Professor and Head
Division of Dermatology
Department of Medicine
University of Washington
Paul Nghiem, MD, has disclosed that he has received consulting fees from EMD Serono and funds for research support from Bristol-Myers Squibb.
The development of PD-1/PD-L1 checkpoint inhibitors has revolutionized care for patients with advanced Merkel cell carcinoma (MCC). In the space of 1 year, treatment options expanded from chemotherapy alone to include the anti–PD-L1 antibody avelumab. This agent was approved in 2017 for advanced MCC based on positive data from a phase II trial, which reported that 31.8% of patients with chemotherapy-refractory MCC had a response to avelumab; responses occurred most often in patients previously treated with only 1 line of systemic therapy. Other encouraging phase II data were reported for the anti–PD-1 antibody pembrolizumab, which was associated with a response rate of 56% in treatment-naive MCC. Intriguingly, extensive tumor infiltration by CD8+ T-cells is associated with better survival in MCC.
Despite these promising results, approximately one half of patients with MCC will not respond to checkpoint inhibitor monotherapy. This could be due to the tumor downregulating HLA class I expression or—among the 80% of MCC cases associated with Merkel cell polyomavirus (MCPyV)—low levels of MCPyV-specific T-cells. An inadequate response is more likely in patients who are heavily chemotherapy experienced. Thus, our team is investigating whether patients with nonresponding MCC could benefit from a novel “triple-therapy” approach of adoptive T-cell therapy combined with HLA upregulation plus avelumab. I am pleased to say that our interim results are very encouraging.
Triple Therapy: Encouraging Efficacy and Safety Results
At ASCO 2017, we reported preliminary efficacy and safety results from 8 patients treated with either double therapy (T-cell therapy plus HLA upregulation) or triple therapy. All patients had MCPyV-associated metastatic MCC and had not been treated with a checkpoint inhibitor. Both therapy groups received up to 2 rounds of treatment, which consisted of MHC class I HLA upregulation via radiotherapy or interferon-β injection to a single lesion, plus 2 infusions per round of T-cell therapy derived from MCPyV-specific tumor-infiltrating lymphocytes expanded ex vivo. The triple-therapy group also received avelumab every 2 weeks.
In the double-therapy group, 3 out of 4 patients had disease progression and only 1 patient achieved a CR. By contrast, the triple-therapy group had a 100% response rate, with 3 patients attaining a CR and 1 patient achieving a PR. These triple therapy responses were durable, with all 3 CRs persisting at our median follow-up of 10 months.
We also characterized peripheral blood T-cells over time. The infused MCPyV-specific T‑cells persisted for more than 100 days in most patients. In the triple-therapy group, 2 patients even exhibited epitope spreading—a phenomenon where the immune response effectively broadens as other T‑cells begin targeting different cancer epitopes.
Regarding safety, the main risks are the immune-related adverse events associated with the checkpoint inhibitor. These are generally quite manageable with corticosteroids and holding therapy, depending on the severity of the event. The second risk is the interferon-β or small dose of radiation used for HLA upregulation, although both were well tolerated. The third risk is from the adoptive T‑cells. All 4 patients receiving triple therapy experienced lymphopenia for up to several weeks; we also observed fever and tachycardia. Although 1 patient experienced cytokine release syndrome, this lasted for less than 24 hours and was managed in an outpatient setting. I consider this safety profile to be both manageable and superior to chemotherapy.
Triple Therapy: Who Could Benefit?
Based on these promising results, we think that triple therapy could rescue some patients not responding to checkpoint inhibitor monotherapy. Like the patients in our study, this approach would be best for patients with MCPyV-associated MCC, no major immune suppression issues, and an HLA type that allows for ex vivo expansion and infusion with MCPyV-specific T-cells. In particular, this approach could benefit people who have inadequate numbers of MCPyV-specific T‑cells.
In theory, triple therapy could be used for the 20% of patients with ultraviolet-associated (non-MCPyV–related) MCC. However, the T-cells would have to be individualized to each patient’s specific neoantigens.
Future Directions in MCC and Other Cancers
To build on these promising early results, our team is developing transgenic T‑cell receptors to further augment the adoptive T-cell therapy while reducing the risk of autoimmune issues. These results in our patients with MCC also serve as a proof of concept, suggesting that this approach could be beneficial in other cancers—like those associated with human papillomaviruses—that share antigens across patients.
How will you manage MCC patients who have an inadequate response to checkpoint inhibitor monotherapy? Please leave your feedback below.