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

项目摘要 移植后环磷酰胺（PTCy）显著降低了致死性移植物抗宿主病的风险 异基因造血细胞移植（alloHCT）后的GVHD。然而，与其他形式的GVHD一样， 尽管PTCy是预防性的，但PTCy仍然依赖于被动移植物抗白血病（GVL）来预防疾病复发。 alloHCT后的无进展生存率在很大程度上限于41- 50%。因此，并发GVHD和白血病 预防复发仍然是移植中未满足的关键需求。alloHCT的创新现在必须 将GVHD预防维持在PTCy水平，并增加直接减少复发的工具， 维持或保存GVL。与药物免疫抑制不同，我们开发了新的， 人CD 83靶向嵌合抗原受体（CAR）T细胞用于同时保护以防止 CD 83+白血病以及GVHD。CD 83是免疫球蛋白超家族的成员。我们发现CD 83是 在人髓性白血病（AML）、急性淋巴细胞白血病（ALL）和同种异体反应性T细胞上表达 与GVHD有关重要的是，我们已经证明了CD 83 CAR T细胞在体内杀死白血病， 根除GVHD而不损害抗病毒免疫。此外，CD 83在造血干细胞中很大程度上不存在。 细胞、髓样祖细胞和中性粒细胞，限制了靶向/非肿瘤毒性或髓样发育不全的风险。 我们还开发了一种“OR”逻辑门控的CD 19/CD 83 CAR T，其可以杀死表达CD 19或CD 83的B细胞ALL。 或CD 83通过共享的激活胞内域。我们表明，我们的“或”门控CD 19/CD 83 CAR T可以 克服了CD 19抗原丢失，这在临床上见于25%的ALL患者接受CD 19单克隆抗体治疗后， CAR T.在本申请中，我们将（目的1，小鼠实验）测试人CD 83靶向CAR T细胞是否 可同时预防白血病复发和GVHD。要与预期并行 在初步临床试验中，我们还将研究PTCy后CD 83 CAR T巩固的顺序使用， 消除白血病复发和GVHD。我们的初步数据表明，CD 83表达在CD 4+细胞上， 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，（目的2，生物标志物验证研究）我们将研究CD 83是否是生物标志物和治疗性药物。 靶向急性和慢性GVHD发作和治疗反应效应子。成功完成 这项工作将指导人类CD 83 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。

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.