Adoptive transfer of bryostatin-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro.
Adoptive transfer of bryostatin-activated tumor-sensitized lymphocytes prevents or destroys tumor metastases without expansion in vitro.
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苔藓抑素激活的肿瘤致敏淋巴细胞的过继转移可预防或破坏肿瘤转移，而无需体外扩增。
DOI：
10.1097/00002371-199510000-00002
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
Barrett,SK
中科院分区：
文献类型：
--
作者：
Fleming,MD;Bear,HD;Lipshy,K;Kostuchenko,PJ;Portocarero,D;McFadden,AW;Barrett,SK
由于长期细胞培养的要求会使过继细胞免疫疗法变得繁琐，因此设计了实验来确定用bryostatin 1和离子霉素(B/I)短暂激活的较小数量的肿瘤致敏T细胞是否可以立即返回到受体小鼠，而不需要体外扩增，并且仍然具有体内的抗肿瘤作用。从荷有进展性MCA-105和MCA-203足垫肉瘤的小鼠的延髓肿瘤引流淋巴结(DLN)中获取细胞，用B/I处理18h，然后洗涤这些细胞并立即转移到幼小C57B1/6小鼠。在一些实验中，这些小鼠在过继转移前接受500rad的照射，并在接受激活的淋巴细胞后给予白细胞介素2(IL-2,7500IU ip，bid，连续3天)。受体小鼠在接受活化的淋巴细胞后6~32天用肉瘤细胞(4×105，iv)攻击。在肿瘤攻击前接受106B/I活化淋巴细胞的小鼠的转移率明显低于对照组。这种保护作用不需要外源IL-2或宿主照射。用Thy-1同源供体，在给予IL-2的同时，受者体内有B/I激活的T细胞扩增，这些细胞是静脉注射肿瘤攻击后7天小鼠肺内浸润液中的显著成分(占总细胞的15%)。将这些B/I“脉冲”细胞与环磷酰胺(CYP)和IL-2结合。治疗已经建立的(3天)转移的小鼠可以显著减少肺结节，在许多接受治疗的小鼠中完全消退，这是单独使用CYP或CYP+IL-2很少看到的。因此，过继转移肿瘤致敏的B/I激活的DLN细胞可提供对iv肿瘤攻击的保护，而无需事先体外扩增效应细胞。表型研究表明，B/I激活的供体细胞在过继转移后确实在受体小鼠中扩张，并可以移动到肿瘤部位。此外，当与化疗相结合时，这些细胞可以介导对已确定的肿瘤转移的治疗效果。
Because the requirement for long-term cell culture can make adoptive cellular immunotheraphy cumbersome, experiments were designed to determine whether smaller numbers of tumer-sensitized T cells activated briefly with bryostatin 1 and ionomycin (B/I) could be returned immediately to recipient mice without in vitro expansion and still have an anti-tumor effect in vivo. Popliteal tumor-draining lymph nodes (DLNs) from mice bearing progressive MCA-105 and MCA-203 footpad sarcomas were harvested and treated for 18 h with B/I. These cells were then washed and transferred immediately to naive C57B1/6 mice. In some experiments, these mice were irradiated (500 rads) before adoptive transfer and were given interleukin-2 (IL-2, 7,500 IU ip, bid for 3 days) after receiving the activated lymphocytes. Recipient mice were challenged with sarcoma cells (4 x 10 5 iv) 6 to 32 days after receiving the activated lymphocytes. Mice receiving 10 6 B/I activated lymphocytes before tumor challenge had significantly fewer metastases than did controls. This protective effect did not require exogenous IL-2 or host irradiation. Using Thy-1 congenic donors, it was shown that B/I-activated T cells expanded in recipients when IL-2 was also given, and these cells were a prominent component (15% of total cells) in the infiltrates found in the lungs of mice 7 days after iv tumor challenge. Combining these B/I-“pulsed” cells with cyclophosphamide (CYP) and IL-2. to treat mice with estabilished (3-day) metastases resulted in significant reduction in pulmonary nodules, with complete regression in many of the treated mice, which was rarely seen with CYP alone or with CYP+ IL-2. Thus, adoptive transfer of tumor-sensitized, B/I activated DLN cells confers protection against iv tumor challenge, without prior in vitro expansion of the effector cells. Phenotyping studies demonstrate that donor cells activated with B/I do expand in recipient mice after adoptive transfer and can move to sites of tumor. Moreover, these cells can mediate a therapeutic effect on established tumor metastases, when combined with chemotherapy.