Innate Immune Cell Therapy with Stem Cell Transplants

描述（由申请人提供）：大约80%的化疗耐药中级非霍奇金淋巴瘤（NHL）患者在自体干细胞移植（ASCT）大剂量化疗后会复发。我们进一步加强化疗以改善ASCT预后的能力已达到平台期，因此需要开发新的治疗策略。利妥昔单抗是一种靶向CD20的嵌合单克隆抗体，在大多数b细胞NHL中发现。作为单一药物，利妥昔单抗对复发性淋巴瘤患者的完全缓解率<10%。尽管利妥昔单抗活性的其他机制已经被提出，但最近的研究已经确定抗体依赖性细胞毒性（ADCC）对其体内活性至关重要，这一过程涉及抗体Fc部分与Fc- γ受体（Fc- γ - r）在先天免疫系统细胞上的相互作用，特别是自然杀伤细胞（NK）细胞和单核细胞。此外，我们在人类B细胞淋巴细胞增殖小鼠模型中的结果显示，美罗华与低剂量白细胞介素(IL)-2联合使用时，疗效得到改善，进一步表明美罗华与IL-2应答的FcR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性先天免疫细胞治疗，并有效地在临床验证fc - γ - r对于体内有效对抗淋巴瘤细胞的ADCC至关重要。具体来说，我们的目标是：(1)对利妥昔单抗联合大剂量化疗ASCT进行免疫治疗的安全性和可行性研究，然后在移植前使用IL-2和GM-CSF在体内扩增后收集的NK细胞和单核细胞进行先天免疫细胞治疗。(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潜力。(3)研究IL-2和GM-CSF联合启动后NK细胞和单核细胞上fc - γ - r激活型和抑制性亚型的表达。总的假设是，IL-2和GM-CSF的启动将导致体内FcR的显著扩增，携带免疫效应物，并且这些收集的细胞在给予高剂量化疗的循环利妥昔单抗存在下输注时，将创造一个环境，促进逃脱高剂量化疗杀死的残余淋巴瘤细胞的ADCC。来自该试验的临床和实验室数据将成为未来II期研究的基础，以调查这种免疫治疗方法的有效性。

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.