Karpanen Terhi, Olweus Johanna
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet and K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Ullernchausseen 70, N-0379 Oslo, Norway.
Mol Oncol. 2015 Dec;9(10):2019-42. doi: 10.1016/j.molonc.2015.10.006. Epub 2015 Oct 20.
T lymphocytes can be redirected to recognize a tumor target and harnessed to combat cancer by genetic introduction of T-cell receptors of a defined specificity. This approach has recently mediated encouraging clinical responses in patients with cancers previously regarded as incurable. However, despite the great promise, T-cell receptor gene therapy still faces a multitude of obstacles. Identification of epitopes that enable effective targeting of all the cells in a heterogeneous tumor while sparing normal tissues remains perhaps the most demanding challenge. Experience from clinical trials has revealed the dangers associated with T-cell receptor gene therapy and highlighted the need for reliable preclinical methods to identify potentially hazardous recognition of both intended and unintended epitopes in healthy tissues. Procedures for manufacturing large and highly potent T-cell populations can be optimized to enhance their antitumor efficacy. Here, we review the current knowledge gained from preclinical models and clinical trials using adoptive transfer of T-cell receptor-engineered T lymphocytes, discuss the major challenges involved and highlight potential strategies to increase the safety and efficacy to make T-cell receptor gene therapy a standard-of-care for large patient groups.
通过基因导入具有特定特异性的T细胞受体，可使T淋巴细胞重新定向识别肿瘤靶点，并用于对抗癌症。最近，这种方法在先前被认为无法治愈的癌症患者中引发了令人鼓舞的临床反应。然而，尽管前景广阔，T细胞受体基因疗法仍面临诸多障碍。识别能够有效靶向异质性肿瘤中的所有细胞同时又不损伤正常组织的表位，可能仍然是最具挑战性的任务。临床试验经验揭示了与T细胞受体基因疗法相关的风险，并凸显了需要可靠的临床前方法来识别健康组织中对预期和非预期表位的潜在有害识别。制造大量高效T细胞群体的程序可以进行优化，以增强其抗肿瘤功效。在此，我们回顾了使用过继性转移T细胞受体工程化T淋巴细胞的临床前模型和临床试验所获得的现有知识，讨论其中涉及的主要挑战，并强调提高安全性和有效性的潜在策略，以使T细胞受体基因疗法成为广大患者群体的标准治疗方法。
