Mazumder A, Eberlein T J, Grimm E A, Wilson D J, Keenan A M, Aamodt R, Rosenberg S A
Cancer. 1984 Feb 15;53(4):896-905. doi: 10.1002/1097-0142(19840215)53:4<896::aid-cncr2820530414>3.0.co;2-e.
In previous in vitro studies, the authors showed that phytohemagglutinin (PHA) stimulated peripheral blood lymphocytes (PBL) from cancer patients to generate cells that were lytic for fresh autologous tumor but not for lymphocytes or lymphoblasts. Thus, after IRB approval, a phase I clinical protocol was instituted in cancer patients who had failed all other therapy to determine the toxicity and effects, in vivo, of the infusion of large numbers of such PHA activated autologous PBL. Ten patients were treated on the protocol, six with sarcoma, one with melanoma, and three with colorectal cancer. Up to a total of 1.7 X 10(11) PBL were obtained from 7 to 15 successive leukaphereses, the cells from each leukapheresis being incubated in vitro in medium containing PHA and human AB serum for 2 days and then reinfused following the next leukapheresis 2 days later. Toxicity encountered included fever and chills in 10/10 patients, headaches in 5/10, nausea and vomiting in 3/10, and requirement for erythrocyte transfusion in 8/10. No evidence for autoimmune disease, abnormal serum chemical or coagulation studies, or pulmonary emboli was found. 111Indium trafficing studies showed distribution of infused cells mainly to the spleen and liver, with some accumulation in the lungs and tumor especially after repeated infusions. In 9/10 patients, activated PBL were detected in the peripheral circulation by the sixth leukapheresis. Evidence for this was found by assaying the incorporation of tritiated thymidine (3H-Tdr) into, and lysis of fresh tumor cells by, unstimulated PBL from successive leukaphereses. No tumor regression was seen in these patients with bulk disease. These studies demonstrated that large numbers of PHA-activated PBL can be safely obtained and infused into humans, achieving an increase in the number of circulating activated cells with evidence of migration of cells to tumor, lungs, liver and spleen. Further studies of the use of activated lymphocyte infusion in conjunction with chemotherapy in humans are in progress.
在先前的体外研究中，作者表明植物血凝素（PHA）刺激癌症患者的外周血淋巴细胞（PBL）产生对新鲜自体肿瘤具有裂解作用的细胞，但对淋巴细胞或淋巴母细胞无裂解作用。因此，在获得机构审查委员会（IRB）批准后，针对所有其他治疗均告失败的癌症患者制定了一项I期临床方案，以确定输注大量此类PHA激活的自体PBL在体内的毒性和效果。10名患者按照该方案接受治疗，其中6例为肉瘤患者，1例为黑色素瘤患者，3例为结直肠癌患者。通过7至15次连续的白细胞分离术，总共获得了高达1.7×10¹¹个PBL，每次白细胞分离术所获细胞在含有PHA和人AB血清的培养基中于体外孵育2天，然后在2天后的下一次白细胞分离术后回输。所遇到的毒性反应包括10/10的患者出现发热和寒战，5/10的患者出现头痛，3/10的患者出现恶心和呕吐，8/10的患者需要输注红细胞。未发现自身免疫性疾病、血清化学或凝血检查异常或肺栓塞的证据。铟-111示踪研究显示，输注的细胞主要分布于脾脏和肝脏，在肺部和肿瘤中也有一些聚集，尤其是在重复输注后。在9/10的患者中，到第6次白细胞分离术时在外周循环中检测到了激活的PBL。通过检测连续白细胞分离术中未受刺激的PBL对氚标记胸腺嘧啶核苷（³H-Tdr）的掺入以及对新鲜肿瘤细胞的裂解作用，发现了这方面的证据。在这些有大块病灶的患者中未观察到肿瘤消退。这些研究表明，可以安全地获得大量PHA激活的PBL并输注给人类，使循环中的激活细胞数量增加，且有证据表明细胞迁移至肿瘤、肺、肝和脾。关于在人类中联合化疗使用激活淋巴细胞输注的进一步研究正在进行中。
