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Recurrent and/or refractory (R/R) pediatric acute myeloid leukemia (AML) remains a recalcitrant disease with poor outcomes. Cell therapy with genetically modified immune effector cells holds the promise to improve outcomes for R/R AML since it relies on cytotoxic mechanisms that are distinct from chemotherapeutic agents. While T cells expressing chimeric antigen receptors (CAR T cells) showed significant anti-AML activity in preclinical models, early phase clinical studies have demonstrated limited activity, irrespective of the targeted AML antigen. Lack of efficacy is most likely multifactorial, including: (i) a limited array of AML-specific targets and target antigen heterogeneity; (ii) the aggressive nature of R/R AML and heavy pretreatment of patients; (iii) T-cell product manufacturing, and (iv) limited expansion and persistence of the CAR T cells, which is in part driven by the immunosuppressive AML microenvironment. Here we review the results of early phase clinical studies with AML-specific CAR T cells, and avenues investigators are exploring to improve their effector function.

The outcome of patients with acute myeloid leukemia remains poor, and immunotherapy has the potential to improve this. T cells expressing chimeric antigen receptors or bispecific T-cell engagers targeting CD123 are actively being explored in preclinical and/or early phase clinical studies. We have shown that T cells expressing CD123-specific bispecific T-cell engagers (CD123.ENG T cells) have anti-acute myeloid leukemia activity. However, like chimeric antigen receptor T cells, their effector function diminishes rapidly once they are repeatedly exposed to antigen-positive target cells. Here we sought to improve the effector function of CD123.ENG T cells by expressing inducible co-stimulatory molecules consisting of MyD88 and CD40 (iMC), MyD88 (iM), or CD40 (iC), which are activated by a chemical inducer of dimerization. CD123.ENG T cells expressing iMC, iM, or iC maintained their antigen specificity in the presence of a chemical inducer of dimerization, as judged by cytokine production (interferon-γ, interleukin-2) and their cytolytic activity. In repeat stimulation assays, activating iMC and iM, in contrast to iC, enabled CD123.ENG T cells to secrete cytokines, expand, and kill CD123-positive target cells repeatedly. Activating iMC in CD123.ENG T cells consistently improved antitumor activity in an acute myeloid leukemia xenograft model. This translated into a significant survival advantage in comparison to that of mice that received CD123.ENG or CD123.ENG.iC T cells. In contrast, activation of only iM in CD123.ENG T cells resulted in donor-dependent antitumor activity. Our work highlights the need for both toll-like receptor pathway activation via MyD88 and provision of co-stimulation via CD40 to consistently enhance the antitumor activity of CD123.ENG T cells.