Abstract
The approval of CD19 chimeric antigen receptor (CAR)-engineered T (CAR-T) cell products in B-cell malignancies represents a breakthrough in CAR-T cell immunotherapy. However, the remaining limitations concerning the graft-versus-host disease (GVHD) and other adverse effects (e.g., cytokine release syndromes [CRS] and neurotoxicity) still restrict their wider applications. Natural killer (NK) cells have been identified as promising candidates for CAR-based cellular immunotherapy because of their unique characteristics. No HLA-matching restriction and abundant sources make CAR-engineered NK (CAR-NK) cells potentially available to be off-the-shelf products that could be readily available for immediate clinical use. Therefore, researchers have gradually shifted their focus from CAR-T cells to CAR-NK cells in hematological malignancies. This review discusses the current status and applications of CAR-NK cells in hematological malignancies, as well as the unique advantages of CAR-NK cells compared with CAR-T cells. It also discusses challenges and prospects regarding clinical applications of CAR-NK cells.
Highlights
Hematological malignancies, which contribute to approximately 7% of all newly diagnosed cancers, represent a class of malignant clonal diseases originating in the hematopoietic system, mainly including leukemia, lymphoma and multiple myeloma (MM) [1, 2]
Despite considerable progress in chimeric antigen receptor (CAR)-T cell-based immunotherapy for patients with blood diseases, there remain restrictions that inhibit its broader application in future treatment of hematological malignancies: [1] CRS and neurotoxicity are notable acute side effects that occur during CD19 CAR-T cell therapy [12]; [2] on-target off-tumor effects may occur related to the recognition of molecular biomarkers that are expressed on healthy tissues (e.g., B cell aplasia in anti-CD19/CD20 CAR-T cell therapy) [13]; [3] antigen escape/ loss may lead to disease relapse [14]; [4] life-threatening graft-versus-host disease (GVHD) may be caused by allogeneic CAR-T cells [15]; [5] restrictions concerning inclusion in commercialized and “off-the-shelf” products have been implemented because of the HLA restriction and insufficient sources of T cells
The emergence of CAR-T cells is a breakthrough in cancer immunotherapy, especially for B-cell malignancies
Summary
Hematological malignancies, which contribute to approximately 7% of all newly diagnosed cancers, represent a class of malignant clonal diseases originating in the hematopoietic system, mainly including leukemia, lymphoma and multiple myeloma (MM) [1, 2]. Immunotherapy (e.g., cytokine therapy, immune checkpoint blockade, and CAR-T cell therapy) has enriched treatment methods and improved the prognosis of patients with hematological tumors [3, 6]. Transfusion of NK cells is an effective adoptive immunotherapy method to improve the number and the function of NK cells [30] These approaches used for NK cell therapy are applicable for CAR-NK cell therapy. Similar to the structures of CAR-T cells, CAR-NK cells are composed of CARs (genetically engineered transmembrane receptors) and effector cells (NK cells)
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