Project 6- Targeting AML using bispecific and antibody drug conjugates

急性髓系白血病(AML)是一种血液系统肿瘤，其特征是骨髓或外周血中存在恶性未成熟的成髓细胞。预计到2021年，急性髓细胞白血病将导致美国20,000例新病例和11,000例死亡。AML的治疗模式包括诱导化疗，目的是实现缓解，然后是大剂量化疗或异基因造血细胞移植(AllHCT)的巩固治疗。对于那些接受异基因HCT的患者，30%-50%的患者在5年内实现了长期的无病生存。不幸的是，大约40%的急性髓系白血病患者将在异基因红细胞移植后复发，并面临着预后不佳的问题，的两年存活率为20%。对于接受异基因HCT后复发的AML患者，没有标准的护理标准。对于异基因红细胞移植后复发，最常见的治疗方法是回输供体细胞(供者淋巴细胞输注，DLI)，有时在回输之前先去除化疗或去甲基化药物，在选定的个体中进行第二次异基因红细胞移植。然而，许多复发的患者并不适合强化治疗，而那些确实接受了进一步治疗的患者充其量只有短暂的反应。因此，需要更多的新疗法来改善异基因血细胞移植后复发的结果，同时减少相关的毒性。该项目的长期目标是开发一种基于双特异性抗体的治疗方法，用于治疗异基因造血细胞移植(AllHCT)后复发的急性髓细胞白血病(AML)。复发的原因有两个：(1)由于移植条件方案未消除的残留白血病细胞逃避供者免疫细胞提供的免疫反应，或(2)由于免疫反应不能持续。我们假设，CD3 x CD123双特异性双亲和性靶向制剂(DART)治疗异基因HCT后复发的AML是安全、耐受的，并促进对白血病细胞的优先T细胞杀伤，从而改善患者预后。此外，供者淋巴细胞输注(DLI)与氟替珠单抗联合应用将是安全、耐受的，并可能提供额外的治疗效果。

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.