Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China.
Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China.
Clin Cancer Res. 2019 Sep 15;25(18):5595-5607. doi: 10.1158/1078-0432.CCR-19-0916. Epub 2019 Jul 12.
CD19 chimeric antigen receptor (CAR)-T therapy has shown impactful results in treatment of B-cell malignancies. However, immune recognition of the murine scFv may render subsequent infusion(s) ineffective. Also, nonselective expansion of both CAR-transduced and nontransduced T cells during the production stage affects the yield and purity of final products. Here, we aim to develop a humanized selective (hs) CD19 CAR to solve the above problems. A CD19 hsCAR was designed, which incorporated a short selective domain between the humanized heavy chain and light chain. The CAR was examined for its property, and then trialed in 5 highly treated B-ALL patients.
hsCAR possessed around 6-fold higher affinity to CD19 versus murine CAR (mCAR). Incubation with selective domain-specific mAbs (SmAb) selectively expanded CAR-transduced T cells, and led to a higher proportion of central memory T cells in the final products. SmAb-stimulated CD19 hsCAR-T cells exhibited superior antitumor cytotoxic functions and . Autologous ( = 2) and allogeneic donor ( = 3, with hematopoietic stem cell transplantation) hsCAR-T cells were infused into 5 patients who had relapsed after receiving mCAR-T treatments. Two patients received mCAR-T treatments twice previously but the second treatments were ineffective. In contrast, subsequent hsCAR-T treatments proved effective in all 5 patients and achieved complete molecular remission in four, including one with extramedullary disease with central nervous system involvement.
hsCD19 CAR-T treatment shows efficacy in highly treated B-ALL patients who have relapsed after receiving CD19 mCAR-T therapies.
嵌合抗原受体（CAR）-T 疗法在治疗 B 细胞恶性肿瘤方面已显示出显著疗效。然而，对鼠源 scFv 的免疫识别可能会使随后的输注无效。此外，在生产阶段，CAR 转导和未转导 T 细胞的非选择性扩增会影响最终产品的产量和纯度。在此，我们旨在开发一种人源化选择性（hs）CD19 CAR 来解决上述问题。设计了一种 CD19 hsCAR，在人源化重链和轻链之间加入了一个短的选择性结构域。对 CAR 的性能进行了检测，并在 5 例经过高度治疗的 B-ALL 患者中进行了试验。
hsCAR 对 CD19 的亲和力比对鼠源 CAR（mCAR）高约 6 倍。与特异性选择性结构域 mAb（SmAb）孵育可选择性扩增 CAR 转导的 T 细胞，并导致最终产物中中央记忆 T 细胞的比例更高。SmAb 刺激的 CD19 hsCAR-T 细胞表现出优越的抗肿瘤细胞毒性作用和增殖能力。两名患者之前接受过两次 mCAR-T 治疗但第二次治疗无效，随后对 5 例接受 mCAR-T 治疗后复发的患者输注了自体（n=2）和同种异体供体（n=3，接受造血干细胞移植）hsCAR-T 细胞。相反，后续的 hsCAR-T 治疗在所有 5 例患者中均有效，其中 4 例达到完全分子缓解，包括 1 例有髓外疾病伴中枢神经系统受累。
hsCD19 CAR-T 治疗在接受 CD19 mCAR-T 治疗后复发的高度治疗 B-ALL 患者中显示出疗效。
