Krishnamurthy Janani, Rabinovich Brian A, Mi Tiejuan, Switzer Kirsten C, Olivares Simon, Maiti Sourindra N, Plummer Joshua B, Singh Harjeet, Kumaresan Pappanaicken R, Huls Helen M, Wang-Johanning Feng, Cooper Laurence J N
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2015 Jul 15;21(14):3241-51. doi: 10.1158/1078-0432.CCR-14-3197. Epub 2015 Mar 31.
The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T-cell surface, such that they target tumors in advanced stages of melanoma.
Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immunohistochemical (IHC) analysis. HERV-K env-specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env-specific CAR(+) T cells were expanded ex vivo on activating and propagating cells (AaPC) and characterized for CAR expression and specificity. This includes evaluating the HERV-K-specific CAR(+) T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model.
We detected HERV-K env protein on melanoma but not in normal tissues. After electroporation of T cells and selection on HERV-K(+) AaPC, more than 95% of genetically modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env(+) tumor targets in an antigen-specific manner. Even though there is apparent shedding of this TAA from tumor cells that can be recognized by HERV-K env-specific CAR(+) T cells, we observed a significant antitumor effect.
Adoptive cellular immunotherapy with HERV-K env-specific CAR(+) T cells represents a clinically appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors.
人类内源性逆转录病毒（HERV-K）包膜（env）蛋白是一种肿瘤相关抗原（TAA），在黑色素瘤细胞而非正常细胞上表达。本研究旨在构建一种嵌合抗原受体（CAR），使其表达于T细胞表面，从而靶向晚期黑色素瘤肿瘤细胞。
采用免疫组织化学（IHC）分析方法，检测220例黑色素瘤样本（处于不同疾病阶段）和139例正常器官供体组织中HERV-K蛋白的表达情况。利用基于转座子的睡美人（SB）系统，将源自小鼠单克隆抗体的HERV-K env特异性CAR导入T细胞。HERV-K env特异性CAR(+) T细胞在激活和增殖细胞（AaPC）上进行体外扩增，并对CAR的表达和特异性进行鉴定。这包括评估HERV-K特异性CAR(+) T细胞在小鼠异种移植模型中杀伤A375-SM转移性肿瘤的能力。
我们在黑色素瘤中检测到HERV-K env蛋白，而在正常组织中未检测到。T细胞电穿孔并在HERV-K(+) AaPC上进行筛选后，超过95%的基因修饰T细胞表达CAR，具有效应记忆表型，并以抗原特异性方式裂解HERV-K env(+)肿瘤靶标。尽管这种TAA明显从肿瘤细胞上脱落，仍可被HERV-K env特异性CAR(+) T细胞识别，但我们观察到显著的抗肿瘤作用。
采用HERV-K env特异性CAR(+) T细胞进行过继性细胞免疫治疗是晚期黑色素瘤一种具有临床吸引力的治疗策略，并为靶向其他实体瘤中的这种TAA提供了一种方法。
