Immune escape from NY-ESO-1-specific T-cell therapy via loss of heterozygosity in the MHC

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Z K Klippel1, J Chou1, A M Towlerton2

  • 11] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Medicine, University of Washington, Seattle, WA, USA.

Gene Therapy
|January 24, 2014
PubMed

Insights

Tumor cells can escape NY-ESO-1 adoptive immunotherapy by losing HLA-A*02:01 expression. This major histocompatibility complex (MHC) loss, identified via loss of heterozygosity, suggests a mechanism for tumor recurrence after T-cell therapy.

Area of Science:

  • Immunology
  • Oncology
  • Genetics

Background:

  • Adoptive T-cell therapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors.
  • Tumor recurrence after NY-ESO-1 immunotherapy necessitates understanding evasion mechanisms.

Purpose of the Study:

  • Investigate mechanisms of tumor recurrence following NY-ESO-1-specific adoptive T-cell therapy in a multiple myeloma model.

Main Methods:

  • Utilized a murine xenograft model of NY-ESO-1-positive multiple myeloma.
  • Administered CD8+ T cells genetically engineered to target NY-ESO-1 peptide presented by HLA-A*02:01.
  • Analyzed recurrent myeloma cells for expression of NY-ESO-1, B2M, and HLA-A*02:01.
  • Performed loss of heterozygosity analysis of the major histocompatibility complex (MHC) locus.

Main Results:

  • Observed tumor recurrence after T-cell therapy in the murine model.
  • Recurrent myeloma cells exhibited complete loss of cell surface HLA-A*02:01 expression.
  • NY-ESO-1 and B2M expression remained intact in recurrent tumor cells.
  • Identified loss of heterozygosity (LOH) in the MHC, specifically involving the HLA-A locus and loss of the HLA-A*02:01 allele.

Conclusions:

  • Selective loss of MHC molecules, including HLA-A*02:01, is a mechanism of tumor escape from NY-ESO-1-specific T-cell therapy.
  • MHC loss via LOH may contribute to tumor persistence and recurrence.
  • Recommend evaluating MHC loss in patients with myeloma and other cancers relapsing after NY-ESO-1-specific T-cell therapy.

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