Lymphatic delivery of immunotherapy to prevent irAEs

淋巴递送免疫治疗以预防 irAE

• 批准号: 10552012
• 负责人: Eva M. Sevick-Muraca
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552012
• 关键词: 4T1; Adaptive Immune System; Advanced Malignant Neoplasm; Agonist; Animals; Antigens; Antitumor Response; Autoimmune Diseases; Biodistribution; Blood; Breast; Cancer Patient; Clinical; Clinical Research; Colon; Cross Presentation; Data; Development; Devices; Disease; Distant Metastasis; Dose; Drug Delivery Systems; Drug Exposure; Effectiveness; Fluorescence; Formulation; Histology; Home; Immune; Immune response; Immune system; Immunity; Immunologics; Immunotherapy; Implant; In complete remission; Inbred BALB C Mice; Innate Immune Response; Intravenous; Lymphatic; Lymphatic System; Malignant Neoplasms; Modeling; Mus; Needles; Neoplasm Metastasis; Normal tissue morphology; Patients; Pharmaceutical Preparations; Predisposition; Regulatory T-Lymphocyte; Route; Sea; Self Tolerance; Site; Specificity; Stream; System; T-Lymphocyte; Therapeutic; Translating; Tumor Antigens; Tumor Immunity; Vaccine Therapy; Vertebrates; Work; adaptive immune response; antagonist; anti-4-1BB; anti-41BB therapy; anti-CTLA4; anti-PD-1; cancer immunotherapy; cancer therapy; cancer type; central tolerance; clinical translation; draining lymph node; drug action; immune checkpoint blockade; immune modulating agents; immune-related adverse events; immunogenic; immunological synapse; improved; intravenous administration; lymph nodes; lymphatic imaging; lymphatic vasculature; lymphatic vessel; mammary; melanoma; mouse model; novel therapeutics; phase 1 study; pre-clinical; preclinical study; preservation; prevent; response; single-cell RNA sequencing; tumor; tumor microenvironment

As higher vertebrates evolved from the sea into land dwellers and terrestrial antigen (Ag) exposure increased, the adaptive immune system evolved from a centralized system to one dependent upon regional draining lymph nodes (dLNs) that allow immune responses to multiple Ags while preserving central tolerance. Despite the importance of LNs initiating immune responses for systemic immunity/tolerance, checkpoint blockade immunotherapies (CBIs) are administered intravenously, often failing to reach the dLNs that are the sites of dysfunctional T cell priming responsible for tolerance to tumor Ags (tAgs). When administered systemically, these therapies act in an Ag-indiscriminate and system-wide fashion often breaching self-tolerance and leading to severe immune related adverse events (irAEs). We hypothesize that regional delivery of immunotherapies within the distinct lymphatic watersheds to dLNs will (i) enhance systemic immunity or tolerance and (ii) substantially reduce irAEs when compared to systemic delivery. Scientific justification for our hypothesis comes from our data in preclinical, orthotopic breast (4T1) and melanoma (B16F10) studies of cancer metastases. We show that lymphatic delivery of αCTLA-4 alone or in combination with αPD-1 (i) improves anti-tumor responses, (ii) results in complete responses not seen with systemic or i.v. administration, and/or (iii) ameliorates distant metastases in these otherwise non-immunogenic models. Preclinical and clinical studies using microneedle array devices and near-infrared fluorescence lymphatic imaging shows the technical ability to deliver drug specifically to regional lymph nodes. However, there has been no preclinical demonstration that lymphatic delivery will alleviate irAEs, due to the lack of a susceptible mouse model. Before further study of lymphatic delivery can be made or translated into cancer patients, the benefit of reduced irAEs needs to be demonstrated. Because irAEs limit combinational αCTLA-4/αPD-1 therapy and the more toxic, agonist α4-1BB CBIs, lymphatic delivery could provide a substantial breakthrough needed expand the use of CBIs to treat more cancer patients at earlier stages of disease. In this NCI Clinical and Translational Exploratory/Developmental R21 (PAR-20-292) project, we propose to use a well-characterized Foxp3-DTR mouse model of transient Treg depletion to provide a readout of irAEs from i.v. and lymphatically delivered CBIs. Our specific aims are to (1) characterize immunological consequences resulting from i.v. and lymphatic delivery of αCTLA-4/αPD-1 and α4-1BB in non-tumor bearing, C57BL/6 and Balb/C strains of Foxp3-DTR mice and to (2) compare anti-tumor immunity and readouts of immunological consequences from i.v. and lymphatic delivery of CBIs in 4T1 and B16F10 tumor bearing animals. In practice, clinical observations of irAEs are associated as early indication of CBI response. If successful, we will decouple irAEs from anti-tumor immunity and improve cancer treatments by changing the way we deliver immune modifying therapeutics.

