Innate Immune Cell Therapy with Stem Cell Transplants

描述(申请人提供)：大约80%的化疗耐药的中级非霍奇金淋巴瘤(NHL)患者将在大剂量化疗和自体干细胞移植(ASCT)后复发。我们进一步加强化疗以改善ASCT结果的能力已经达到了平台期，需要开发新的治疗策略。利妥昔单抗是一种针对CD20的嵌合单抗，存在于大多数B细胞非霍奇金淋巴瘤中。作为单一药物，利妥昔单抗对复发淋巴瘤患者的完全缓解率为10%，效果不明显。尽管利妥昔单抗的活性有其他机制被提出，但最近的研究表明，抗体依赖的细胞毒性(ADCC)是其体内活性的关键，这一过程涉及抗体的Fc部分与Fc-Gamma受体(Fc-Gamma-R)在天然免疫系统的细胞，特别是自然杀伤(NK)细胞和单核细胞上的相互作用。此外，我们在人B细胞淋巴细胞增殖的小鼠模型中的结果显示，当利妥昔单抗与低剂量白介素2(IL-2)联合使用时，其疗效得到改善，进一步表明利妥昔单抗与IL-2反应的FCR承载细胞之间存在重要的相互作用。我们建议在这些结果的基础上，研究一种新的免疫治疗方法，在接受ASCT的NHL患者中使用利妥昔单抗和过继的天然免疫细胞治疗，并在临床上有效地检验Fc-Gamma-R对于体内有效的ADCC抗淋巴瘤细胞至关重要的概念。具体地说，我们的目标是：(1)开展同时进行利妥昔单抗与大剂量化疗、ASCT结合的免疫治疗的安全性和可行性研究，然后使用移植前经IL-2和GM-CSF体内扩增后收集的NK细胞和单核细胞进行天然免疫细胞治疗；(2)对细胞因子启动后收集的免疫效应细胞进行表型和功能分析，包括ADCC潜能；以及(3)表征IL-2和GM-CSF联合启动后NK细胞和单核细胞上激活和抑制Fc-Gamma-R亚型的表达。总体假设是，用IL-2和GM-CSF启动将导致携带免疫效应器的FCR在体内显著扩大，当这些收集的细胞在大剂量化疗的循环利妥昔单抗存在的情况下输注时，将创造一个环境，促进逃脱高剂量化疗杀死的残留淋巴瘤细胞的ADCC。从这项试验中获得的临床和实验室数据将成为未来第二阶段研究的基础，以调查这种免疫疗法的有效性。

DESCRIPTION (provided by applicant): Approximately 80% of patients with chemo-resistant intermediate grade non-Hodgkin's lymphoma (NHL) will relapse following high-dose chemotherapy with autologous stem cell transplantation (ASCT). Our ability to further intensify chemotherapy to improve the outcome of ASCT has reached a plateau, necessitating a need for development of novel therapeutic strategies. Rituximab is a chimeric monoclonal antibody directed against CD20, found on most B-cell NHL. As a single agent, rituximab is modestly effective with <10% complete responses in patients with relapsed lymphoma. Although other mechanisms have been proposed for the activity of rituximab, recent work has established that antibody dependent cytotoxicity (ADCC) is critical for its in vivo activity, a process involving the interaction of the Fc portion of the antibody with Fc-gamma receptors (Fc-gamma-R) on cells of the innate immune system, particularly natural killer (NK) cells and monocytes. Furthermore, our results in a mouse model of human B cell lymphoproliferation show that the efficacy of rituximab is improved when it is given in combination with low dose interleukin (IL)-2, further suggesting an important interaction between rituximab and IL-2-responsive FcR bearing cells. We propose to build on these results and investigate a novel immunotherapy approach using rituximab with adoptive innate immune cellular therapy in NHL patients undergoing ASCT, and in effect clinically test the notion that Fc-gamma-R is critical to effective ADCC against lymphoma cells in vivo. Specifically, our aims are: (1) To conduct a safety and feasibility study of immunotherapy combining concurrent rituximab with high-dose chemotherapy, ASCT, followed by innate immune cellular therapy using NK cells and monocytes collected after in vivo expansion with IL-2 and GM-CSF prior to transplantation, (2) To perform phenotypic and functional analyses, including ADCC potential, of immune effector cells collected following cytokine priming, and (3) To characterize the expression of activating and inhibitory Fc-gamma-R subtypes on NK cells and monocytes following priming with the combination of IL-2 and GM-CSF. The overall hypothesis is that priming with IL-2 and GM-CSF will result in significant in vivo expansion of FcR, bearing immune effectors, and that these collected cells when infused in the presence of circulating rituximab, given with high-dose chemotherapy, will create an environment that will promote ADCC of residual lymphoma cells that escaped killing by high-dose chemotherapy. The clinical and laboratory data derived from this trial will form the basis for future phase II studies to investigate the efficacy of this immunotherapy approach.