CLINICAL TRIAL: ADMINISTRATION OF LMP1- AND LMP2-SPECIFIC CYTATOXIC T-LYMPHOCYTE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项I期剂量递增试验旨在评估递增剂量的自体LMP 1和LMP 2特异性CTL的安全性。我们一直在使用修改后的持续再评估方法（mCRM）设计基于T细胞疗法的新试验。我们使用这种基于模型的适应性设计的理由源于我们对这些细胞抑制疗法的大量经验，与细胞毒性药物不同，这些疗法在拟定剂量范围内具有较浅的剂量毒性特征。因此，加速剂量递增的设计不应损害患者的安全性。基于先前的T细胞免疫治疗试验的模拟表明，这种设计提供了将适当剂量宣布为MTD的更高概率，并允许在较低和可能次优的剂量水平下累积较少数量的患者。更重要的是，我们的模拟表明，与标准3+3设计相比，使用mCRM策略不会导致毒性增加。 没有随机分组或对照组。 我们和其他人已经证明了免疫功能正常的患者中EBV阳性NPC的CTL治疗的可行性，提供了EBV-CTL在该患者群体中抗肿瘤活性的初步证据。34，35然而，并非所有患者都有反应，这表明需要进一步改进。我们建议，CTL失败可以通过增加输注的CTL产物的特异性来克服。也就是说，输注LMP 1和LMP 2特异性CTL将产生比EBV特异性CTL更大的临床益处。这种方法的基本原理是直截了当的：通过标准方法产生的EBV特异性CTL系由T细胞克隆主导，而T细胞克隆对NPC中表达的亚显性EBV蛋白LMP 1和LMP 2不反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This Phase I dose-escalation trial is designed to evaluate the safety of escalating doses of autologous LMP1- and LMP2-specific CTL. We have been using a modified version of the continual reassessment method (mCRM) in the design of new trials on T-cell based therapies. Our rationale for the use of this model-based, adaptive design stems from our considerable experience with these cytostatic therapies, which unlike cytotoxic agents, have shallow dose-toxicity profiles over the range of doses proposed. As such, designs with more accelerated dose escalations should not compromise the safety of our patients. Simulations based on previous T-cell immunotherapy trials, indicate that this design provides higher probabilities of declaring the appropriate dose as the MTD and allows smaller numbers of patients to be accrued at lower and possibly suboptimal dose levels. More importantly, our simulations indicate that use of the mCRM strategy will not lead to increased toxicities, compared with standard 3+3 designs. There is no randomization or control groups. We and others have demonstrated the feasibility of CTL therapy for EBV-positive NPC in immunocompetent patients, providing preliminary evidence of anti-tumor activity of EBV-CTL in this patient population.34,35 Not all patients responded, however, suggesting the need for further improvement. We propose that CTL failure can be overcome by increasing the specificity of the infused CTL product. That is, infusion of CTL specific for LMP1 and LMP2 will produce greater clinical benefit than EBV-specific CTL. The rationale for this approach is straight forward: EBV-specific CTL lines generated by standard methods are dominated by T-cell clones not reactive to the subdominant EBV proteins LMP1 and LMP2 expressed in NPC.