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.

项目概要 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 然而，与其他形式的 GVHD 一样，同种异体造血细胞移植 (alloHCT) 后。 预防方面，PTCy 仍然依赖被动移植物抗白血病 (GVL) 来预防疾病复发。 alloHCT 后的无进展生存率很大程度上限于 41-50%，因此，并发 GVHD 和白血病。 预防复发仍然是移植领域未满足的一个关键需求，现在必须进行 alloHCT 创新。 将 GVHD 预防维持在 PTCy 水平，并添加工具来直接减少复发，而不仅仅是简单地减少复发 与药物免疫抑制不同，我们开发了新的、 人 CD83 靶向嵌合抗原受体 (CAR) T 细胞可同时预防癌症复发 CD83+ 白血病和 GVHD 都是免疫球蛋白超家族的成员。 在人骨髓性白血病 (AML)、急性淋巴细胞白血病 (ALL) 和同种异体反应性 T 细胞中表达 重要的是，我们已经证明 CD83 CAR T 细胞可以在体内杀死白血病，并且 根除GVHD而不损害抗病毒免疫力此外，造血干细胞中基本上不存在CD83。 细胞、骨髓祖细胞和中性粒细胞，限制了靶点/肿瘤外毒性或骨髓再生障碍的风险。 我们还开发了一种“OR”逻辑门控 CD19/CD83 CAR T，可以杀死表达 CD19 的 B 细胞 ALL 通过共享激活内域 OR CD83 我们证明我们的“OR”门控 CD19/CD83 CAR T 可以。 克服了 CD19 抗原丢失，这种情况在接受 CD19 单药治疗后 25% 的 ALL 患者中临床可见 CAR T。在这个应用中，我们将（目标1，小鼠实验）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复发和 GVHD。 初步临床试验中，我们还将研究 PTCy 后序贯使用 CD83 CAR T 巩固治疗 消除白血病复发和 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 辅助滤泡细胞。 因此，（目标 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药物 急性和慢性 GVHD 发病和治疗反应的效应器中的目标 成功完成。 这项工作将指导人类 CD83 CAR T 细胞从发现到临床转化的无缝过渡 同时消除 alloHCT 后危及生命的复发和 GVHD。