Natural Killer Cell-Mediated Immunotherapy for Leukemia

Abstract

Leukemia is a malignancy of the bone marrow and blood resulting from the abnormal differentiation of hematopoietic stem cells (HSCs). There are four main types of leukemia including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). While chemotherapy and radiation have been conventional forms of treatment for leukemia, these therapies increase infection susceptibility, adverse side effects and immune cell inactivation. Immunotherapies are becoming promising treatment options for leukemia, with natural killer (NK) cell-mediated therapy providing a specific direction of interest. The role of NK cells is critical for cancer cell elimination as these immune cells are the first line of defense against cancer proliferation and are involved in both recognition and cytolysis of rapidly dividing and abnormal cell populations. NK cells possess various activating and inhibitory receptors, which regulate NK cell function, signaling either inhibition and continued surveillance, or activation and subsequent cytotoxic activity. In this review, we describe NK cells and NK cell receptors, functional impairment of NK cells in leukemia, NK cell immunotherapies currently under investigation, including monoclonal antibodies (mAbs), adoptive transfer, chimeric antigen receptor-NKs (CAR-NKs), bi-specific/tri-specific killer engagers (BiKEs/TriKEs) and future potential targets of NK cell-based immunotherapy for leukemia.

The KIR2DL family serves as prognostic biomarkers and correlates with immune infiltrates in acute myeloid leukaemia

“…However, the microenvironment of AML not only attenuates NK cell degranulation but also upregulates inhibitory receptor expression and diminishes TNFα production by NK cells. 33,34 T cells are thought to reveal altered functional and phenotypic traits in the leukaemic milieu, which contribute to an immunosuppressive environment. 35,36 Traditional T helper cells that have potent immunosuppressive activity and are closely related to the progression and prognosis of tumours can differentiate into regulatory T cells (Tregs).…”

“…discovered that interleukin (IL)‐12, IL‐15 and IL‐18 induce memory‐like NK cells that exhibit augmented killing against AML, regardless of KIR‐ligand interactions, leading to an expanded NK cell pool of AML‐reactive effector cells. However, the microenvironment of AML not only attenuates NK cell degranulation but also upregulates inhibitory receptor expression and diminishes TNF‐α production by NK cells 33,34 …”

The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities

“…The use of expanded NK cell immunotherapy to eliminate MRD in CML is being explored clinically [111] and may represent an option for adjuvant therapy in patients attempting TFR. Other novel NK-based therapeutics include anti-leukemic mAbs which induce targeted NK antibody-mediated responses and CAR-NK cell therapy, neither of which is described for CML, but for other malignancies, as reviewed by Allison et al [112]…”

Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy

“…Although chemotherapy has been the traditional form of treatment for these diseases, this approach augments infection vulnerability, comorbidities, and immunosuppression. Moreover, immunotherapies demonstrate hopeful treatment opportunities for leukemia [ 28 ].…”