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.

项目总结 移植后的环磷酰胺(PTCy)大大降低了致命移植物抗宿主病的风险 异基因造血细胞移植后发生移植物抗宿主病(GVHD)。然而，与其他形式的GVHD一样， 在预防方面，PTCy仍然依靠被动的移植物抗白血病(GVL)来防止疾病复发。 异基因HCT后的无进展存活率在很大程度上被限制在41-50%。因此，并发移植物抗宿主病和白血病 预防复发仍然是移植中一个尚未得到满足的关键需求。同种异体红细胞移植的创新现在必须 将GVHD预防维持在PTCy的水平，并添加工具直接减少复发，而不是简单地 维护或保留GVL。与药物免疫抑制不同，我们开发了新的， 以CD83为靶向的人嵌合抗原受体(CAR)T细胞同时预防复发 CD83+白血病和移植物抗宿主病。CD83是免疫球蛋白超家族的成员。我们展示了CD83是 在人髓系白血病(AML)、急性淋巴细胞白血病(ALL)和同种异体反应性T细胞上的表达 与GVHD有牵连。重要的是，我们已经证明了CD83 CAR T细胞在体内杀死白血病和 在不损害抗病毒免疫的情况下根除GVHD。此外，CD83在造血干细胞中大部分缺失。 细胞、髓系祖细胞和中性粒细胞，限制靶上/肿瘤外毒性或髓系再生障碍性疾病的风险。 我们还开发了一种或逻辑门控CD19/CD83 CAR T，它可以杀死表达CD19或CD19的B细胞ALL 或CD83通过一个共享的激活内域。我们证明了我们的“或”门CD19/CD83轿车T可以 克服CD19抗原丢失，临床上有25%的患者在CD19单抗治疗后出现这种情况。 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 与标准的PTCy相比，可以同时预防白血病复发和移植物抗宿主病。预期为并行 初步临床试验，我们还将调查PTCy后CD83CAR T巩固的序贯使用情况 消除白血病复发和移植物抗宿主病。我们的初步数据显示CD83在CD4+细胞上表达 急性GVHD时的常规T细胞，以及慢性GVHD时的B细胞和辅助性滤泡细胞。 因此，(目标2，生物标记物验证研究)我们将调查CD83是否是生物标记物和治疗性的 急性和慢性移植物抗宿主病发病和治疗反应的靶点。成功完成 这项工作将指导人类CD83汽车T细胞从发现到临床的无缝过渡 同时消除异基因红细胞移植后危及生命的复发和移植物抗宿主病。