Thistlethwaite Fiona C, Elkord Eyad, Griffiths Richard W, Burt Deborah J, Shablak Alaaeldin M, Campbell John D M, Gilham David E, Austin Eric B, Stern Peter L, Hawkins Robert E
Cancer Research UK Department of Medical Oncology, University of Manchester and Christie Hospital NHS Foundation Trust, Manchester, UK.
Cancer Immunol Immunother. 2008 May;57(5):623-34. doi: 10.1007/s00262-007-0400-6. Epub 2007 Sep 27.
CD4(+)CD25(+) regulatory T (T(reg)) cells are present in increased numbers in patients with advanced cancer and CD25(+) T cell depletion potentiates tumour immunity in animal models. The aim of this study was to assess the feasibility and safety of adoptive transfer of CD25(+) depleted autologous T cells in patients with advanced renal cell carcinoma and to examine resulting changes in lymphocyte subsets.
Six patients with advanced renal cell carcinoma underwent leukapheresis followed by conditioning chemotherapy with cyclophosphamide and fludarabine. The autologous leukapheresis product was depleted of CD25(+) cells using CliniMACS System then re-infused into the patient.
Efficient CD25(+) depletion from all leukapheresis products was achieved and 0.55-5.87 x 10(7)/kg CD3(+) cells were re-infused. Chemotherapy related haematological toxicity was observed, but blood counts recovered in all patients allowing discharge after a mean inpatient stay of 21 days. One patient subsequently developed a rapidly progressive neurological syndrome. A transient reduction in CD25(+) subset was noted in the peripheral blood of 5 out of 6 patients with evidence of increased T cell responses to PHA in 4 out of 6 patients. One patient showed increased specific proliferative responses to the tumour associated antigen h5T4 coinciding with the nadir of T(reg) cells.
Given the transient nature of the reduction in CD25(+) subset and the observed toxicity there is a need to explore further strategies to improve the safety and efficacy of this approach. Nevertheless, the results provide proof of concept in potentiation of tumour antigen T cell responses when T(reg) cell levels are depleted.
晚期癌症患者体内CD4(+)CD25(+)调节性T（T(reg)）细胞数量增多，在动物模型中，CD25(+) T细胞耗竭可增强肿瘤免疫。本研究旨在评估晚期肾细胞癌患者过继性转移CD25(+)耗竭的自体T细胞的可行性和安全性，并检测淋巴细胞亚群的变化。
6例晚期肾细胞癌患者接受白细胞分离术，随后接受环磷酰胺和氟达拉滨预处理化疗。使用CliniMACS系统从自体白细胞分离产物中去除CD25(+)细胞，然后重新注入患者体内。
所有白细胞分离产物均实现高效CD25(+)耗竭，重新注入的CD3(+)细胞为0.55 - 5.87×10(7)/kg。观察到化疗相关血液学毒性，但所有患者血细胞计数均恢复，平均住院21天后出院。1例患者随后出现快速进展的神经综合征。6例患者中有5例外周血CD25(+)亚群短暂减少，6例患者中有4例对PHA的T细胞反应增强。1例患者对肿瘤相关抗原h5T4的特异性增殖反应增强，同时T(reg)细胞处于最低点。
鉴于CD25(+)亚群减少的短暂性以及观察到的毒性，需要进一步探索改善该方法安全性和有效性的策略。尽管如此，结果为T(reg)细胞水平耗竭时增强肿瘤抗原T细胞反应提供了概念验证。
