Regression of Metastatic Merkel Cell Carcinoma Following Transfer of Polyomavirus-Specific T Cells and Therapies Capable of Reinducing HLA Class-I

Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer that typically requires the persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins that can serve as ideal immunotherapeutic targets. Several immune evasion mechanisms are active in MCC including down-regulation of HLA class-I expression on tumor cells and dysfunctional endogenous MCPyV-specific CD8 T cell responses. To overcome these obstacles, we combined local and systemic immune therapies in a 67-year-old man, who developed metastatic MCPyV-expressing MCC. Intralesional IFNβ-1b or targeted single-dose radiation was administered as a pre-conditioning strategy to reverse the down-regulation of HLA-I expression noted in his tumors and to facilitate the subsequent recognition of tumor cells by T cells. This was followed by the adoptive transfer of ex vivo expanded polyclonal, polyomavirus-specific T cells as a source of reactive antitumor immunity. The combined regimen was well-tolerated and led to persistent up-regulation of HLA-I expression in the tumor and a durable complete response in two of three metastatic lesions. Relative to historical controls, the patient experienced a prolonged period without development of additional distant metastases (535 days compared to historic median of 200 days, 95% confidence interval = 154–260 days). The transferred CD8+ T cells preferentially accumulated in the tumor tissue, remained detectable and functional for >200 days, persisted with an effector phenotype, and exhibited evidence of recent in vivo activation and proliferation. The combination of local and systemic immune stimulatory therapies was well-tolerated and may be a promising approach to overcome immune evasion in virus-driven cancers.

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…MCPyV-specific T cells isolated from MCC tumors and peripheral blood have been shown to express elevated levels of the inhibitory markers PD-1 and TIM-3 relative to control CMV-or EBV-specific cells (Figure 2: process 'E') [49]. Additionally, MCPyV-specific CD8 T cells often have a limited ability to secrete the effector cytokine IFN-γ following antigenic stimulation and TILs within MCC tumors have markedly lower expression of the early activation marker CD69 relative to T cells isolated from normal skin, supporting the notion that these cells are dysfunctional and exhausted [43,69,70].…”

“…The majority of MCCs downregulate MHC-I expression thereby evading cellular immune responses, however, several case reports have described MHC-I upregulation on MCC tumors following either intralesional IFN-β injections or local radiation therapy [52,69]. The use of IFN-β injections clinically has also induced lesion shrinkage, which may be due to enhanced T-cell recognition of these tumors [52,69,108].…”

“…The use of IFN-β injections clinically has also induced lesion shrinkage, which may be due to enhanced T-cell recognition of these tumors [52,69,108]. Notably, a woman in Japan with multiple MCC metastases on the right arm was treated with IFN-β injections and experienced a complete response that continued for more than 8 years, indicating the potential efficacy of this approach [108].…”

“…This approach has shown efficacy in treating several cancers including other virally-induced malignancies and melanoma [129][130][131]. In 2013, an MCC patient received three infusions of MCPyV-specific CD8s in combination with subcutaneous administration of IL-2 and HLA-I upregulating agents (single-dose radiation and IFN-β injections) [69]. This patient experienced mixed tumor responses but did not develop a recurrence for 535 days, significantly longer than median time (200 days) to next metastasis experienced by historical controls [69].…”

“…In 2013, an MCC patient received three infusions of MCPyV-specific CD8s in combination with subcutaneous administration of IL-2 and HLA-I upregulating agents (single-dose radiation and IFN-β injections) [69]. This patient experienced mixed tumor responses but did not develop a recurrence for 535 days, significantly longer than median time (200 days) to next metastasis experienced by historical controls [69]. It appears that this immune therapy may have conferred benefit, in part because functional infused T cells persisted for >200 days and preferentially accumulated within tumor tissue [69].…”