CAR-NK Cells: A Chimeric Hope or a Promising Therapy?

Abstract

Immunotherapy with chimeric antigen receptor-engineered T cells (CAR-T) has revolutionized the treatment landscape of relapsed/refractory B-cell malignancies. Nonetheless, the use of autologous T cells has certain limitations, including the variable quality and quantity of collected effector T cells, extended time of cell processing, limited number of available CAR cells, toxicities, and a high cost. Thanks to their powerful cytotoxic capabilities, with proven antitumor effects in both haploidentical hematopoietic stem cell transplantation and adoptive cell therapy against solid tumors and hematological malignancies, Natural Killer cells could be a promising alternative. Different sources of NK cells can be used, including cellular lines, cord blood, peripheral blood, and induced pluripotent stem cells. Their biggest advantage is the possibility of using them in an allogeneic context without major toxic side effects. However, the majority of the reports on CAR-NK cells concern preclinical or early clinical trials. Indeed, NK cells might be more difficult to engineer, and the optimization and standardization of expansion and transfection protocols need to be defined. Furthermore, their short persistence after infusion is also a major setback. However, with recent advances in manufacturing engineered CAR-NK cells exploiting their cytolytic capacities, antibody-dependent cellular cytotoxicity (ADCC), and cytokine production, “off-the-shelf” allogeneic CAR-NK cells can provide a great potential in cancer treatments.

Induced Pluripotent Stem Cells: Advances and Applications in Regenerative Medicine

“…Other studies worth mentioning include the successful use of autologous iPSC-derived platelets for the treatment of aplastic anemia [149] and the derivation of an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting B-cell malignancies developed by Fate Therapeutics (NCT04629729). An iPSC-derived, off-the-shelf, CAR natural killer (NK) cell therapy is currently being tested in a Phase I clinic trial for refractory B-cell lymphoma (NCT 04245722) and is showing promising therapeutic efficacy [150]. Other studies have been reviewed by Kim et al [99].…”

Cellular Therapies in Chronic Lymphocytic Leukemia and Richter’s Transformation: Recent Developments in Chimeric Antigen Receptor T-Cells, Natural Killer Cells, and Allogeneic Stem Cell Transplant

“…While CAR-T treatments have shown significant promise as a novel therapy in relapsed and refractory hematological malignancies, treatment can be limited by the logistical issues of autologous CAR-T production and the inherent risk of GVHD with alloCAR-T. Consequently, natural killer CARs (CAR NK) offer a potential alternative therapeutic strategy [ 100 , 101 ].…”

“…NK cells are part of innate immunity, with the ability to kill tumor cells without any prior activation or expression of MHC molecules, through cytotoxic secretion of perforin/granzyme granules that induce apoptosis [ 101 ]. In ALL, the presence of NK cells in the bone marrow was associated with better prognosis and response to chemotherapeutic agents [ 102 ].…”

“…Trogocytosis and subsequent fratricide may limit the efficacy of CAR-NK cells, though preclinical work using a dual-CAR system that adds an NK self-recognizing inhibitory signal may be one way to prevent this barrier [ 108 ]. CAR-NK are also hampered by limited persistence though the addition of IL-15 in CAR construction may help improve the lifespan [ 101 , 107 ].…”

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells

“…Thus, keeping in mind all these considerations, the NK-92 cell line is an attractive platform for off-the-shelf CAR therapy since it also avoids the graft/host reaction. In fact, several clinical studies have shown the effectiveness of engineered NK-92 cells against a variety of cancers, including blood malignancies and solid tumors [ 29 , 30 ].…”