Novel Biologic Therapies for GVHD

GVHD 的新型生物疗法

• 批准号: 10664835
• 负责人: Leslie S Kean
• 金额: $ 116.93万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664835
• 关键词: Acute Graft Versus Host Disease; Address; Antibodies; Automobile Driving; Back; Biological Response Modifier Therapy; Biopsy; Blood; CD28 gene; CD34 gene; CD80 gene; Calcineurin inhibitor; Categories; Cell Therapy; Cessation of life; Clinic; Clinical; Clinical Trials; Cyclophosphamide; Development; Disease; Disease model; Dose; Eragrostis; Evaluation; Gastrointestinal tract structure; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunity; Immunology; Immunosuppression; Impact evaluation; Infection; Infiltration; Inflammation; Inflammatory Bowel Diseases; Interferons; Life; Ligands; Link; Malignant - descriptor; Metabolism; Methotrexate; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Multicenter Trials; Mus; Non-Malignant; Pathogenesis; Patient Care; Patient-Focused Outcomes; Patients; Positioning Attribute; Prevention strategy; Procedures; Prophylactic treatment; Public Health; Refractory; Refractory Disease; Regimen; Regulatory T-Lymphocyte; Relapse; Research; Residencies; Resistance; Risk; Sampling; Signal Transduction; Stains; Steroids; System; T cell infiltration; TNFSF4 gene; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; Viral; antiviral immunity; aurora kinase; clinical candidate; clinical translation; cohort; cytokine; design; disease diagnosis; disorder prevention; effector T cell; evidence base; graft vs host disease; graft vs leukemia effect; high risk; improved; in vivo; infection risk; inhibitor; isoimmunity; migration; mortality; multiple omics; new therapeutic target; next generation; nonhuman primate; notch protein; novel; novel therapeutics; personalized diagnostics; post-transplant; pre-clinical; preservation; prevent; response; single-cell RNA sequencing; targeted treatment; therapeutic candidate; therapy development; trafficking; transcriptome; translational pipeline; treatment strategy; tumor

Novel Biologic Therapies for GVHD Abstract: For patients with high-risk malignant and non-malignant hematologic diseases, hematopoietic stem cell transplant (HCT) often represents the only option for cure. However, HCT is fraught with complications, leading to high rates of toxicity and patient death. The principal cause of early non-relapse mortality is acute graft-versus-host disease (AGVHD), with death from infection a close second. These two are interrelated, as intensifying global immune suppression to control AGVHD increases infection risk. Moreover, augmented immunosuppression can also increase the risk of malignant relapse. To move the field forward, we must develop targeted, evidence-based prevention and treatment strategies, designed to specifically control alloreactivity while preserving anti-tumor and anti-viral protective immunity. Perhaps the greatest need for these targeted therapeutics is in GI AGVHD, the leading cause of AGVHD- related death. Two issues predominate, which significantly impede progress: (1) We do not adequately understand the distinct mechanisms controlling GI T cell infiltration versus tissue residency or damage, which inhibits development of specific therapies. (2) We do not understand the mechanisms driving steroid-refractory GI AGVHD, significantly slowing treatment development for this most deadly type of AGVHD. The goal of this proposal is to address these unmet needs, and thereby discover the next generation of therapeutics for GI AGVHD. We will do so by completing the following three Specific Aims: (1): Prioritize and validate next-generation GI-targeted therapeutics with a novel translational pipeline. We will test the hypothesis that a pipeline from patient/NHP-derived therapeutic candidates → mouse → NHP AGVHD models can prioritize new AGVHD therapeutics. (2) Determine the impact of Notch ligand blockade on the blood and GI immune landscape in NHP and transplant patients. We will test the hypothesis that Notch ligand blockade with the anti-DLL4 mAb REGN421 protects against GI AGVHD, and that it does so by inhibiting effector T cell infiltration into the GI tract. (3) Identify predictors of steroid responsive and resistant GI AGVHD in patients. We will test the hypothesis that unifying mechanisms of steroid response and resistance can be identified in patients by comprehensive linked immune studies of the blood and GI tract at AGVHD diagnosis. By completing these aims, we will discern the mechanisms driving GI AGVHD, and thus fundamentally advance our ability to care for patients undergoing HCT.

