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; 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.

随着较高的脊椎动物从海洋演变为陆地居民，陆地抗原（Ag）暴露增加， 自适应免疫系统从集中式系统演变为一个取决于区域排水的系统 淋巴结（DLN），可在保留中心耐受性的同时对多个AG进行免疫反应。尽管 LNS对全身免疫/耐受性，检查点封锁的重要性的重要性 免疫疗法（CBI）是静脉内给药的，通常无法到达DLN的位置 功能失调的T细胞启动负责耐受性AG（TAG）的耐受性。当系统地管理时 这些疗法以Ag-Indiscriminate and System Wide的方式行动，经常违反自我耐受和领导 发生严重的免疫力事件（IRAE）。 我们假设在不同的淋巴流域内的区域传递免疫疗法将 （i）增强全身免疫力或公差，（ii）与全身性相比，大大降低了伊拉斯 送货。我们假设的科学理由来自临床前，原位乳腺（4T1）和黑色素瘤（B16F10）研究的数据。我们表明，单独的αCTLA-4淋巴输送或 结合αPD-1（i）改善了抗肿瘤反应，（ii）导致完全反应未见 系统性或i.v.给药和/或（iii）在这些非免疫原性中改善遥远的转移 型号。使用微针阵列设备和近红外荧光的临床前和临床研究 淋巴成像显示了专门为区域淋巴结提供药物的技术能力。然而， 由于缺乏 易感鼠标模型。在进一步研究淋巴输送之前，可以进行癌症或翻译成癌症 患者需要证明伊拉斯减少的好处。由于IRAES限制了组合αCTLA-4/αPD-1治疗和毒性更具毒性，激动剂α4-1BBCBI，淋巴输送可以提供大量 突破需要扩大CBI的使用来治疗疾病早期阶段的更多癌症患者。 在这个NCI临床和翻译探索/发育R21（PAR-20-292）项目中，我们建议使用 瞬态Treg部署的特征良好的FOXP3-DTR鼠标模型，可从 I.V.和淋巴传递的CBI。我们的具体目的是（1）表征免疫学后果 由i.v.产生以及非肿瘤轴承中的αCTLA-4/αPD-1和α4-1BB的淋巴输送，C57BL/6和 FOXP3-DTR小鼠的BALB/C菌株，与（2）比较抗肿瘤免疫学和免疫学的读数 i.v.的后果以及在4T1和B16F10肿瘤轴承动物中CBI的淋巴传递。 实际上，伊拉斯的临床观察结果是CBI反应的早期指示。如果成功，我们 通过改变我们提供的方式，将使伊拉斯与抗肿瘤的免疫力相结合，并改善癌症治疗方法 免疫修饰疗法。