Lymphatic delivery of immunotherapy to prevent irAEs

淋巴递送免疫治疗以预防 irAE

• 批准号: 10435692
• 负责人: Eva M. Sevick-Muraca
• 金额: $ 21.88万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435692
• 关键词: 4T1; Adaptive Immune System; Advanced Malignant Neoplasm; Agonist; Animals; Antigens; Antitumor Response; Autoimmune Diseases; Biodistribution; Blood; Breast; CTLA4 gene; Cancer Patient; Cell physiology; Clinical; Clinical Research; Colon; Cross Presentation; Data; Development; Devices; Disease; Distant Metastasis; Dose; Drug Delivery Systems; Drug Exposure; Effectiveness; FOXP3 gene; Fluorescence; Formulation; Histology; Home; Immune; Immune response; Immune system; Immunity; Immunologics; Immunomodulators; Immunotherapy; Implant; In complete remission; Inbred BALB C Mice; Intravenous; Investigation; Lymphatic; Lymphatic System; Malignant Neoplasms; Modeling; Mus; Neoplasm Metastasis; Normal tissue morphology; Patients; Pharmaceutical Preparations; Regulatory T-Lymphocyte; Route; Sea; Self Tolerance; Site; Specificity; Stream; System; Systemic Therapy; T-Lymphocyte; Therapeutic; Translating; Tumor Antigens; Tumor Immunity; Vaccine Therapy; Vertebrates; Work; adaptive immune response; antagonist; anti-PD1 therapy; cancer immunotherapy; cancer therapy; cancer type; central tolerance; clinical translation; draining lymph node; drug action; immune checkpoint blockade; immune-related adverse events; immunogenic; immunological synapse; improved; lymph nodes; lymphatic imaging; lymphatic vasculature; lymphatic vessel; mammary; melanoma; mouse model; novel therapeutics; phase 1 study; pre-clinical; preclinical study; preservation; prevent; programmed cell death protein 1; 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，并且陆地抗原 (Ag) 暴露增加， 适应性免疫系统从集中式系统演变为依赖于区域引流的系统 淋巴结（dLN）允许对多种抗原做出免疫反应，同时保持中枢耐受性。尽管 LN 启动免疫反应对于系统免疫/耐受、检查点封锁的重要性 免疫疗法 (CBI) 通过静脉注射，通常无法到达 dLN，这是免疫治疗的部位。 功能失调的 T 细胞引发导致对肿瘤抗原 (tAg) 的耐受。当全身给药时， 这些疗法以一种不加区别和全系统的方式发挥作用，常常违反自我耐受性并导致 严重的免疫相关不良事件（irAE）。 我们假设在不同淋巴分水岭内向 dLN 进行免疫治疗的区域性递送将 (i) 增强全身免疫力或耐受性，以及 (ii) 与全身相比显着降低 irAE 送货。我们的假设的科学依据来自于我们在癌症转移的临床前、原位乳腺癌 (4T1) 和黑色素瘤 (B16F10) 研究中的数据。我们表明，αCTLA-4 单独或 与 αPD-1 联合使用 (i) 改善抗肿瘤反应，(ii) 产生与 αPD-1 联合使用时未见的完全反应 全身性或静脉注射给药，和/或（iii）改善这些原本非免疫原性的远处转移 模型。使用微针阵列装置和近红外荧光进行临床前和临床研究 淋巴成像显示了将药物特异性输送至区域淋巴结的技术能力。然而， 由于缺乏有效的方法，尚无临床前证据表明淋巴输送可以减轻 irAE。 易感小鼠模型。在进一步研究淋巴输送或转化为癌症之前 对于患者来说，减少 irAE 的益处需要得到证明。由于 irAE 限制了联合 αCTLA-4/αPD-1 治疗以及毒性更强的激动剂 α4-1BB CBI，因此淋巴输送可以提供大量的 需要取得突破，扩大 CBI 的使用，以治疗更多处于疾病早期阶段的癌症患者。 在此 NCI 临床和转化探索/开发 R21 (PAR-20-292) 项目中，我们建议使用 一个特征明确的 Foxp3-DTR 小鼠瞬时 Treg 耗竭模型，可提供 irAE 读数 静脉注射和淋巴递送的 CBI。我们的具体目标是 (1) 表征免疫学后果 由静脉注射引起αCTLA-4/αPD-1 和 α4-1BB 在非肿瘤荷瘤、C57BL/6 和中的淋巴递送 Foxp3-DTR 小鼠的 Balb/C 品系和 (2) 比较抗肿瘤免疫力和免疫学读数 静脉注射的后果以及 CBI 在 4T1 和 B16F10 荷瘤动物中的淋巴递送。 在实践中，irAE 的临床观察与 CBI 反应的早期指示相关。如果成功的话，我们 将通过改变我们的给药方式将 irAE 与抗肿瘤免疫分离并改善癌症治疗 免疫调节疗法。