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Oncoimmunology. 2016 Feb 18;5(5):e1138199. doi: 10.1080/2162402X.2016.1138199. eCollection 2016 May.

Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA.

Author information

1
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
2
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet , Oslo, Norway.
3
K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
4
Max Delbrück Center for Molecular Medicine and Institute of Biology, Humboldt University , Berlin, Germany.
5
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
6
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Department of Cell Therapy, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.

Abstract

T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs. T cells re-directed with the A23 and A94 TCR constructs efficiently recognized malignant HLA-A2(pos) B cells endogenously expressing CD20, including patient-derived follicular lymphoma and chronic lymphocytic leukemia (CLL) cells. In contrast, a wide range of HLA-A2(pos)CD20(neg) cells representing different tissue origins, and HLA-A2(neg)CD20(pos) cells, were not recognized. Cytotoxic T cells re-directed with CD20p/HLA-A2-specific TCRs or CD19 CARs responded with similar potencies to cells endogenously expressing comparable levels of CD20 and CD19. The CD20p/HLA-A2-specific TCRs recognized CD20p bound to HLA-A2 with high functional avidity. The results show that T cells expressing CD20p/HLA-A2-specific TCRs efficiently and specifically target B cells. When used in context of an HLA-haploidentical allogeneic stem cell transplantation where the donor is HLA-A2(neg) and the patient HLA-A2(pos), these T cells would selectively kill patient-derived B cells and allow reconstitution of the B-cell compartment with HLA-A2(neg) donor cells. These results should pave the way for clinical testing of T cells genetically engineered to target malignant B cells without permanent depletion of normal B cells.

KEYWORDS:

B-cell malignancies; CD20; T-cell receptor; gene therapy; haploidentical allogeneic stem cell transplantation; immunotherapy

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