A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer
A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer
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DOI：
10.1158/1078-0432.ccr-06-1183
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发表时间：
2006-10-15
影响因子：
11.5
通讯作者：
Hwu, Patrick
中科院分区：
文献类型：
--
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
目的：进行I期研究以评估使用基因修饰的自体T细胞治疗转移性卵巢癌的过继免疫疗法的安全性。具有抗卵巢癌相关抗原α-叶酸受体（FR）反应性的T细胞通过用嵌合基因遗传修饰自体T细胞产生，所述嵌合基因掺入抗FR单克隆抗体。在一个实施方案中，抗体是与Fc受体γ链的信号传导结构域连接的抗体链。患者被分配到研究中的两个队列之一。队列1中的8名患者接受了剂量递增的T细胞联合高剂量白细胞介素-2治疗，队列2中的6名患者接受了双特异性T细胞治疗。（与FR和同种异体细胞反应），然后用同种异体外周血单核细胞免疫。队列1中的5名患者经历了一些3至4级治疗相关毒性，这可能是由于白细胞介素-2给药，这可以通过标准措施来控制。队列2中的患者出现相对轻度的副作用，症状为1至2级。在任何患者中均未观察到肿瘤负荷降低。追踪队列1中In-111标记的过继转移T细胞显示，除了一名患者在腹膜存款中检测到一些信号外，T细胞缺乏对肿瘤的特异性定位。PCR分析显示，基因修饰的T细胞在转移后的前2天大量存在于循环中，但在大多数患者中，这些细胞在1个月后迅速下降到几乎检测不到。一种抑制因子在治疗期间，这显着降低了基因修饰的T细胞对FR+ tumor cells.Conclusions的反应能力，在血清中测试的6例患者中的3例，大量的基因修饰的肿瘤反应性T细胞可以安全地给予患者，但这些细胞不坚持大量长期。未来的研究需要采用策略来延长T细胞的持久性。这份报告是第一份记录使用遗传重定向T细胞治疗卵巢癌的报告。
Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer.Experimental Design: T cells with reactivity against the ovarian cancer-associated antigen a-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor gamma chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells.Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking In-111-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells.Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.