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

Abstract

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.

• Authors: Haiying Qin, Monica Cho, Waleed Haso, Ling Zhang, Sarah K Tasian, Htoo Zarni Oo, Gian Luca Negri, Yongshun Lin, Jizhong Zou, Barbara S Mallon, Shannon Maude, David T Teachey, David M Barrett, Rimas J Orentas, Mads Daugaard, Poul H B Sorensen, Stephan A Grupp, Terry J Fry
• Journal: Blood (Blood) Vol. 126 Issue 5 Pg. 629-39 (Jul 30 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 26041741 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD19
• CRLF2 protein, human
• Receptors, Cytokine
• Recombinant Fusion Proteins

Topics

• Animals
• Antigens, CD19 (metabolism)
• Cell Line, Tumor
• Humans
• Immunotherapy, Adoptive (methods)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (immunology, therapy)
• Receptors, Cytokine (antagonists & inhibitors)
• Recombinant Fusion Proteins (genetics, immunology, therapeutic use)
• T-Lymphocytes (immunology)
• Xenograft Model Antitumor Assays