Targeting of the CD19 antigen has emerged as a promising approach, inspired by the success of the anti-CD20 monoclonal antibody Rituximab. CD19 is an attractive target as it is restricted to B-lineage, not lost in the neoplastic transformation, present on most of the B-lineage malignancies and absent on hematopoietic stem cells, and ablation of CD19-positive cells is compatible with life. Preclinical and clinical data show proof of concept, but a major limitation in clinical applications is the limited persistence of modified effector cells, typically ex vivo expanded mature T-cells. The first trials evaluating CAR T cells for B-cell malignancies focused on NHL, and targeted CD19 or CD20 antigens. One of the most important observations came from a group at the Baylor College of Medicine, whose work confirmed the results of preclinical studies comparing first-generation and second-generation CAR T cells. Savoldo and colleagues infused patients with NHL with a mixture of T cells that were modified with either a first-generation CD19-specific CAR or a second-generation CD19-specific CAR that contained a CD28 costimulatory domain. They demonstrated that the second-generation CAR T cells expanded better and persisted longer than the first-generation CAR T cells, although responses were modest. In addition, investigators at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that lymphodepletion with conditioning chemotherapy was required for optimal CAR T-cell function. Brentjens and colleagues treated patients with T cells modified with a second-generation CAR that included a CD28 costimulatory domain. The first cohort was infused with CD19-targeted CAR T cells alone, whereas the second cohort was treated with cyclophosphamide conditioning chemotherapy (1.5 to 3.0 g/m2) prior to CAR T-cell infusion. They demonstrated that expansion, persistence, and responses were improved in the conditioned cohort.
Davila M L, Brentjens R J. CD19-Targeted CAR T Cells as Novel Cancer Immunotherapy for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia[J]. Clinical advances in hematology & oncology: H&O, 2016, 14(10): 802.
De Oliveira SN, Ryan C, Giannoni F, et al. Modification of Hematopoietic Stem/Progenitor Cells with CD19-Specific Chimeric Antigen Receptors as a Novel Approach for Cancer Immunotherapy. Human Gene Therapy. 2013;24(10):824-839.