Project 2: The New Era of Cellular Therapies For Lung Transplant Tolerance

项目 2：肺移植耐受细胞疗法的新时代

基本信息

批准号：
10622128
负责人：
Leslie S Kean
金额：
$ 106.68万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-23 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622128
关键词：
Ablation Address Allograft Tolerance Antibodies Antibody-drug conjugates Antigens Area Autoimmune Diseases Biotechnology Bone Marrow Calcineurin inhibitor Cell Therapy Characteristics Chimerism Chronic Clinical Data Defect Development Drug Kinetics Engineering Environment Equilibrium FOXP3 gene Goals Half-Life Human Immune Immune Targeting Immune Tolerance Immunity Immunomodulators Immunosuppression Infection Inflammatory Infusion procedures Kidney Knock-out Life Lung Lung Transplantation Lymphoproliferative Disorders Maintenance Marrow Monoclonal Antibodies Mus PTPRC gene Patient-Focused Outcomes Protocols documentation Public Health Regimen Regulation Regulatory T-Lymphocyte Research Research Personnel Resistance Risk Safety Signal Transduction Sirolimus Specificity Steroid Resistance Steroids T-Cell Activation T-Lymphocyte TNFSF4 gene TNFSF5 gene Testing Toxic effect Transplantation Transplantation Tolerance Treg therapy Virus allograft rejection base editing chemotherapy chimeric antigen receptor clinical translation conditioning design evidence base graft vs host disease high risk immunoregulation improved innovation insight irradiation isoimmunity lung allograft lung basal segment nonhuman primate novel novel strategies post-transplant preservation success synergism

项目摘要

PROJECT SUMMARY / ABSTRACT The current half-life of a lung allograft is unacceptably short at just 6.7 years, and all recipients encounter significant complications, both from allograft rejection and from immunosuppression-associated toxicities. Immune tolerance provides the ultimate solution to these issues, with the promise of life-long graft acceptance without chronic immunosuppression, and, or critical importance, with maintenance of protective immunity. While tolerance to kidneys has been achieved in non-human primates (NHPs) and humans with transient mixed chimerism, the same protocols have thus far failed for lungs. Importantly, however, we have recently successfully induced durable (ie stable for the life of the transplant) mixed-chimerism and tolerance during NHP lung transplantation, representing a major advance. However, this first success employed non-clinically available agents and conferred a high risk of post- transplant lymphoproliferative disorder (PTLD). These data suggest that durable chimerism-based lung transplant tolerance is possible, but that improved strategies are needed, to reset recipient immunity towards tolerance, preserve protective immunity, and enable rapid clinical translation. To address these goals, Project 2 focuses on 3 areas: 1) Developing safe, targeted bone marrow conditioning regimens for chimerism-induction; (2) Discovering Treg-supportive immunomodulation strategies; and (3) Engineering optimal CD4+/FoxP3+ regulatory T cell (Treg)- based cellular therapies, to enhance and stabilize chimerism-based immune tolerance. We do so through the following two Specific Aims: Aim 1: CD45-antibody-drug-conjugate (ADC)-based conditioning and targeted immunomodulation: the new era of mixed-chimerism induction for clinical translation. Aim 1 encompasses 3 Objectives: (1) To test the hypothesis that a CD45-ADC can successfully create marrow and immune space. (2) To test the hypothesis that Treg- supportive, tolerogenic immunomodulation, through anti-OX40L, CD137-ADC, or anti- CD154, will successfully induce durable chimerism across MHC barriers and maintain protective immunity. (3) To test the hypothesis that CD45-ADC- based chimerism and targeted immune modulation can induce lung allograft tolerance by establishing a Treg- supportive systemic and intragraft environment. Aim 2: Engineering an optimal Treg cellular therapy to augment chimerism-based tolerance induction. Aim 2 encompasses 3 Objectives designed to optimize Treg safety/efficacy for chimerism- and tolerance-induction. (1) To test the hypothesis that OX40L- or CD83-CAR-Tregs will be more suppressive than unmodified Treg, and will enhance control of inflammatory signaling, inhibit alloreactivity, and stabilize chimerism. (2) To test the hypothesis that Tregs that are base-edited to enforce FOXP3 expression and be resistant to calcineurin inhibitors, sirolimus, and/or steroids, will be maximally persistent and stable after infusion. (3) To test the hypothesis that these Tregs will optimize chimerism- based lung allograft tolerance, by reinforcing a Treg- supportive systemic and intragraft environment. Together, these Aims are designed to develop innovative approaches for durable chimerism-based lung transplant tolerance.

项目概要/摘要目前同种异体肺移植物的半衰期短得令人无法接受，仅为 6.7 年，并且所有接受者都会遇到显着的影响。并发症，包括同种异体移植排斥和免疫抑制相关毒性。免疫耐受为这些问题提供了最终的解决方案，承诺终身接受移植，而不会出现慢性病免疫抑制，和/或至关重要，与维持保护性免疫。同时对肾脏的耐受性已在非人类灵长类动物 (NHP) 和具有短暂混合嵌合状态的人类中实现，相同的方案迄今为止，肺部已经失败。然而，重要的是，我们最近成功地诱导了持久（即稳定） NHP 肺移植期间的混合嵌合和耐受性，代表了一项重大进步。然而，这第一次成功使用了非临床可用的药物，并带来了移植后的高风险淋巴组织增生性疾病（PTLD）。这些数据表明，基于嵌合体的持久肺移植耐受性是可能，但需要改进策略，将受体免疫力重置为耐受性，保持保护性免疫，并实现快速临床转化。为了实现这些目标，项目 2 重点关注 3 个领域：1) 开发用于嵌合诱导的安全、有针对性的骨髓调理方案； (2)发现Treg支持免疫调节策略； (3) 基于 CD4+/FoxP3+ 调节性 T 细胞 (Treg) 的工程优化细胞疗法，以增强和稳定基于嵌合的免疫耐受。我们通过以下两个具体措施来做到这一点目标：目标 1：基于 CD45 抗体药物偶联物 (ADC) 的调理和靶向免疫调节：临床转化混合嵌合诱导的新时代。目标 1 包含 3 个目标： (1) 测试假设 CD45-ADC 可以成功创建骨髓和免疫空间。 (2) 检验Treg-的假设通过抗 OX40L、CD137-ADC 或抗 CD154 进行支持性、耐受性免疫调节，将成功诱导跨越 MHC 屏障的持久嵌合并维持保护性免疫。 (3) 检验 CD45-ADC- 的假设基于嵌合和靶向免疫调节可以通过建立Treg-诱导肺同种异体移植耐受支持性系统和移植内环境。目标 2：设计最佳的 Treg 细胞疗法来增强基于嵌合的耐受诱导。目标 2 包含 3 个旨在优化 Treg 安全性/功效的目标用于嵌合和耐受诱导。 (1) 检验 OX40L- 或 CD83-CAR-Tregs 会更有效的假设比未修饰的 Treg 具有抑制性，并且会增强对炎症信号传导的控制，抑制同种异体反应性，并且稳定嵌合状态。 (2) 检验这样的假设：经过碱基编辑以强制 FOXP3 表达的 Tregs 是对钙调神经磷酸酶抑制剂、西罗莫司和/或类固醇的耐药性，在输注后将保持最大程度的持久性和稳定性。 (3) 为了检验这些 Tregs 将通过增强 Treg 来优化基于嵌合的肺同种异体移植物耐受性的假设，支持性系统和移植内环境。这些目标共同旨在开发创新方法用于持久的基于嵌合的肺移植耐受。