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Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma
P C Schuberth1, G Jakka, S M Jensen
1Department of Oncology, University Hospital Zurich, Zürich, Switzerland.
Abstract:
The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.
Insights
Chimeric antigen receptors (CARs) targeting NY-ESO-1 redirected T cells to kill multiple myeloma cells. This immunotherapy approach showed promise in preclinical models, recognizing cancer cells expressing NY-ESO-1 and HLA-A*02:01.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- The cancer-testis antigen NY-ESO-1 is expressed in a subset of multiple myeloma patients.
- NY-ESO-1 presents a potential target for novel immunotherapies.
Purpose of the Study:
- To develop chimeric antigen receptors (CARs) targeting the NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01.
- To evaluate the efficacy of NY-ESO-1-specific CAR T cells against multiple myeloma in vitro and in vivo.
Main Methods:
- Generation of CARs recognizing NY-ESO-1 peptide 157-165/HLA-A*02:01.
- Redirection of autologous CD8(+) T cells.
- Assessment of T cell cytotoxicity and cytokine secretion (IFNγ, IL-2).
- Phenotypic analysis of T cells (CCR7, effector/memory markers).
- Immunohistochemical screening of multiple myeloma patient samples for NY-ESO-1 expression.
- Evaluation in a mouse xenograft model.
Main Results:
- NY-ESO-1 protein expression detected in 9.7% of multiple myeloma patient samples.
- NY-ESO-1-specific CAR T cells effectively lysed NY-ESO-1(157-165)/HLA-A*02:01-positive myeloma cells.
- CAR T cells secreted IFNγ and IL-2 upon antigen stimulation.
- Effector and central memory T cell populations were identified and characterized.
- Adoptive transfer of CAR T cells conferred protection against myeloma challenge in a xenograft model.
Conclusions:
- NY-ESO-1 is a viable target antigen for immunotherapy in a subset of multiple myeloma patients.
- NY-ESO-1-specific CAR T cells demonstrate potent anti-myeloma activity in vitro and in vivo.
- This CAR T cell strategy holds potential for treating NY-ESO-1-positive multiple myeloma.
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