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.
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