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

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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., Ying, F., Sheng, V.O.Y., Yang, W., Walseng, E., Kumari, S., Fallang, L.E., Kolstad, A., Uckert, W., Malmberg, K.J., 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
Source:	OncoImmunology
ISSN:	2162-402X
Publisher:	Taylor & Francis
Volume:	5
Number:	5
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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