Emerging Immunotherapy for Acute Myeloid Leukemia

Abstract

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia

“…Over the past two decades, AML and other hematological malignancies have become targets for the developing field of immune therapy, such as antibody-based therapeutics, dendritic cell vaccines, TCR-T-cell therapy, and gene-engineered chimeric antigen receptor (CAR)-T-cells, coupled with conventional chemotherapy and molecular targeted therapy [ 8 , 9 , 10 , 11 ]. Following the discovery of immune inhibitory mechanisms and cancer-related antigens on leukemic cells, immune approaches are evolving constantly.…”

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

“…In recent years, different treatment platforms have overall been developed to harness anti-neoplastic T-cell activity in individuals affected with cancer, including hematologic malignancies: (a) recruitment of T cells independently of TCR specificity through T-cellengaging antibody constructs, (b) reactivation of endogenous T-cell immune responses through either immune-checkpoint inhibitors (ICPIs) or other immunological strategies, and (c) genetic engineering of T cells, namely TCR-modified and chimeric antigen receptor (CAR) T cells, to be utilized as adoptive immunotherapy [1,[63][64][65]. Relevant to this latter point, van der Lee et al, isolated and sequenced the CLAVEEVSL-specific TCR from one clone that specifically and strongly recognized HLA-A*02:01 peptide-pulsed targets and NPM1-mutated AML blasts [20].…”

“…However, single-agent ICPIs have so far demonstrated very modest anti-leukemic activity in clinical trials for relapsed/refractory AML patients, maybe due to suboptimal patient selection and lower mutational load of AML compared to solid tumors [1,68]. The role of several combination approaches of ICPIs with either hypomethylating agents (HMAs) or more intensive cytotoxic chemotherapy has recently been evaluated and is still under investigation in clinical trials enrolling AML patients at different disease stages, as comprehensively reviewed elsewhere [1,[63][64][65]69]. Interestingly, Greiner et al, recently performed flow-cytometry and microarray analyses on a total of 30 AML samples, including 15 cases with NPM1 mutations, to assess PD-L1 expression in leukemic cells at diagnosis [17,70].…”

Nanoparticle T cell engagers for the treatment of acute myeloid leukemia

“…The survival curves for AML patients have remained stagnant in the past decades due to the lack of newly approved therapies for AML. However, recent development in novel therapeutics and technologies have shown promising results in preclinical and clinical settings [3][4][5].…”