New approaches for the immunotherapy of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a set of related diseases characterized by the immortalization and uncontrolled expansion of myeloid precursor cells. Core therapy for AML has remained unchanged for nearly 30 years, and survival rates remain unsatisfactory. However, advances in the immunotherapy of AML have created opportunities for improved outcomes. Enforcing a tumor-specific immune response through the re-direction of the adaptive immune system, which links remarkable specificity with potent cytotoxic effector functions, has proven particularly compelling. This may be coupled with immune checkpoint blockade and conventional therapies for optimal effect. Engineered antibodies are currently in use in AML and the repertoire of available therapeutics will expand. NK cells have shown effectiveness in this disease. New methods to optimize their activation and the targeting of AML show potential. Most significantly, adoptive immunotherapy with tumor-specific T cells, and particularly T cells re-directed using genetically introduced TCR or chimeric antigen receptors, have demonstrated promise. Each of these approaches has unique benefits and challenges that we explore in this review.

Figure 1. Adoptive immunotherapy of AML

Depiction of methods to target AML, including: (A) Infusion of AML-antigen-specific cytolytic T lymphocytes. These can be generated through the in vitro expansion of tumor antigen-specific lines or transduction of T cells with tumor-specific TCR; (B) Infusion of tumor antigen-specific CD4⁺ T cells. These may promote direct tumor lysis or act through their ability to support CD8⁺ T cell expansion and memory; (C) transfer of CAR-modified CD8⁺ T cells re-directed through a scFv-TCR hybrid specific for lineage or tumor antigens expressed by AML blasts; (D) infusion of AML-specific antibodies modified to enhance their cytolytic potential through conjugated therapeutics; (E) transfer of NK cells that are activated and target AML in response to FcR binding, AML-specific antibodies or other activating receptors. NK cells can be infused fresh after collection or activated and expanded in vitro; (F) transfer of NK cells modified to express activating CAR. Blue arrows indicate direction of helper activities, red arrows indicate cytotoxic activities.