Applying precision MEdicine to optimize desensitization with noveL bIOlogics or cellular theRApies in highly sensiTized kidney transplant patiEnts (AMELIORATE)

应用精准医学，通过新型生物制剂或细胞疗法对高度敏感的肾移植患者优化脱敏（AMELIORATE）

• 批准号: 10647863
• 负责人: Flavio Vincenti
• 金额: $ 63.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647863
• 关键词: Adverse event; Aftercare; Antibodies; Antigens; Autologous; B cell therapy; B-Lymphocytes; Binding; Biological Response Modifier Therapy; Bone Marrow; CAR T cell therapy; Cell Compartmentation; Cell Maturation; Cell Therapy; Cells; Cessation of life; Chronic; Clinical; Elements; Enrollment; Equipoise; Freedom; Frequencies; Genotype; Goals; Graft Survival; IL-6 inhibitor; Immunity; Incidence; Infection; Infusion procedures; Injury; Interleukin 6 Receptor; Interleukin-6; Intervention Studies; Kidney; Kidney Transplantation; Malignant Neoplasms; Measurement; Mediating; Memory B-Lymphocyte; Multiple Myeloma; Natural Killer Cells; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmacotherapy; Plasma Cells; Prevention; Randomized; Reaction; Receptor Gene; Regimen; Research Design; Safety; Severities; Specificity; Structure of germinal center of lymph node; Surface; System; T cell therapy; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Transplant Recipients; Transplantation; Work; antagonist; arm; cell killing; chimeric antigen receptor T cells; desensitization; efficacious treatment; high risk population; improved; killer immunoglobulin-like receptor; lymph nodes; molecular marker; novel; novel marker; novel therapeutics; open label; pathogen; patient stratification; post-transplant; precision medicine; prevent; prospective; response; safety assessment; success; treatment response

PROJECT ABSTRACT HLA sensitization is a significant barrier in organ transplantation. Kidney transplant candidates who are very highly sensitized (cPRA ≥99.9%) continue to have very poor access to a compatible donor and are more likely to be removed from the list or die than undergo transplantation. Desensitization has a clear survival benefit; however previous approaches have met with limited success especially in patients with the highest levels of HLA antibodies, and are hamstrung by the problem of antibody rebound. We hypothesize that durable reduction in HLA antibodies can be achieved by a two pronged approach: elimination of plasma cells plus prevention of the compensatory expansion of the germinal center. Both anti-CD38 antibodies and chimeric antigen receptor (CAR) T cells directed against plasma cells have emerged as novel therapeutic options in multiple myeloma. Germinal center activation can be inhibited by blockade of the IL-6 or CD40/CD40L pathway. Furthermore, we have identified a novel biomarker (specific HLA/KIR genotype combinations) which predicts poor plasma cell killing by NK cells in response to anti- CD38 antibodies. We propose to conduct a multicenter, prospective, open-label, interventional study in 68 patients with cPRA ≥99.9% who will be assigned to receive dual biologic therapy (n=60) or cellular therapy (n=8) for desensitization. Allocation into the dual biologic therapy or cellular therapy will be based on our novel biomarker using a precision medicine approach. Those assigned to dual biologic therapy will be further randomized to receive the anti-CD38 antibody, isatuximab, in combination with either VIB4920, a CD40L antagonist (n=30) or sarilumab, an IL- 6R antagonist (n=30). Those assigned to the cell therapy arm will receive a single infusion of ide- cel, a CAR T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of plasma cells. The primary efficacy endpoint is a ≥0.4% reduction in cPRA or receipt of transplant from a previously incompatible donor and is assessed at 16 weeks after completion of therapy. The primary safety endpoint is freedom from ≥grade 3 infusion reactions, ≥grade 3 or higher infections, and malignancy assessed at 16 weeks after completion of therapy or until receiving a transplant, whichever occurs earlier. Mechanistic analyses will focus on changes in the bone marrow and circulating T and B cell compartments after treatment, as well as in the lymph nodes of those who receive a transplant during the study. Transplanted subjects will receive additional study-directed therapy after transplant and be evaluated for post-transplant outcomes including freedom from rejection, graft loss and death.

项目摘要

项目成果

Mechanisms and biomarkers of immune quiescence in kidney transplantation.

肾移植中免疫静止的机制和生物标志物。

• DOI: 10.1016/j.humimm.2018.01.016
• 发表时间: 2018
• 期刊: Human immunology
• 影响因子: 2.7
• 作者: Chan-On,Chitranon;Liberto,JulianeM;Sarwal,MinnieM
• 通讯作者: Sarwal,MinnieM

Polyclonal Regulatory T Cell Therapy for Control of Inflammation in Kidney Transplants.

• DOI: 10.1111/ajt.14415
• 发表时间: 2017-11
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Chandran S;Tang Q;Sarwal M;Laszik ZG;Putnam AL;Lee K;Leung J;Nguyen V;Sigdel T;Tavares EC;Yang JYC;Hellerstein M;Fitch M;Bluestone JA;Vincenti F
• 通讯作者: Vincenti F

Impact of Immune-Modulatory Drugs on Regulatory T Cell.

• DOI: 10.1097/tp.0000000000001379
• 发表时间: 2016-11
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Furukawa A;Wisel SA;Tang Q
• 通讯作者: Tang Q

IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function.

• DOI: 10.3389/fimmu.2021.783282
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Skartsis N;Peng Y;Ferreira LMR;Nguyen V;Ronin E;Muller YD;Vincenti F;Tang Q
• 通讯作者: Tang Q