Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory...

Area of Science:

• Oncology
• Immunotherapy
• Genetics

Background:

• Immune checkpoint inhibitors (CPIs) have advanced Merkel cell carcinoma (MCC) treatment, but CPI-refractory cases lack effective options.
• Merkel cell polyomavirus T-antigens are ideal targets for T-cell receptor (TCR)-based immunotherapy in MCC.
• Downregulation of human leukocyte antigen (HLA) expression in MCC hinders T-cell recognition and requires targeted strategies.

Purpose of the Study:

• To evaluate the efficacy of TCR gene therapy targeting a Merkel cell polyomavirus T-antigen in CPI-refractory metastatic MCC.
• To investigate strategies for overcoming HLA downregulation to enhance T-cell mediated anti-tumor responses.

Main Methods:

• Identified TCR_MCC1 recognizing a T-antigen epitope restricted to HLA-A*02:01.
• Administered CD4 and CD8 T cells transduced with TCR_MCC1 (T_TCR-MCC1) to seven patients, preceded by lymphodepleting chemotherapy or HLA-upregulating regimens (SFRT/IFNγ) with avelumab.
• Utilized a xenograft mouse model with a CD200R-CD28 switch receptor to assess T_TCR-MCC1 efficacy against HLA-downregulated MCC cells.

Main Results:

• Two patients receiving preceding SFRT or IFNγ experienced tumor regression, with one showing regression of most lesions.
• T_TCR-MCC1 cells infiltrated tumors, but progressing lesions lacked HLA expression.
• SFRT/IFNγ did not immediately upregulate HLA; however, endogenous T-cell responses and HLA upregulation were observed in a regressing tumor.
• The CD200R-CD28 switch receptor enabled T_TCR-MCC1 to control HLA-downregulated MCC cells and upregulate HLA in a mouse model.

Conclusions:

• TCR gene therapy holds potential for treating metastatic MCC, particularly in CPI-refractory cases.
• Strategies to counteract HLA downregulation, such as combining TCR therapy with HLA-upregulating regimens or co-stimulatory signals, are essential.
• In situ immune responses can potentially reverse HLA downregulation, suggesting a pathway for enhancing immunotherapy efficacy.