Redirecting the Immune Microenvironment in Acute Myeloid Leukemia

SIMPLE SUMMARY: Despite remarkable progress in the outcome of childhood acute myeloid leukemia (AML), risk of relapse and refractory diseases remains high. Treatment of the chemo-refractory disease is restricted by dose-limiting therapy-related toxicities which necessitate alternative tolerable efficient therapeutic modalities. By disrupting its immune environment, leukemic blasts are known to gain the ability to evade immune surveillance and promote disease progression; therefore, many efforts have been made to redirect the immune system against malignant blasts. Deeper knowledge about immunologic alterations has paved the way to the discovery and development of novel targeted therapeutic concepts, which specifically override the immune evasion mechanisms to eradicate leukemic blasts. Herein, we review innovative immunotherapeutic strategies and their mechanisms of action in pediatric AML. ABSTRACT: Acute myeloid leukemia is a life-threatening malignant disorder arising in a complex and dysregulated microenvironment that, in part, promotes the leukemogenesis. Treatment of relapsed and refractory AML, despite the current overall success rates in management of pediatric AML, remains a challenge with limited options considering the heavy but unsuccessful pretreatments in these patients. For relapsed/refractory (R/R) patients, hematopoietic stem cell transplantation (HSCT) following ablative chemotherapy presents the only opportunity to cure AML. Even though in some cases immune-mediated graft-versus-leukemia (GvL) effect has been proven to efficiently eradicate leukemic blasts, the immune- and chemotherapy-related toxicities and adverse effects considerably restrict the feasibility and therapeutic power. Thus, immunotherapy presents a potent tool against acute leukemia but needs to be engineered to function more specifically and with decreased toxicity. To identify innovative immunotherapeutic approaches, sound knowledge concerning immune-evasive strategies of AML blasts and the clinical impact of an immune-privileged microenvironment is indispensable. Based on our knowledge to date, several promising immunotherapies are under clinical evaluation and further innovative approaches are on their way. In this review, we first focus on immunological dysregulations contributing to leukemogenesis and progression in AML. Second, we highlight the most promising therapeutic targets for redirecting the leukemic immunosuppressive microenvironment into a highly immunogenic environment again capable of anti-leukemic immune surveillance.