Targeting CD83 to reduce leukemia relapse and GVHD after allogeneic hematopoietic cell transplantation

靶向CD83减少同种异体造血细胞移植后白血病复发和GVHD

• 批准号: 10573570
• 负责人: Brian C Betts
• 金额: $ 74.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573570
• 关键词: Acute; Acute Graft Versus Host Disease; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Address; Aftercare; Allogenic; Antigens; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Binding; Biological Markers; Blood specimen; CD19 Antigens; CD19 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line; Cell Therapy; Cells; Cessation of life; Clinical; Clinical Trials; Colony-Forming Units Assay; Cyclophosphamide; Data; Disease; Effector Cell; FDA approved; Hematopoiesis; Hematopoietic stem cells; Human; Immunoglobulins; Immunosuppression; Impairment; Infusion procedures; Kinetics; Knowledge; Life; Link; Logic; Luciferases; Lymphoblastic Leukemia; Modeling; Mus; Myelogenous; Myeloid Leukemia; Onset of illness; Outcome; Patients; Prognosis; Prognostic Marker; Progression-Free Survivals; Prophylactic treatment; Recurrent disease; Regulatory T-Lymphocyte; Relapse; Risk; Source; T-Cell Activation; T-Lymphocyte; Tacrolimus; Testing; Toxic effect; Transplant Recipients; Transplantation; Viral; Work; antileukemic activity; antiviral immunity; biomarker validation; cell killing; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; chronic graft versus host disease; clinical biomarkers; clinical translation; cytotoxicity; differential expression; disorder prevention; experimental study; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; high risk; improved; improved outcome; in vivo; innovation; leukemia; leukemia relapse; member; mortality; neutrophil; novel; overexpression; patient derived xenograft model; pharmacologic; phase I trial; post-transplant; post-transplant disease; potential biomarker; preservation; prevent; progenitor; prospective; relapse prevention; relapse risk; stem cells; success; therapeutic biomarker; therapeutic target; tool; transplant centers; treatment response; tumor; validation studies

PROJECT SUMMARY Post-transplant cyclophosphamide (PTCy) has substantially reduced the risk of lethal graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (alloHCT). However, like other forms of GVHD prophylaxis, PTCy still relies upon passive graft-versus-leukemia (GVL) to prevent disease relapse. Progression-free survival after alloHCT is largely limited to 41-50%. Thus, concurrent GVHD and leukemia relapse prevention remains a critical unmet need in transplantation. Innovation in alloHCT must now maintain GVHD prevention at the level of PTCy and add tools to directly reduce relapse and not simply maintain or preserve GVL. Distinct from pharmacologic immune suppression, we have developed novel, human, CD83-targeted chimeric antigen receptor (CAR) T cells for concurrent protection against relapse of CD83+ leukemia as well as GVHD. CD83 is a member of the immunoglobulin superfamily. We show CD83 is expressed on human myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and alloreactive T cells implicated in GVHD. Importantly, we have demonstrated that CD83 CAR T cells kill leukemia in vivo and eradicate GVHD without impairing antiviral immunity. Further, CD83 is largely absent from hematopoietic stem cells, myeloid progenitors, and neutrophils, limiting the risk for on-target/off-tumor toxicity or myeloid aplasia. We also developed an ‘OR’ logic gated CD19/CD83 CAR T that can kill B cell ALL that expresses either CD19 OR CD83 via a shared activating endodomain. We show that our ‘OR’ gated CD19/CD83 CAR T can overcome CD19 antigen loss, which is clinically seen in 25% of ALL patients after treatment with CD19 mono- CAR T. In this application, we will (Aim 1, mouse experiments) test whether human CD83-targeted CAR T cells can concurrently prevent leukemia relapse and GVHD, as compared to standard PTCy. To parallel expected initial clinical trials, we will also investigate the sequential use of CD83 CAR T consolidation after PTCy to eliminate leukemia relapse and GVHD. Our preliminary data demonstrates that CD83 is expressed on CD4+ conventional T cells during acute GVHD, as well as B cells and T helper follicular cells during chronic GVHD. Thus, (Aim 2, biomarker validation study) we will investigate whether CD83 is a biomarker and therapeutic target among effectors of acute and chronic GVHD onset and therapeutic response. Successful completion of this work will guide the seamless transition from discovery to clinical translation of human CD83 CAR T cells to concurrently eliminate life-threatening relapse and GVHD after alloHCT.

项目摘要 移植后环磷酰胺（PTCY）大大降低了致命的移植物抗宿主病的风险 （GVHD）同种异体造血细胞移植（allOHCT）。但是，像其他形式的GVHD一样 预防性，PTCY仍然依赖被动移植物 - 抗血通血（GVL）来防止疾病缓解。 AllOHCT后无进展生存率在很大程度上限制为41-50％。那并发GVHD和白血病 预防复发仍然是移植的关键需求。现在必须在AlloHCT中进行创新 保持PTCY级别的GVHD预防，并添加工具直接减少缓解，而不仅仅是简单 维护或保留GVL。与药物免疫抑制不同，我们开发了新颖的， 人类CD83靶向的嵌合抗原受体（CAR）T细胞，以防止缓解 CD83+白血病以及GVHD。 CD83是免疫球蛋白超家族的成员。我们显示CD83是 以人髓样白血病（AML），急性淋巴细胞白血病（ALL）和同种反应性T细胞表示 在GVHD中实施。重要的是，我们已经证明了CD83 CAR T细胞在体内杀死白血病 根除GVHD而不会损害抗病毒免疫史。此外，CD83在很大程度上没有造血茎 细胞，髓样祖细胞和嗜中性粒细胞，限制了靶向/非肿瘤毒性或髓样性的风险。 我们还开发了一个“或”逻辑门控CD19/CD83 CAR t，它可以杀死B单元所有表达CD19 或通过共享激活内分域的CD83。我们证明我们的'或''''或''CD19/CD83汽车T可以 克服CD19抗原丧失，在用CD19单声道治疗后，所有患者中有25％在临床上看到了抗原损失 在此应用中，我们将（AIM 1，鼠标实验）测试人类CD83靶向的CAR T细胞是否 与标准PTCY相比，可以同时预防白血病继电器和GVHD。并行预期 最初的临床试验，我们还将研究PTCY后CD83 CAR T巩固的顺序使用 消除白血病继电器和GVHD。我们的初步数据表明，CD83在CD4+上表达 急性GVHD期间的常规T细胞，以及慢性GVHD期间的B细胞和T辅助细胞。 （AIM 2，生物标志物验证研究）我们将研究CD83是否是生物标志物和治疗 急性和慢性GVHD发作和治疗反应的影响。成功完成 这项工作将指导从发现到人CD83 CAR T细胞的临床翻译的无缝过渡到 同时消除抗生命后的威胁生命的继电器和GVHD。