A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas.
A high molecular weight melanoma-associated antigen-specific chimeric antigen receptor redirects lymphocytes to target human melanomas.
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DOI：
10.1158/0008-5472.can-09-2824
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Morgan RA
中科院分区：
文献类型：
--
作者：
Burns WR;Zhao Y;Frankel TL;Hinrichs CS;Zheng Z;Xu H;Feldman SA;Ferrone S;Rosenberg SA;Morgan RA
免疫治疗，特别是肿瘤浸润淋巴细胞（TIL）的过继细胞转移（ACT），是一种非常有前途的治疗转移性黑色素瘤的方法。一些无法接受TIL的患者已经成功地用自体外周血淋巴细胞（PBL）治疗，基因修饰表达HLA I类抗原受限，黑色素瘤抗原反应性t细胞受体；然而，由于缺乏限制性HLA I类等位基因的表达，大量患者仍然不符合条件。我们试图通过设计一种非mhc限制性嵌合抗原受体（CAR）来克服这一局限性，靶向高分子量黑色素瘤相关抗原（HMW-MAA）， HMW-MAA在超过90%的人类黑色素瘤中高度表达，但在正常组织中分布有限。在逆转录病毒载体中构建了含有基于hmw - maa特异性单克隆抗体（mAb） 225.28S变异的抗原识别域和基于CD28, 4-1BB和CD3ζ激活基元组合的t细胞激活域的hmw - maa特异性car，以允许稳定的基因转移到细胞及其后代中。在优化了HMW-MAA特异性CAR在人PBL中的表达和功能后，这些基因修饰的T细胞分泌细胞因子，并对表达HMW-MAA的细胞系产生细胞溶解和增殖反应。此外，该受体在CD4+和CD8+细胞中均起作用，不受mhc限制，并对外植的人类黑色素瘤起作用。为了评估这种hmw - maa特异性CAR在转移性黑色素瘤患者中的作用，我们开发了一种临床级逆转录病毒包装系列。这可能代表了一种治疗大多数晚期黑色素瘤患者的新方法，尤其是那些无法接受当前ACT治疗的患者。
Immunotherapy, particularly the adoptive cell transfer (ACT) of tumor infiltrating lymphocytes (TIL), is a very promising therapy for metastatic melanoma. Some patients unable to receive TIL have been successfully treated with autologous peripheral blood lymphocytes (PBL), genetically modified to express HLA class I antigen restricted, melanoma antigen-reactive T-cell receptors; however, substantial numbers of patients remain ineligible due to the lack of expression of the restricting HLA class I allele. We sought to overcome this limitation by designing a non-MHC-restricted, chimeric antigen receptor (CAR) targeting the high molecular weight-melanoma associated antigen (HMW-MAA), which is highly expressed on over 90% of human melanomas but has a restricted distribution in normal tissues. HMW-MAA-specific CARs containing an antigen recognition domain based on variations of the HMW-MAA-specific monoclonal antibody (mAb) 225.28S and a T-cell activation domain based on combinations of CD28, 4-1BB, and CD3ζ activation motifs were constructed within a retroviral vector to allow stable gene transfer into cells and their progeny. Following optimization of the HMW-MAA-specific CAR for expression and function in human PBL, these gene-modified T cells secreted cytokines, were cytolytic, and proliferated in response to HMW-MAA expressing cell lines. Furthermore, the receptor functioned in both CD4+ and CD8+ cells, was non-MHC-restricted, and reacted against explanted human melanomas. To evaluate this HMW-MAA-specific CAR in patients with metastatic melanoma, we developed a clinical-grade retroviral packaging line. This may represent a novel means to treat the majority of patients with advanced melanoma, most notably those unable to receive current ACT therapies.