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

 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，以开发一种广泛的肿瘤识别免疫疗法，这种免疫疗法能够自我维持并适应肿瘤的演变。初步结果：我们已经发现了天然的IgM产生吞噬B细胞（NIMPAB）。在小鼠中，L2 pB 1细胞是产生天然IgM抗体的主要NIMPAB细胞，这些抗体以其广谱癌症识别而闻名。我们的研究表明，L2 pB 1细胞能够抑制肿瘤细胞的生长并吞噬凋亡的肿瘤细胞。L2 pB 1细胞也是组成型表达抗炎细胞因子IL-10的主要B细胞，并且在所有B细胞中诱导表达最高水平的IL-10。假设：我们假设L2 pB 1细胞具有广泛的癌症识别天然IgM抗体的独特库以及多种抗癌功能。L2 pB 1细胞可能通过癌细胞识别、抑制、抗原呈递和吞噬清除在癌症免疫监视中发挥重要作用，并严格控制炎症，防止组织损伤。提高L2 pB 1细胞的数量和功能可以诱导癌症缓解并防止继发性癌症的发展。方法：为了测试这一点，我们建议利用一种联合治疗模型，使用（1）肿瘤内注射包装在纳米颗粒中的L2 pB 1细胞吸引趋化因子，以控制释放。(2)从自身或健康供体连续转移PtC-脂质体扩增的L2 pB 1细胞。为了促进这些实验，我们产生了一种新的敲入动物模型，这使我们能够在体内跟踪，监测和定量L2 pB 1细胞。它还允许在任何时间诱导L2 pB 1细胞的耗竭。我们将在这些小鼠中接种3种不同的肿瘤细胞系，并评估这种联合治疗的肿瘤抑制作用。新奇：目前的免疫治疗策略利用“武器”（分子）和“士兵”（细胞）。我们提出的癌症疗法引入了我们免疫监视系统的“指挥官”，以建立一个可持续的“指挥中心”，更有效地调节和适应肿瘤的异质性。未来的临床应用：如果我们实现了我们的研究目标，我们将能够在化疗前冷冻保存患者的NIMPAB细胞。或者，如果一些患者缺乏NIMPAB细胞，他们可以接受来自健康供体的NIMPAB转移。由于NIMPAB可以自我更新，因此可以从健康供体或年轻时的任何个体建立NIMPAB血库，以在相应供体变老时需要细胞的情况下使用。重要性：所提出的新型治疗模式将通过为癌症治疗和癌症预防提供潜在的自我更新疗法来显著推进癌症免疫治疗领域。这种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的飞跃。

 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.