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

 描述(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测机制，以开发一种广泛的肿瘤识别免疫疗法，这种疗法是自我维持的，并适应肿瘤的演变。初步结果：我们发现了天然的产生IgM的吞噬细胞B细胞(NIMPAB)。在小鼠中，L2pB1细胞是产生天然IgM抗体的主要NIMPAB细胞，这种抗体以其广谱的癌症识别而闻名。我们的研究表明，L2pB1细胞可以抑制肿瘤细胞的生长，并吞噬凋亡的肿瘤细胞。在所有B细胞中，L2pB1细胞也是主要的B细胞，它结构性地表达抗炎细胞因子IL-10，并诱导表达最高水平的IL-10。假设：我们假设L2pB1细胞具有独特的广泛识别癌症的天然IgM抗体以及多种抗癌功能。L2pB1细胞可能通过对癌细胞的识别、抑制、抗原呈递和吞噬清除以及严格控制炎症来防止组织损伤，在癌症免疫监测中发挥重要作用。增加L2pB1细胞的数量和功能可能会诱导癌症缓解，防止癌症的继发性发展。方法：为了验证这一点，我们建议使用一种联合治疗模式，使用(1)瘤内注射以纳米颗粒包装的L2pB1细胞吸引趋化因子进行控制释放。(2)过继转移PTC-脂质体扩增的自身或健康供者的L2pB1细胞。为了方便这些实验，我们建立了一种新的敲入动物模型，使我们能够在体内跟踪、监测和量化L2pB1细胞。它还允许L2pB1细胞在任何时候被诱导耗尽。我们将在这些小鼠体内接种3种不同的肿瘤细胞系，并评估这种联合治疗对肿瘤的抑制作用。新颖性：目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方法引入了我们免疫监测系统的“指挥官”，以建立一个可持续的“指挥中心”，对肿瘤的异质性进行更有效的调节和适应。未来的临床应用：如果我们实现了研究的目标，我们将能够在化疗前冷冻患者的NIMPAB细胞。或者，如果一些患者缺乏NIMPAB细胞，他们可以接受健康捐赠者的NIMPAB转移。由于NIMPAB可以自我更新，可以从健康的捐赠者或任何年轻的个人建立NIMPAB血库，以备各自捐赠者变老时需要使用。意义：拟议的新治疗模式将显著推进癌症免疫治疗领域，为癌症治疗和癌症预防提供一种潜在的自我更新的治疗方法。这一新疗法解决了目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实现巨大飞跃。

 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.