Project 6- Targeting AML using bispecific and antibody drug conjugates

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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.