Anti-FLT3 monoclonal antibody, clone 8C8D4

Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (>= 75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a "hypermetabolic" phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved Tcells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus-sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.

Acute myeloid leukemia (AML) with t(8:21)(q22;q22.1);RUNX1-RUNX1T1, one of the core binding factor leukemias, is one of the most common subtypes of AML with recurrent genetic abnormalities and is associated with a favorable outcome. The translocation leads to the formation of a pathological RUNX1-RUNX1 Ti fusion that leads to the disruption of the normal function of the core-binding factor, namely, its role in hematopoietic differentiation and maturation. The consequences of this alteration include the recruitment of repressors of transcription, thus blocking the expression of genes involved in hematopoiesis, and impaired apoptosis. A number of concurrent and cooperating mutations clearly play a role in modulating the proliferative potential of cells, including mutations in KIT, FLT3, and possibly JAK2. RUNX1-RUNX1T1 also appears to interact with microRNAs during leukemogenesis. Epigenetic factors also play a role, especially with the recruitment of histone deacetylases. A better understanding of the concurrent mutations, activated pathways, and epigenetic modulation of the cellular processes paves the way for exploring a number of approaches to achieve cure. Potential approaches include the development of small molecules targeting the RUNX1-RUNX1T1 protein, the use of tyrosine kinase inhibitors such as dasatinib and FLT3 inhibitors to target mutations that lead to a proliferative advantage of the leukemic cells, and experimentation with epigenetic therapies. In this review, we unravel some of the recently described molecular pathways and explore potential therapeutic strategies.