Development of a novel cell-based immune therapy using Nanoparticles and natural IgM-producing phagocytic B cells

使用纳米颗粒和天然产生 IgM 的吞噬 B 细胞开发新型细胞免疫疗法

基本信息

批准号：
9262189
负责人：
Xuemei Zhong
金额：
$ 18.68万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262189
关键词：
Address Adoptive Immunotherapy Adoptive Transfer Advanced Malignant Neoplasm Age Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Antigen Presentation Apoptotic Autoantigens B-Lymphocytes Blood Banks Body cavities CD19 gene Cancer Patient Cancer Remission Cancerous Cell Count Cell Death Cell physiology Cells Code Combined Modality Therapy Development Diphtheria Toxin Drug resistance Environment Evolution Future Germ Cells Goals Human Immune response Immune system Immunofluorescence Immunologic Immunoglobulin M Immunologic Monitoring Immunologic Surveillance Immunotherapy In Vitro Incubated Individual Infiltration Inflammation Injection of therapeutic agent Interleukin-10 Lecithin Lipids Liposomes Maintenance Malignant Neoplasms Mediating Melanoma Cell Methods Modeling Monitor Mus Neoplasm Metastasis Normal Cell Patients Peritoneal Phagocytes Phagocytosis Phospholipids Play Primary Neoplasm Process Production Regulation Reporting Research Resistance development Role Second Primary Cancers Signal Pathway Soldier System Testing Time Tissues Tumor Antigens Tumor Cell Line anticancer research base body cavity cancer cell cancer heterogeneity cancer immunotherapy cancer prevention cancer therapy carcinogenesis cell growth cell motility chemokine chemotherapy clinical application combat controlled release cytokine design drug development experimental study in vivo knockin animal melanoma mouse model nanoparticle neoplastic cell novel novel therapeutics prevent protein expression public health relevance self-renewal success tumor tumor heterogeneity weapons

项目摘要

DESCRIPTION (provided by applicant): Tumor heterogeneity and drug-resistance are the leading challenges for cancer immunotherapy. Our goal is to explore the immune surveillance mechanism to develop a broad tumor-recognizing immunotherapy that is self-sustaining and adaptive to tumor evolution. PRELIMINARY RESULTS: We have discovered natural IgM-producing phagocytic B cells (NIMPAB). In mice, L2pB1 cells are the major NIMPAB cells that produce natural IgM antibodies, which are known for their broad-spectrum cancer recognition. Our research has shown that L2pB1 cells can inhibit tumor cell growth and phagocytose apoptotic tumor cells. L2pB1 cells are also the predominant B cells that constitutively express the anti-inflammatory cytokine IL-10 and inducibly express the highest level of IL-10 among all B cells. HYPOTHESIS: We hypothesize that L2pB1 cells have a unique repertoire of broad cancer-recognizing natural IgM antibodies as well as multiple anti-cancer functions. L2pB1 cells might play fundamental roles in cancer immune surveillance through cancer cell recognition, inhibition, antigen presentation and clearance by phagocytosis with tight control of inflammation that prevents tissue damage. Boosting L2pB1 cell number and functions may induce cancer remission and prevent secondary cancer development. APPROACH: To test this, we propose to utilize a combined therapy model using (1) intratumoral injection of L2pB1 cell-attracting chemokines packaged in nanoparticles for controlled release. (2) Adoptive transfer of PtC-liposome expanded L2pB1 cells from self or healthy donors. To facilitate these experiments, we generated a novel knock-in animal model, which allows us to track, monitor and quantify L2pB1 cells in vivo. It also allows inducible depletion of L2pB1 cells at any time. We will inoculate 3 different tumor cell lines in these mice and evaluate tumor inhibition with this combined treatment. NOVELTY: Current immunotherapy strategies utilize the "weapons" (molecules) and "soldiers" (cells). Our proposed cancer therapy introduces the "commander" of our immune surveillance system to establish a sustainable "command center" with more efficient regulation and adaptation to the heterogeneity of tumors. FUTURE CLINICAL APPLICATION: If we achieve the goals of our study, we would be able to cryopreserve patients' NIMPAB cells before chemotherapy. Alternatively, if some patients are deficient in NIMPAB cells, they could receive a NIMPAB transfer from healthy donors. As NIMPAB can self-renew, a blood bank of NIMPAB can be established from healthy donors or any individual at a young age to use in case the cells are needed when the respective donor becomes older. SIGNIFICANCE: The proposed novel therapy model will significantly advance the cancer immunotherapy field by providing a potential self-renewable therapy for both cancer treatment and cancer prevention. This new therapy addresses the current challenges of lack of sustainability and adaptation to cancer heterogeneity, and will provide a giant leap forward in the cancer immunotherapy field.

描述（由申请人提供）：肿瘤异质性和耐药性是癌症免疫治疗的主要挑战，我们的目标是探索免疫监视机制，以开发一种可自我维持且初步适应肿瘤进化的广泛肿瘤识别免疫疗法。结果：我们在小鼠中发现了天然产生 IgM 的吞噬 B 细胞 (NIMPAB)，L2pB1 细胞是产生 IgM 的主要 NIMPAB 细胞。产生天然 IgM 抗体，以其广谱癌症识别而闻名，我们的研究表明，L2pB1 细胞可以抑制肿瘤细胞生长并吞噬凋亡的肿瘤细胞，也是组成性表达抗炎细胞因子的主要 B 细胞。 IL-10 且在所有 B 细胞中诱导表达 IL-10 的水平最高。假设：我们认为 L2pB1 细胞具有独特的功能。广泛的癌症识别天然 IgM 抗体以及多种抗癌功能可能通过癌细胞识别、抑制、抗原呈递和吞噬作用清除，并严格控制炎症来防止组织损伤，从而在癌症免疫监视中发挥重要作用。增加 L2pB1 细胞数量和功能可能会诱导癌症缓解并预防继发性癌症发展。方法：为了测试这一点，我们建议采用 (1) 瘤内注射的联合治疗模型。 L2pB1 细胞吸引趋化因子包装在纳米颗粒中用于控制释放 (2) 来自自身或健康供体的 PtC 脂质体扩增的 L2pB1 细胞的过继转移为了促进这些实验，我们生成了一种新的敲入动物模型，这使我们能够追踪。、体内监测和定量 L2pB1 细胞它还允许随时诱导消耗 L2pB1 细胞。我们将在这些细胞中接种 3 种不同的肿瘤细胞系。新颖性：当前的免疫治疗策略利用“武器”（分子）和“士兵”（细胞），我们提出的癌症治疗引入了我们的免疫监视系统的“指挥官”，以建立可持续的“免疫监视系统”。指挥中心”，具有更有效的调节和适应肿瘤异质性的能力。未来的临床应用：如果我们实现研究目标，我们将能够冷冻保存患者的 NIMPAB如果某些患者缺乏 NIMPAB 细胞，他们可以接受健康捐献者的 NIMPAB 移植。由于 NIMPAB 可以自我更新，因此可以从健康捐献者或任何年轻个体建立 NIMPAB 血库。意义：所提出的新型治疗模型将为癌症治疗和癌症预防提供潜在的自我更新疗法，从而显着推进癌症免疫治疗领域。该疗法解决了当前缺乏可持续性和适应癌症异质性的挑战，并将在癌症免疫治疗领域带来巨大飞跃。