Wallen Herschel, Thompson John A, Reilly J Zachary, Rodmyre Rebecca M, Cao Jianhong, Yee Cassian
Department of Clinical Research, Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America.
PLoS One. 2009;4(3):e4749. doi: 10.1371/journal.pone.0004749. Epub 2009 Mar 9.
Adoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence.
METHODS/FINDINGS: We conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 10(10)/m(2); the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m(2)/dayx5 days). This design permits intra-patient comparison of in vivo T cell persistence pre- and post-fludarabine. Nineteen CTL infusions were administered to ten patients. No serious toxicities were observed. Three of nine evaluable patients experienced minor response or stable disease for periods of 5.8-11.0 months with two additional patients demonstrating delayed disease stabilization. The median overall survival in this heavily pre-treated population was 9.7 months. Fludarabine led to a 2.9 fold improvement in the in vivo persistence of transferred CTL clones from a median of 4.5 days (range 0-38+) to 13.0 days (range 2-63+) (p<0.05). Fludarabine lymphodepletion increased plasma levels of the homeostatic cytokines IL-7 and IL-15. Surprisingly, fludarabine also increased the relative percentage of CD4+ T cells expressing the regulatory protein Foxp3.
CONCLUSIONS/SIGNIFICANCE: Lymphodepletion with fludarabine enhances transferred T cell persistence but suggest that additional improvements to optimize T cell survival and address regulatory T cells are critical in providing anti-tumor efficacy.
ClinicalTrials.gov NCT00317759.
过继性T细胞疗法涉及使用体外产生的抗原特异性细胞毒性T淋巴细胞，为免疫治疗提供了一种有前景的方法。越来越明显的是，使用过继转移T细胞的抗肿瘤疗效与其在体内的持续时间相关，并且只有在与某种形式的输注前患者预处理方案联合使用时才能实现。尚未确定一种既能带来积极益处又无严重毒性的最佳预处理方案。我们建立了一个独特的临床模型，可用于评估给定的预处理方案对人类过继转移T细胞的影响。在这项首次人体研究（FHCRC #1796）中，我们评估了氟达拉滨的使用，氟达拉滨是一种经美国食品药品监督管理局批准的试剂，具有可预测的淋巴细胞清除动力学和作用持续时间，作为一种预处理方案，可促进有助于体内T细胞持续存在的细胞因子和生长信号的稳态上调。
方法/发现：我们对难治性转移性黑色素瘤患者进行了一项I期研究。患者接受两次输注单一肿瘤反应性抗原特异性CTL克隆，扩增至10(10)/m(2)；第一次输注未进行氟达拉滨预处理，第二次CTL输注在氟达拉滨疗程（25 mg/m(2)/天×5天）后进行。这种设计允许在患者体内比较氟达拉滨治疗前后T细胞的体内持续时间。对10名患者进行了19次CTL输注。未观察到严重毒性。9名可评估患者中有3名经历了轻微反应或疾病稳定期，持续时间为5.8 - 11.0个月，另外2名患者表现出延迟的疾病稳定。在这个经过大量预处理的人群中，中位总生存期为9.7个月。氟达拉滨使转移的CTL克隆的体内持续时间提高了2.9倍，从中位4.5天（范围0 - 38 +）提高到13.0天（范围2 - 63 +）（p<0.05）。氟达拉滨淋巴细胞清除增加了稳态细胞因子IL - 7和IL - 15的血浆水平。令人惊讶的是，氟达拉滨还增加了表达调节蛋白Foxp3的CD4 + T细胞的相对百分比。
结论/意义：氟达拉滨淋巴细胞清除增强了转移T细胞的持续时间，但表明进一步优化T细胞存活和解决调节性T细胞问题对于提供抗肿瘤疗效至关重要。
ClinicalTrials.gov NCT00317759。