GVHD的新生物疗法 摘要： 对于高危恶性和非恶性血液病患者，造血干细胞移植 (HCT)往往是治愈的唯一选择然而，HCT充满了并发症，导致高比率的 毒性和患者死亡。早期非复发性死亡的主要原因是急性移植物抗宿主病 （AGVHD），感染死亡紧随其后。这两者是相互关联的，因为加强全球免疫 抑制AGVHD会增加感染风险。此外，增强的免疫抑制也可以增加 恶性复发的风险。为了推进这一领域的工作，我们必须制定有针对性的循证预防措施， 治疗策略，旨在特异性控制同种异体反应性，同时保留抗肿瘤和抗病毒保护性， 免疫力也许对这些靶向治疗的最大需求是GI AGVHD，AGVHD的主要原因- 相关死亡主要有两个问题严重阻碍了进展：（1）我们没有充分了解 控制GI T细胞浸润与组织驻留或损伤的不同机制， 发展特殊疗法。(2)我们不了解类固醇难治性GI AGVHD的驱动机制， 显著减缓了这种最致命的AGVHD类型的治疗发展。本提案的目的是 解决这些未满足的需求，从而发现下一代GI AGVHD的治疗方法。 我们将通过完成以下三个具体目标来实现这一目标：（1）：优先考虑并验证下一代GI目标 一个新的平移管道治疗。我们将检验一个假设，即从患者/NHP衍生的管道 治疗候选物→小鼠→ NHP AGVHD模型可以优先考虑新的AGVHD治疗剂。(2)确定 Notch配体阻断对NHP和移植患者血液和GI免疫状况的影响。我们将测试 假设用抗DLL 4 mAb REGN 421阻断Notch配体可保护免受GI AGVHD， 通过抑制效应T细胞向胃肠道的浸润来实现。(3)确定类固醇反应的预测因素， 耐药GI AGVHD患者。我们将检验统一类固醇反应机制和 通过对AGVHD患者的血液和胃肠道进行全面的联合免疫研究， 诊断.通过完成这些目标，我们将辨别驱动GI AGVHD的机制，从而从根本上 提高我们对接受HCT的患者的护理能力。

项目成果

Abatacept for GVHD prophylaxis can reduce racial disparities by abrogating the impact of mismatching in unrelated donor stem cell transplantation.

• DOI: 10.1182/bloodadvances.2021005208
• 发表时间: 2022-02-08
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Qayed M;Watkins B;Gillespie S;Bratrude B;Betz K;Choi SW;Davis J;Duncan C;Giller R;Grimley M;Harris AC;Jacobsohn D;Lalefar N;Norkin M;Farhadfar N;Pulsipher MA;Shenoy S;Petrovic A;Schultz KR;Yanik GA;Waller EK;Langston A;Kean LS;Horan JT
• 通讯作者: Horan JT

Innate Lymphoid Cell Activation and Sustained Depletion in Blood and Tissue of Children Infected with HIV from Birth Despite Antiretroviral Therapy.

尽管接受抗逆转录病毒治疗，但出生后感染艾滋病毒的儿童的血液和组织中的先天淋巴细胞激活和持续耗竭。

• DOI: 10.1016/j.celrep.2020.108153
• 发表时间: 2020
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Singh,Alveera;Kazer,SamuelW;Roider,Julia;Krista,KamiC;Millar,Jane;Asowata,OsaretinE;Ngoepe,Abigail;Ramsuran,Duran;Fardoos,Rabiah;Ardain,Amanda;Muenchhoff,Maximilian;Kuhn,Warren;Karim,Farina;Ndung'u,Thumbi;Shalek,AlexK;Gou
• 通讯作者: Gou

Creating an international network for science and clinical progress: democratizing dissemination of advances in global hematology.

创建科学和临床进步的国际网络：全球血液学进展的民主化传播。

• DOI: 10.1182/bloodadvances.2020004108
• 发表时间: 2021
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Kean,LeslieS

HIV infection drives interferon signaling within intestinal SARS-CoV-2 target cells.

• DOI: 10.1172/jci.insight.148920
• 发表时间: 2021-08-23
• 期刊: JCI insight
• 影响因子: 8
• 作者: Fardoos R;Asowata OE;Herbert N;Nyquist SK;Zungu Y;Singh A;Ngoepe A;Mbano IM;Mthabela N;Ramjit D;Karim F;Kuhn W;Madela FG;Manzini VT;Anderson F;Berger B;Pers TH;Shalek AK;Leslie A;Kløverpris HN
• 通讯作者: Kløverpris HN

Identification and Tracking of Alloreactive T Cell Clones in Rhesus Macaques Through the RM-scTCR-Seq Platform.

• DOI: 10.3389/fimmu.2021.804932
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Gerdemann U;Fleming RA;Kaminski J;McGuckin C;Rui X;Lane JF;Keskula P;Cagnin L;Shalek AK;Tkachev V;Kean LS
• 通讯作者: Kean LS