T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease linked to a broad spectrum of molecular alterations, and as such, long-term disease control requires multiple therapeutic approaches. Driven largely by an improved understanding and targeting of these molecular aberrations, AML treatment has rapidly evolved over the last 3–5 years. The stellar successes of immunotherapies that harness the power of T cells to treat solid tumors and an improved understanding of the immune systems of patients with hematologic malignancies have led to major efforts to develop immunotherapies for the treatment of patients with AML. Several immunotherapies that harness T cells against AML are in various stages of preclinical and clinical development. These include bispecific and dual antigen receptor-targeting antibodies (targeted to CD33, CD123, CLL-1, and others), chimeric antigen receptor (CAR) T-cell therapies, and T-cell immune checkpoint inhibitors (including those targeting PD-1, PD-L1, CTLA-4, and newer targets such as TIM3 and STING). The current and future directions of these T-cell-based immunotherapies in the treatment landscape of AML are discussed in this review.

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

“…The graft-versus-leukemia (GvL) effect associated with allogeneic hematopoietic stem cell transplantation (HSCT) and the efficacy of donor lymphocyte infusion (DLI) to eradicate residual disease after HSCT still actually represent cornerstones of immunotherapy for the treatment of acute myeloid leukemia (AML) [1]. However, apart from mediating the beneficial GvL effect, the immune system, mainly through antigen-reactive T cells, may also induce graft-versus-host disease (GvHD), leading to potentially harmful post-transplant complications.…”

“…However, apart from mediating the beneficial GvL effect, the immune system, mainly through antigen-reactive T cells, may also induce graft-versus-host disease (GvHD), leading to potentially harmful post-transplant complications. These observations suggest the need for innovative suitable immunotherapeutic approaches aiming to obtain robust anti-leukemic activity while avoiding T-cell cytotoxicity directed against healthy tissues [1]. Of interest, harnessing antigen-specific anti-leukemic T-cell activity, minimizing the risk of "on-target/off-tumor" toxicity, should also increasingly be translated into AML management outside the allogeneic HSCT setting, but certainly still represents a clinical challenge [1,2].…”

“…These observations suggest the need for innovative suitable immunotherapeutic approaches aiming to obtain robust anti-leukemic activity while avoiding T-cell cytotoxicity directed against healthy tissues [1]. Of interest, harnessing antigen-specific anti-leukemic T-cell activity, minimizing the risk of "on-target/off-tumor" toxicity, should also increasingly be translated into AML management outside the allogeneic HSCT setting, but certainly still represents a clinical challenge [1,2]. Any ideal target antigen for AML immunotherapy should display strong and homogeneous expression levels in most to all leukemic cells, potentially including leukemic stem cell (LSC) subpopulation, with minimal to absent expression in normal hematopoietic cells and extramedullary tissues.…”

“…Furthermore, optimal target antigens should be expressed in most AML cases, showing a clearly defined indispensable leukemogenic role and possibly harboring strong immunogenic properties. While leukemia-associated antigens (LAA) are overexpressed on AML cells relative to normal tissues but are not usually lineage-specific and may also be found on non-hematopoietic cells, leukemia-specific antigens, resulting from aberrant proteins encoded by ideally leukemogenic mutations, are exclusively expressed in malignant clones, therefore representing optimal candidate targets for anti-leukemic immunity [1][2][3]. Indeed, neoantigens are composed of peptides derived from full-length leukemia-specific proteins through a multistep intracellular process, eventually resulting in the antigen presentation on the cell surface in the context of Human Leukocyte Antigen (HLA) molecules, with the subsequent potential recognition of peptide-HLA complex by specific T-cell receptor (TCR) [3].…”

“…Indeed, neoantigens are composed of peptides derived from full-length leukemia-specific proteins through a multistep intracellular process, eventually resulting in the antigen presentation on the cell surface in the context of Human Leukocyte Antigen (HLA) molecules, with the subsequent potential recognition of peptide-HLA complex by specific T-cell receptor (TCR) [3]. However, it should be noted that not all intracellular neoantigens derived from leukemia-specific gene lesions are finally presented on the cell surface and, in addition, that aberrant proteins will not necessarily yield target neoantigens [1,3]. Furthermore, some neoantigens could be encoded by patient-specific passenger mutations, which could be lost due to immune editing, a phenomenon especially observed in solid tumors with higher mutational load, resulting in tumor immune evasion, which could also be observed in case of either altered proteosomal processing of the immunogenic epitope or downregulation/loss of HLA molecules expression [3,4].…”