Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia
Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia
复制标题
DOI：
10.1182/blood-2017-07-794214
复制
发表时间：
2018-03-01
期刊：
影响因子：
20.3
通讯作者：
Teachey, David T.
中科院分区：
文献类型：
--
作者：
Bride, Karen L.;Vincent, Tiffaney L.;Teachey, David T.
由于获得性或内在的疾病抗性，复发性或难治性T细胞急性淋巴细胞白血病（T-ALL）患者的预后令人沮丧。显然需要新型的、毒性较小的药物。靶向免疫治疗是癌症治疗中最有前途的新兴治疗策略之一。免疫疗法改善了其他恶性血液病（包括B细胞ALL）患者的结局;然而，尚未成功开发用于T-ALL的免疫疗法。我们假设靶向CD 38将对T-ALL有效。我们证明了T-ALL患者的原始细胞具有强大的表面CD 38表面表达，并且这种表达在暴露于多药化疗后保持稳定。CD 38在正常淋巴细胞和骨髓细胞以及少数非造血来源的组织上以非常低的水平表达，这表明CD 38可能是理想的靶点。达雷妥尤单抗是一种结合CD 38的人免疫球蛋白G1 κ单克隆抗体，已被证明在难治性多发性骨髓瘤患者中安全有效。我们在大量T-ALL患者来源的异种移植物（PDX）中测试了达雷妥尤单抗，并在15种不同PDX中的14种中发现了惊人的疗效。这些数据表明，达雷妥尤单抗是儿童T-ALL患者的一种有前途的新型疗法。
As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1 kappa monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.