PHASE I/II STUDY OF ANTI-CTLA-4 MONOCLONAL ANTIBODY (MDX-010) IN FOLLICULAR N

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 具体目的1.开展一项I/II期临床试验，研究抗CTLA-4单抗治疗滤泡性B细胞非霍奇金淋巴瘤的安全性和临床疗效。 这项多中心研究(加州大学洛杉矶分校和梅奥诊所)将包括36名可测量的滤泡性淋巴瘤患者，这些患者在常规治疗后复发或耐药。我们推测，在这种疾病环境下，CTLA-4阻断将具有临床抗肿瘤效果，特别是在以前接受过肿瘤特异性疫苗治疗的患者中。以前接种过疫苗的患者将占受试者的一半。 特定目的2.确定抗CTLA-4治疗是否导致滤泡性淋巴瘤患者全身性募集抗肿瘤免疫效应机制。 治疗前后采集外周血检测：1)肿瘤特异性细胞因子的释放和细胞毒作用，2)记忆T细胞对Recall抗原刺激的反应性，3)循环T细胞的数量和激活状态，包括组成表达CTLA-4的CD4CD25调节性T细胞群，以及4)肿瘤特异性抗体。 具体目的3.研究抗CTLA-4治疗是否能增加肿瘤微环境中T细胞效应器的数量和功能。 肿瘤治疗前后将进行活组织检查，以确定肿瘤浸润性淋巴细胞亚群(包括CD4、CD8和CD4CD25调节性T细胞)的数量和激活状态，并评估体外扩增的肿瘤浸润性T细胞识别和杀伤自体肿瘤细胞的能力。

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. Specific Aim 1. Perform a phase I/II clinical trial to characterize the safety and clinical efficacy of anti-CTLA-4 monoclonal antibody in patients with follicular B cell non-Hodgkin's lymphoma. This multi-center study (UCLA and Mayo Clinic) will include 36 patients with measurable follicular lymphoma relapsing after or resistant to conventional therapies. We theorize that CTLA-4 blockade will have clinical anti-tumor effects in this disease setting, particularly in patients who have received prior tumor-specific vaccine therapy. Previously vaccinated patients will represent one-half of subjects. Specific Aim 2. Determine whether anti-CTLA-4 treatment results in systemic recruitment of anti-tumor immune effector mechanisms in patients with follicular lymphoma. Before and after therapy, peripheral blood will be sampled for measurement of: 1) Tumor-specific cytokine release and cytotoxicity, 2) Responsiveness of memory T cells to stimulation with recall antigens, 3) The numbers and activation state of circulating T cells, including the CD4+CD25+ regulatory T cell population which constitutively expresses CTLA-4, and 4) Tumor-specific antibodies. Specific Aim 3. Investigate whether anti-CTLA-4 therapy can boost the number and function of T cell effectors in the tumor microenvironment. Tumors will be biopsied pre- and post-treatment to characterize the number and activation state of tumor-infiltrating lymphocyte subpopulations (including CD4+, CD8+, and CD4+CD25+ regulatory T cells), and to evaluate the ability of in vitro-expanded tumor-infiltrating T cells to recognize and kill autologous tumor cells.