Targeting B-cell neoplasia with T-cell receptors recognizing a CD20-derived peptide on patient-specific HLA. (3rd May 2016)

• Record Type: Journal Article
• Authors: Mensali, Nadia; Ying, Fan; Sheng, Vincent Oei Yi; Yang, Weiwen; Walseng, Even; Kumari, Shraddha; Fallang, Lars-Egil; Kolstad, Arne; Uckert, Wolfgang; Malmberg, Karl Johan; Wälchli, Sébastien; Olweus, Johanna
• Is Part Of: Oncoimmunology. Volume 5:Number 5(2016)
• Publication Date: 2016-05-03
• Subjects: B-cell malignancies -- CD20 -- gene therapy -- haploidentical allogeneic stem cell transplantation -- immunotherapy -- T-cell receptor; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1138199
• Languages: English
• ISSNs: 2162-402X

Abstract

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.