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Updated: Jun 21, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory
Yuta Asano1, Joshua Veatch1,2, Megan McAfee1
1Fred Hutchinson Cancer Center, Seattle, WA, USA.
Abstract:
Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCRMCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-MCC1) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although TTCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows TTCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.
Insights
T-cell receptor (TCR) gene therapy targeting Merkel cell carcinoma (MCC) shows promise. Strategies to overcome human leukocyte antigen (HLA) downregulation are crucial for effective immunotherapy in CPI-refractory MCC.
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 TCRMCC1 recognizing a T-antigen epitope restricted to HLA-A*02:01.
- Administered CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-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 TTCR-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.
- TTCR-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 TTCR-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.
