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

Item Type:Article
Title:Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA
Creators Name:Mensali, N. and Ying, F. and Sheng, V.O.Y. and Yang, W. and Walseng, E. and Kumari, S. and Fallang, L.E. and Kolstad, A. and Uckert, W. and Malmberg, K.J. and Waelchli, S. and Olweus, J.
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-A2pos 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)CD20neg cells representing different tissue origins, and HLA-A2(neg)CD20pos 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, Gene Therapy, Haploidentical Allogeneic Stem Cell Transplantation, Immunotherapy, T-Cell Receptor
Publisher:Taylor & Francis (U.S.A.)
Page Range:e1138199
Date:18 February 2016
Official Publication:https://doi.org/10.1080/2162402X.2016.1138199
PubMed:View item in PubMed

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