Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia

作者：Haso, Waleed; Lee, Daniel W.; Shah, Nirali N.; Stetler-Stevenson, Maryalice; Yuan, Constance M.; Pastan, Ira H.; Dimitrov, Dimiter S.; Morgan, Richard A.; FitzGerald, David J.; Barrett, David M.; Wayne, Alan S.; Mackall, Crystal L.; Orentas, Rimas J.^*

来源：Blood, 2013, 121(7): 1165-1174.

DOI：10.1182/blood-2012-06-438002

• T-CELLS
• HEMATOLOGIC MALIGNANCIES
• ANTITUMOR-ACTIVITY
• RECOMBINANT IMMUNOTOXIN
• SIGNAL-TRANSDUCTION
• CHIMERIC RECEPTORS
• CYTOTOXIC ACTIVITY
• ENHANCED SURVIVAL
• FLOW-CYTOMETRY
• CLINICAL-TRIAL

Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains +/- an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28. CD3 zeta constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL. (Blood. 2013; 121(7): 1165-1174)

• 出版日期2013-2-14