Abad John D, Wrzensinski Claudia, Overwijk Willem, De Witte Moniek A, Jorritsma Annelies, Hsu Cary, Gattinoni Luca, Cohen Cyrille J, Paulos Chrystal M, Palmer Douglas C, Haanen John B A G, Schumacher Ton N M, Rosenberg Steven A, Restifo Nicholas P, Morgan Richard A
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunother. 2008 Jan;31(1):1-6. doi: 10.1097/CJI.0b013e31815c193f.
Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-gamma secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.
采用肿瘤浸润淋巴细胞对转移性黑色素瘤患者进行过继性细胞转移治疗已显示出显著的客观缓解率。这些当前疗法的一个主要局限性是经常无法分离出用于治疗的肿瘤反应性淋巴细胞。用编码肿瘤抗原特异性T细胞受体（TCR）的逆转录病毒载体对外周血淋巴细胞进行基因工程改造可绕过这一限制。为了评估TCR基因治疗的疗效，建立了一个小鼠治疗模型。构建了一种逆转录病毒载体，其编码靶向B16黑色素瘤抗原gp100的pmel-1 TCR基因。对C57BL/6淋巴细胞进行转导可有效表达pmel-1 TCR。通过干扰素-γ分泌测定法检测，用这种逆转录病毒转导的淋巴细胞能特异性识别gp100刺激的靶细胞。将基因工程改造的淋巴细胞转移到荷B16肿瘤的小鼠体内后，显著减缓了肿瘤的发展。肿瘤治疗的有效性与所给予的TCR工程化T细胞的数量直接相关。这些结果表明，靶向天然肿瘤抗原的TCR基因治疗可显著延迟已建立肿瘤的生长。当将C57BL/6淋巴细胞添加到抗原反应性pmel-1 T细胞中时，可观察到pmel-1 T细胞治疗B16黑色素瘤的能力下降，这表明未转导的细胞可能对TCR基因治疗有害。该模型可能是评估未来基于TCR基因转移策略的有力工具。
