双靶向CD19/CD22嵌合抗原受体治疗急性B淋巴细胞白血病的应用基础研究

Cancers figure among the leading causes of morbidity and mortality worldwide. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics.Despite obvious successes, there have been documented relapses in which CART-19 cells were still present, but the leukemia cells lost surface expression of CD19 epitopes, as detected raising questions about its signifi cance for neoplastic growth.loss. The group at the NCI observed that CD19-negative blasts emerged in the two patients treated with CD19-directed therapy who retained the expression of CD22, and based on this retention they developed CAR T-cells targeting the B-cell antigen CD22 that can be used for treating CD19-negative relapse and can be combined with a CD19-modified CAR in the future. Combination or tandem CARs targeting both CD19 and CD22 may prevent escape because of antigen loss, but further studies are needed.Thus, we aim to create CD19/CD22 CART cells, perform multi-layered reseaches to reveal its anti-tumor function and mechanism, and providing CD19/CD22 CART cells as a new potential drug for cancer therapy.

癌症是人类发病及死亡的主要原因之一，最近多项临床试验表明了CAR修饰的T细胞在肿瘤免疫治疗领域的应用前景。尤其在急性B淋巴细胞白血病中，CART-19细胞取得了令人瞩目的疗效。然而，10%-20%接受治疗后的病人中出现了CD19表位逃脱变异体；我们需要新的治疗策略来针对这群CD19变异体的复发病人。我们选择了针对B细胞的另一个靶点CD22-广泛分布B淋巴细胞的受体分子。申请人在前期已构建了CD19的靶向嵌合抗原受体，通过感染构建了工程化T细胞。理论上讲，双靶向CART细胞可特异的识别CD19/CD22任意一种抗原，之后激活共刺激信号分子刺激自身增殖，并杀伤表达CD19/CD22其中之一或共表达的靶细胞。因此，我们拟制备一种双靶向CD19/CD22的CART细胞，并从分子、细胞及动物模型多个层次对其抗肿瘤功能及机制进行研究，为急性B淋巴细胞白血病提供一种新型的潜力药物。

尽管CD19CAR-T细胞治疗在B-ALL中诱导了令人印象深刻的临床疗效，但CD19阴性白血病的出现有时会限制CART-19细胞应用前景。针对CD19和CD22的双特异性CAR修饰T细胞能克服CD19阴性复发的局限性。我们证明了双特异性CD19/CD22 CAR T细胞对靶细胞的强大杀伤活性。6例入选患者获得MRD阴性CR。自体CD19/CD22CAR T细胞在体内增殖，并在血液、骨髓和脑脊液中检测到CD19/CD22CAR T细胞。治疗的6例患者均未发生神经毒性反应。值得注意的是，一名患者在治疗大约5个月后复发，原始细胞不再表达CD19，并显示CD22表达密度降低。总之，自体CD19/CD22CAR T细胞治疗对复发/难治性B-ALL患者是可行和安全的，并显示了强大的抗白血病活性。此外，靶抗原丢失和表达下调的出现突显了预测抗原逃逸的迫切需要。我们的研究证实了双特异性CD19/CD22CAR T细胞疗法在诱导成人复发性/难治性B-ALL患者缓解方面的可靠性。