Eradication of B-ALL using chimeric antigen receptor–expressing T cells targeting the TSLPR oncoprotein

• Published in: Blood Vol. 126; no. 5; pp. 629 - 639
• Main Authors: Qin, Haiying, Cho, Monica, Haso, Waleed, Zhang, Ling, Tasian, Sarah K., Oo, Htoo Zarni, Negri, Gian Luca, Lin, Yongshun, Zou, Jizhong, Mallon, Barbara S., Maude, Shannon, Teachey, David T., Barrett, David M., Orentas, Rimas J., Daugaard, Mads, Sorensen, Poul H.B., Grupp, Stephan A., Fry, Terry J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.07.2015; American Society of Hematology
• Subjects: Animals; Antigens, CD19 - metabolism; Cell Line, Tumor; Humans; Immunotherapy, Adoptive - methods; Lymphoid Neoplasia; Mice; Mice, Inbred NOD; Mice, SCID; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, Cytokine - antagonists & inhibitors; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - therapeutic use; T-Lymphocytes - immunology; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-11-612903

Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting the CD19 B cell–associated protein have demonstrated potent activity against relapsed/refractory B-lineage acute lymphoblastic leukemia (B-ALL). Not all patients respond, and CD19-negative relapses have been observed. Overexpression of the thymic stromal lymphopoietin receptor (TSLPR; encoded by CRLF2) occurs in a subset of adults and children with B-ALL and confers a high risk of relapse. Recent data suggest the TSLPR signaling axis is functionally important, suggesting that TSLPR would be an ideal immunotherapeutic target. We constructed short and long CARs targeting TSLPR and tested efficacy against CRLF2-overexpressing B-ALL. Both CARs demonstrated activity in vitro, but only short TSLPR CAR T cells mediated leukemia regression. In vivo activity of the short CAR was also associated with long-term persistence of CAR-expressing T cells. Short TSLPR CAR treatment of mice engrafted with a TSLPR-expressing ALL cell line induced leukemia cytotoxicity with efficacy comparable with that of CD19 CAR T cells. Short TSLPR CAR T cells also eradicated leukemia in 4 xenograft models of human CRLF2-overexpressing ALL. Finally, TSLPR has limited surface expression on normal tissues. TSLPR-targeted CAR T cells thus represent a potent oncoprotein-targeted immunotherapy for high-risk ALL. •Adoptive transfer of T cells genetically modified to express anti-TSLPR chimeric antigen receptors can cure B-ALL in xenograft models.•Anti-TSLPR CAR constructs containing a CH2CH3 spacer domain were inactive against TSLPR-overexpressing B-ALL.