随着高等脊椎动物从海洋进化为陆地居民和陆地抗原（Ag）暴露的增加， 适应性免疫系统从一个集中的系统进化为一个依赖于区域排水的系统 淋巴结（dLN）允许对多种抗原产生免疫反应，同时保持中枢耐受性。尽管 LN启动免疫应答对全身免疫/耐受、检查点阻断的重要性 免疫疗法（CBI）是静脉内施用的，通常不能到达dLN，而dLN是免疫治疗的部位。 功能失调的T细胞引发负责对肿瘤Ag（tAg）的耐受。当全身给药时， 这些疗法以Ag不加选择和全系统的方式起作用，常常违反自我耐受性， 严重免疫相关不良事件（irAE）。 我们假设，在不同的淋巴流域内向dLN区域递送免疫疗法将 (i)增强全身免疫力或耐受性，和（ii）与全身免疫力或耐受性相比， 交付.我们的假设的科学依据来自我们在癌症转移的临床前原位乳腺（4 T1）和黑色素瘤（B16 F10）研究中的数据。我们表明，淋巴传递αCTLA-4单独或 与αPD-1联合使用（i）改善抗肿瘤反应，（ii）导致完全反应， 全身或静脉内给药，和/或（iii）改善这些原本非免疫原性的肿瘤中的远处转移 模型使用微针阵列装置和近红外荧光的临床前和临床研究 淋巴成像显示了将药物特异性地递送到区域淋巴结的技术能力。然而，在这方面， 目前还没有临床前证据表明淋巴输送会减轻irAE，这是因为缺乏一种有效的治疗方法。 易感小鼠模型。在进一步研究淋巴传递可以使或转化为癌症之前 对于患者，需要证明减少irAE的益处。由于irAE限制了αCTLA-4/αPD-1联合治疗和毒性更大的激动剂α4-1BB CBI，淋巴递送可以提供实质性的 突破需要扩大CBIs的使用，以治疗更多处于疾病早期阶段的癌症患者。 在本NCI临床和转化探索/开发R21（PAR-20-292）项目中，我们建议使用 一种充分表征的瞬时Treg耗竭的Foxp 3-DTR小鼠模型，以提供来自 静脉注射和经导管输注的CBI。我们的具体目标是（1）表征免疫学后果 在非荷瘤C57 BL/6和C57 BL/6中通过静脉注射和淋巴输送αCTLA-4/αPD-1和α4-1BB， Balb/C品系的Foxp 3-DTR小鼠，并（2）比较抗肿瘤免疫和免疫学读数。 在4 T1和B16 F10荷瘤动物中静脉内和淋巴输送CBI的结果。 在实践中，irAE的临床观察结果与CBI缓解的早期指征相关。如果成功，我们 将使irAE与抗肿瘤免疫脱钩，并通过改变我们的治疗方式来改善癌症治疗。 免疫修饰治疗剂。

项目成果

Imaging peripheral lymphatic dysfunction in chronic conditions.

• DOI: 10.3389/fphys.2023.1132097
• 发表时间: 2023
• 期刊: Frontiers in physiology
• 影响因子: 4