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Published on: February 5, 2020
Immunotherapy resistance driven by loss of NY-ESO-1 expression in response to transgenic adoptive cellular therapy
Luke Frankiw1, Arun Singh2, Cole Peters1
1Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of California Los Angeles, Los Angeles, California, USA.
Background:
The tumor antigen NY-ESO-1 has been shown to be an effective target for transgenic adoptive cell therapy (ACT) for the treatment of sarcoma and melanoma. However, despite frequent early clinical responses, many patients ultimately develop progressive disease. Understanding the mechanisms underlying treatment resistance is crucial to improve future ACT protocols. Here, we describe a novel mechanism of treatment resistance in sarcoma involving loss of expression of NY-ESO-1 in response to transgenic ACT with dendritic cell (DC) vaccination and programmed cell death protein-1 (PD-1) blockade.
Methods:
A HLA-A*02:01-positive patient with an NY-ESO-1-positive undifferentiated pleomorphic sarcoma was treated with autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes, NY-ESO-1 peptide-pulsed DC vaccination, and nivolumab-mediated PD-1 blockade.
Results:
Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. There was initial tumor regression, and immunophenotyping of the peripheral transgenic T cells showed a predominantly effector memory phenotype over time. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsy via both TCR sequencing-based and RNA sequencing-based immune reconstitution, and nivolumab binding to PD-1 on transgenic T cells was confirmed at the tumor site. At the time of disease progression, the promoter region of NY-ESO-1 was found to be extensively methylated, and tumor NY-ESO-1 expression was completely lost as measured by RNA sequencing and immunohistochemistry.
Conclusions:
ACT of NY-ESO-1 transgenic T cells given with DC vaccination and anti-PD-1 therapy resulted in transient antitumor activity. NY-ESO-1 expression was lost in the post-treatment sample in the setting of extensive methylation of the NY-ESO-1 promoter region.
Biological/Clinical Insight:
Antigen loss represents a novel mechanism of immune escape in sarcoma and a new point of improvement in cellular therapy approaches.
Trial Registration Number:
NCT02775292.
Insights
Tumor cells lost expression of the NY-ESO-1 antigen, a target for adoptive cell therapy (ACT), due to promoter methylation. This antigen loss represents a novel mechanism of immune escape in sarcoma, hindering effective cancer treatment.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Adoptive cell therapy (ACT) targeting tumor antigen NY-ESO-1 shows early promise for sarcoma but often faces treatment resistance.
- Understanding resistance mechanisms is critical for improving ACT efficacy in sarcoma patients.
- Loss of NY-ESO-1 expression is identified as a novel resistance mechanism.
Purpose of the Study:
- To investigate a novel mechanism of treatment resistance in sarcoma following ACT with dendritic cell (DC) vaccination and programmed cell death protein-1 (PD-1) blockade.
- To elucidate the molecular basis of NY-ESO-1 antigen loss in response to immunotherapy.
Main Methods:
- A patient with NY-ESO-1-positive undifferentiated pleomorphic sarcoma received autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes, NY-ESO-1 peptide-pulsed DC vaccination, and PD-1 blockade (nivolumab).
- Tumor and peripheral blood samples were analyzed for T cell reconstitution, phenotype, tumor infiltration, and NY-ESO-1 expression.
- NY-ESO-1 promoter methylation status was assessed at disease progression.
Main Results:
- NY-ESO-1-specific T cells expanded rapidly in vivo and infiltrated the tumor site, leading to initial tumor regression.
- At disease progression, extensive methylation of the NY-ESO-1 promoter region was observed.
- Tumor NY-ESO-1 expression was completely lost, confirmed by RNA sequencing and immunohistochemistry.
Conclusions:
- Loss of NY-ESO-1 expression, driven by promoter methylation, is a novel mechanism of immune escape in sarcoma.
- This finding highlights a new target for overcoming resistance in cellular therapy approaches for sarcoma.
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