Immunotherapy with peptide MHC tetramer isolated T cells

描述(由申请人提供)：T细胞表型的最新进展和 高速分拣已经聚合，允许直接测试重要的 免疫疗法的基本原则-具体地说，过继免疫疗法 抗原特异性T细胞将在体内清除表达抗原的细胞。 尽管在体外激活和扩增T细胞的免疫疗法已经显示 Promise，一种广泛适用的替代策略可能允许治疗 抗原特异性T细胞在显著激活之前。具体地说，多肽 主要组织相容性复合体(MHC)-四聚体可以识别T细胞 与独特的纳米肽特异结合的细胞 人类白细胞抗原(人类白细胞抗原)等位基因。这项技术允许 高纯度特异性T细胞抗原群体的分离与分离 来自外周血单核细胞(PBMC)的细胞。我们假设过 抗原特异性T细胞纯化群体的过继免疫治疗 细胞将对骨骼后免疫抑制的患者产生临床益处 骨髓/外周血干细胞移植。要测试的相关模型系统 这一假说存在于免疫受损的巨细胞病毒患者身上。 (CMV)感染或EB病毒(EBV)相关的LPD(LPD)。临床 利用扩展的管理CMV特定克隆实现了优势 体外和低至10(7)个细胞/M2PBMC被自体EBV体外激活 转化的B细胞。虽然这些策略在临床上是有效的，但它们 不能广泛应用，因为它们复杂且耗时，以 长达3至4个月的时间才能产生合适的细胞用于给药。 与这一费力的过程相比，一个令人兴奋的选择是直接隔离 外周血中CMV或EBV特异性T细胞的高速分选 与CMV或EBV多肽MHC四聚体结合。这一战略将允许快速 分离高达10-40×10(6)抗原特异性T细胞。这些细胞可以 然后直接给药，或在体外短暂时间后给药 激活和扩展。这项申请提出了临床前研究和 多肽MHC四聚体过继免疫治疗的初步临床试验 分选的T细胞。预计这些研究将提供一个重要的 对这一将有广泛应用的一般概念的原则证明 用于小血管疾病和癌症的抗原特异性过继免疫治疗。

DESCRIPTION (provided by applicant): Recent advances in T cell phenotyping and high speed sorting have coalesced to allow the direct testing of an important basic tenet in immunotherapy-specifically that adoptive immunotherapy with antigen specific T cells will eradicate antigen expressing cells in vivo. Although immunotherapy with T cells activated and expanded in vitro have shown promise, an alternative broadly applicable strategy may allow therapy with antigen specific T cells prior to significant activation. Specifically, peptide major histocompatibility complex (MHC)-tetramers allow the identification of T cells that specifically bind to unique nanopeptides in the context of a specific human leukocyte antigen (HLA) allele. This technology allows for the sorting and isolation of highly purified populations of antigens specific T cells from peripheral blood mononuclear cells (PBMC). We have hypothesized that the adoptive immunotherapy with purified populations of antigen specific T cells will have clinical benefits in patients immunosuppressed following bone marrow/peripheral blood stem cell transplant. A relevant model system to test this hypothesis exists in immuno-compromised patients with cytomegalovirus (CMV) infection or Epstein Barr virus (EBV) associated LPD (LPD). Clinical benefit has been achieved with administration CMV specific clones expanded in vitro and as few as 10(7) cells/M2PBMC activated in vitro with autologous EBV transformed B cells. While these strategies are clinically effective, they cannot be widely applied because they are complex and time-consuming, taking as long as to 3 to 4 months to generate the appropriate cells for administration. An exciting alternative to this laborious process would be to directly isolate CMV or EBV specific T cells from peripheral blood samples by high speed sorting with CMV or EBV peptide MHC tetramers. This strategy would allow for the rapid isolation of up to 10-40 x 10(6) antigen specific T cells. These cells could then be directly administered, or administered after a brief period of ex vivo activation and expansion. This application proposes pre-clinical studies and pilot clinical trials of adoptive immunotherapy with peptide MHC tetramer sorted T cells. It is anticipated that these studies would provide an important proof of principle for this general concept which would have wide application for antigen specific adoptive immunotherapy of vial disorders and cancer.