Brentjens Renier J, Santos Elmer, Nikhamin Yan, Yeh Raymond, Matsushita Maiko, La Perle Krista, Quintás-Cardama Alfonso, Larson Steven M, Sadelain Michel
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5426-35. doi: 10.1158/1078-0432.CCR-07-0674. Epub 2007 Sep 12.
Human T cells targeted to the B cell-specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy.
A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors.
Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement.
Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.
通过逆转录病毒介导的嵌合抗原受体（CAR）（称为19z1）转移靶向B细胞特异性CD19抗原的人T细胞，在严重联合免疫缺陷（SCID）-米色全身性人急性淋巴细胞白血病（NALM-6）肿瘤模型中显示出显著但部分的体内抗肿瘤功效。在此，我们研究该模型中治疗失败的病因，并设计提高这种过继性策略疗效的方法。
构建了一组经修饰的靶向CD19的CAR，旨在向T细胞传递联合激活信号和共刺激信号，并在体外进行测试以鉴定最佳的第二代CAR。在携带全身性共刺激配体缺陷的NALM-6肿瘤的小鼠中分析表达这种最佳共刺激CAR（19-28z）的T细胞的抗肿瘤功效。
与19z1相比，含有CD28受体信号域的19-28z CAR的表达增强了治疗小鼠的全身性T细胞抗肿瘤活性。旨在延长体内T细胞功能的每周4次T细胞注射的治疗方案进一步改善了长期生存率。对治疗小鼠的肿瘤进行生物发光成像未能确定肿瘤复发的保守部位，这与肿瘤特异性T细胞成功归巢至全身性肿瘤累及部位一致。
体内共刺激和重复给药均可增强基因靶向T细胞对全身性肿瘤的清除。CAR设计以及T细胞给药方式的改变能够完全清除全身性疾病这一发现影响了使用该治疗策略的临床试验设计。
