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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 具体目标1。 进行I/II期临床试验，以表征抗CTLA-4单克隆抗体在滤泡B细胞非霍奇金淋巴瘤患者中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马约诊所）将包括36例可测量的滤泡性淋巴瘤复发后或耐药的常规治疗。 我们推测CTLA-4阻断剂在这种疾病背景下具有临床抗肿瘤作用，特别是在既往接受过肿瘤特异性疫苗治疗的患者中。 既往接种过疫苗的患者将占受试者的一半。 具体目标2。 确定抗CTLA-4治疗是否导致滤泡性淋巴瘤患者抗肿瘤免疫效应机制的全身募集。 在治疗之前和之后，将对外周血进行采样以测量：1）肿瘤特异性细胞因子释放和细胞毒性，2）记忆T细胞对回忆抗原刺激的响应性，3）循环T细胞的数量和活化状态，包括组成性表达CTLA-4的CD 4 + CD 25+调节性T细胞群，和4）肿瘤特异性抗体。 具体目标3。 研究抗CTLA-4治疗是否可以增加肿瘤微环境中T细胞效应器的数量和功能。 将在治疗前和治疗后对肿瘤进行活检，以表征肿瘤浸润淋巴细胞亚群（包括CD 4+、CD 8+和CD 4 + CD 25+调节性T细胞）的数量和活化状态，并评价体外扩增的肿瘤浸润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.