel cell virus. This oncovirus in the bloodstream results in the production of oncoproteins that inevitably leads to cancer.
The resulting therapy efficacy was measured through the use of serologic and immunohistochemical testing (immune cells, antibodies and antigens tests), followed by computed tomographic scanning. Out of the 26 research participants, 25 patients after first evaluation showed a response rate of 56%. This response rate was measured over a duration period stretching from 2.2 to 9.7 months. 4 patients showed complete response, while 10 patients had partial response to the drug. The follow-up was made after 33 weeks on average, ranging between 7 to 53 months to evaluation cancer relapse. It was found that amongst 14 patients who had a response rate of 14%, 2 patients had a relapse. Significantly, the rate of cancer progression free survival at 6 months was 67%. 17 out of the 26 patient had virus-positive tumors. In these patents with MCPyV-positive tumors 62%, while amongst virus-negative tumors, 44% response rate was recorded.
Chemotherapy which is the alternate treatment modality for tumor has a relapse after 3 months on an average. On the contrary, the use of pembrolizumab targets specific molecular pathways that inhibit the cancerous growth of cells.
The mode of action of this therapy is known as programmed death 1 (PD-1) targets immune checkpoint pathway. This pathway involves the PD-1 T cell co-inhibitory receptor and the ligand molecules PD-L1 and PD-L2 which are expressed on tumor and immune cells; this in turns mediated localized immune resistance. The monoclonal antibodies help patients of Merkel cell carcinoma by blocking this immune system suppressing pathway. Alongside, this pathway is active in advanced forms of many cancer types, which is why this therapy can be beneficial for patients suffering from other kinds of cancers.
Merkel cell carcinoma is considered as an immunogenic cancer, associated with the presence of MCPy virus in 80% cases. As the tumor progresses, the MCPy virus T-antigen-specific T cells and antibodies increase which ultimately decrease with effective therapy. In patients who have a suppressed immunity owing to another medical condition, the tumor progression is even worse.
Studying Merkel cell carcinoma has opened up venues of better cancer therapeutics. With identified biomarkers, using PD-1 blocking antibodies is a promising therapy.
However, to determine if this therapy would help mitigate a particular cancer, it is recommended that pretreatment tumor specimens be identified. FDA approved PD-1 immunohistochemical tests can performed on the tumor specimens that can estimate tumor’s response to the PD-1 pathway blockade.
The role of such tests is likely to increase in future to offer better cancer treatments. However, the tumor mutational burden may cause a limitation in immune recognition for this therapy, pathway modification and subsequent adaptive resistance to the therapeutic modality.