Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

Abstract

Despite new insights in molecular features of leukemic cells and the availability of novel treatment approaches and drugs, acute myeloid leukemia (AML) remains a major clinical challenge. In fact, many patients with AML relapse after standard therapy and eventually die from progressive disease. The basic concept of leukemic stem cells (LSC) has been coined with the goal to decipher clonal architectures in various leukemia-models and to develop curative drug therapies by eliminating LSC. Indeed, during the past few years, various immunotherapies have been tested in AML, and several of these therapies follow the strategy to eliminate relevant leukemic subclones by introducing LSC-targeting antibodies or LSC-targeting immune cells. These therapies include, among others, new generations of LSC-eliminating antibody-constructs, checkpoint-targeting antibodies, bi-specific antibodies, and CART or CAR-NK cell-based strategies. However, responses are often limited and/or transient which may be due to LSC resistance. Indeed, AML LSC exhibit multiple forms of resistance against various drugs and immunotherapies. An additional problems are treatment-induced myelotoxicity and other side effects. The current article provides a short overview of immunological targets expressed on LSC in AML. Moreover, cell-based therapies and immunotherapies tested in AML are discussed. Finally, the article provides an overview about LSC resistance and strategies to overcome resistance.

The Role of Immune Checkpoint Blockade in Acute Myeloid Leukemia

“…Chemotherapy is still the standard therapy used for AML. Tumor cell death is caused not only by cytostatic effects but also by the restimulation of the immune surveillance with a direct immune response towards tumor cells [58,59].…”

“…The immune response against cancer cells is increased through various processes, from enhancing antigen uptake and chemotactic response via macrophages and dendritic cells to augmenting recognition to the immune system and increasing tumor susceptibility to immune-mediated cytotoxicity [58][59][60].…”

Perspective: Pivotal translational hematology and therapeutic insights in chronic myeloid hematopoietic stem cell malignancies

“…In myeloid leukemias, including CML, chronic myelomonocytic leukemia (CMML), mast cell leukemia (MCL), and AML, leukemia stem cell (LSC) exhibit multiple forms of drug resistance, including primary stem cell resistance, niche-mediated LSC resistance, acquired (secondary) resistance and immune checkpoint-mediated resistance. 93 These forms of resistance act together to protect LSC from drug effects which is a major clinical challenge. In fact, overriding one form of LSC resistance alone may not be sufficient to develop curative (LSC-eradicating) treatment concepts.…”

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

“…The concept of LSCs has been established to explain subclonal architectures and hierarchies in leukemias. LSCs have an unlimited capacity to divide and self-renew, thereby propagating the malignancy for unlimited time periods [ 40 ]. Chemotherapy resistance in cancer stem cells (CSCs) can be attributed to their reduced proliferation or quiescence, heightened DNA repair, reduced apoptosis, increased clearance of reactive oxygen species (ROS), enhanced drug efflux mechanisms and reduced immune clearance [ 41 ].…”