Project 6- Targeting AML using bispecific and antibody drug conjugates

急性髓性白血病（AML）是一种造血系统肿瘤，其特征在于骨髓或外周血中存在恶性未成熟成髓细胞。预计2021年AML将在美国造成> 20，000例新发病例和约11，000例死亡。AML的治疗模式包括诱导化疗，旨在实现缓解，然后是高剂量化疗或异基因造血细胞移植（alloHCT）的巩固治疗。对于接受alloHCT的患者，30 - 50%的患者在5年时实现了长期无病生存。不幸的是，大约40%的AML患者在alloHCT后会复发，并面临着令人沮丧的预后，2年生存率为20%左右。对于alloHCT后复发的AML患者，目前尚无标准治疗。alloHCT后复发的最常见疗法是供体细胞回输（供体淋巴细胞输注，DLI），有时在此之前进行减积化疗或低甲基化剂，并在选定的个体中进行第二次alloHCT。然而，许多复发的患者不是强化治疗的候选者，并且那些接受进一步治疗的患者最多只有短暂的反应。因此，需要额外的新疗法来改善alloHCT后复发结果，同时降低相关毒性。本项目的长期目标是开发一种基于双特异性抗体的治疗药物，用于治疗异基因造血细胞移植（alloHCT）后急性髓性白血病（AML）复发。复发的发生有两个原因之一：（1）因为未被移植预处理方案消除的残留白血病细胞逃避了供体免疫细胞提供的免疫应答，或（2）因为免疫应答不能持续。我们假设，flotetuzumab（一种用于alloHCT后复发性AML的CD3 x CD123双特异性双重亲和力靶向药物（DART））将是安全、可耐受的，并促进优先T细胞杀伤白血病细胞，从而改善患者结局。此外，供体淋巴细胞输注（DLI）与flotetuzumab联合给药将是安全、可耐受的，并可提供额外的治疗疗效。

Acute Myelogenous Leukemia (AML) is a hematopoietic neoplasm characterized by the presence of malignant immature myeloblasts in the bone marrow or peripheral blood. AML is projected to account for >20,000 new cases and ~11,000 deaths in the United States in 2021. The treatment paradigm for AML includes induction chemotherapy, aimed at achieving a remission, followed by consolidation treatment with either high dose chemotherapy or allogeneic hematopoietic cell transplantation (alloHCT). For those undergoing alloHCT, 30-50% of patients achieve long-term, disease-free survival at 5 years. Unfortunately, approximately 40% of AML patients will relapse after alloHCT and face a dismal prognosis with a 2-year survival of 20%. No standard of care exists for patients with AML who relapse after alloHCT. The most common therapy for post-alloHCT relapse is reinfusion of donor cells (donor lymphocyte infusion, DLI), sometimes preceded by debulking chemotherapy or hypomethylating agents, and second alloHCT in select individuals. However, many relapsing patients are not candidates for intensive therapy, and those who do undergo further therapy have transient responses at best. Therefore, additional novel therapies are needed to improve post-alloHCT relapse outcomes while reducing the associated toxicity. The long-term goal of this project is to develop a bispecific antibody-based therapeutic to treat acute myelogenous leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT). Relapse occurs for one of two reasons: (1) because the residual leukemic cells that were not eliminated by the transplant conditioning regimen evade the immune response provided by the donor immune cells or (2) because the immune response cannot be sustained. We hypothesize that flotetuzumab, a CD3 x CD123 bispecific dual affinity targeting agent (DART) for relapsed AML following alloHCT will be safe, tolerable and facilitate preferential T cell killing of leukemic cells resulting in improved patient outcomes. Furthermore, administration of a donor lymphocyte infusion (DLI) in combination with flotetuzumab will be safe, tolerable and may provide additional therapeutic efficacy.