The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers

Abstract

Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL) are the most common leukemias in children and elderly people, respectively. Standard therapies, such as chemotherapy, are only effective in 40% of ALL adult patients with a five-year survival rate and therefore new alternatives need to be used, such as immunotherapy targeting specific receptors of malignant cells. Among all the options, CAR (Chimeric antigen receptor)-based therapy has arisen as a new opportunity for refractory or relapsed hematological cancer patients. CARs were designed to be used along with T lymphocytes, creating CAR-T cells, but they are presenting such encouraging results that they are already in use as drugs. Nonetheless, their side-effects and the fact that it is not possible to infuse an allogenic CAR-T product without causing graft-versus-host-disease, have meant using a different cell source to solve these problems, such as Natural Killer (NK) cells. Although CAR-based treatment is a high-speed race led by CAR-T cells, CAR-NK cells are slowly (but surely) consolidating their position; their demonstrated efficacy and the lack of undesirable side-effects is opening a new door for CAR-based treatments. CAR-NKs are now in the field to stay.

Genetic Engineering and Enrichment of Human NK Cells for CAR-Enhanced Immunotherapy of Hematological Malignancies

“…Infusions of allogeneic NK cells have also been tested in clinical trials and were tolerated well without any GvHD; however, the therapeutic benefits were rather limited, and the concomitant treatment with IL2 or IL15 was associated with profound acute toxicities ( 11 ). Recently, antibody-based immunotherapies with bispecific T cell engagers or CAR T cells have achieved remarkable initial success, predominantly for B cell-associated malignancies ( 53 , 54 ). However, for patients with relapsed/refractory leukemias, the generation of autologous CAR T cells often takes too much time, is technically quite difficult in small children or heavily pretreated patients, and rather impossible for AML patients due to the lack of suitable target antigens for the long-term persistent CAR T cells ( 53 , 54 ).…”

“…Recently, antibody-based immunotherapies with bispecific T cell engagers or CAR T cells have achieved remarkable initial success, predominantly for B cell-associated malignancies ( 53 , 54 ). However, for patients with relapsed/refractory leukemias, the generation of autologous CAR T cells often takes too much time, is technically quite difficult in small children or heavily pretreated patients, and rather impossible for AML patients due to the lack of suitable target antigens for the long-term persistent CAR T cells ( 53 , 54 ). Here, generating allogeneic CAR NK cells for off-the-shelf usage and with limited persistence in vivo in patients might be ideal for inclusion in salvage treatment protocols for relapsed/refractory patients, e.g., as a blast-reductive treatment/bridge to allogeneic stem cell transplantation.…”

Chimeric antigen receptor–based therapies beyond cancer

“…Some disadvantages of CAR-T cells can be overcome by the use of NK cells as effector cells [7,8]. Two ongoing phase I clinical trials are awaiting results on the effect of haploidentical NK cell administration on HIV-infected patients (NCT03346499 and NCT03899480).…”

“…Despite recent progress in safety during prophylaxis and therapy, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenia continue to be the most relevant adverse effects [5]. Some current drawbacks associated with autologous CAR-T cell therapies can be overcome by using natural killer (NK) cells [6][7][8]. In addition to their higher effector efficiency against tumors and pathogens, NK cells are suitable for off-the-shelf allogeneic ACT.…”

Recent findings on chimeric antigen receptor (CAR)-engineered immune cell therapy in solid tumors and hematological malignancies

“…Nonetheless, with CAR-NK cells, we can have an off-the-shelf product so that the patient comes into your clinic and you have these cells frozen, sitting in a biobank, and you can thaw and infuse, making the strategy lot more appealing and also cheaper [ 7 , 43 ]. In addition, CAR-NK cells are safer than CAR T-cells because the cytokines secreted by activated NK cells (e.g., IFN-γ and granulocyte–macrophage colony-stimulating factor (GM-CSF) are safer and typically eliminate the risk of cytokine storm and extreme neurotoxicity caused by pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF- α ), IL-1, and IL-6) released by CAR T-cells [ 44 ], and also allogeneic CAR-NKs decrease the risk of GVHD because they are not restricted to MHC [ 45 ]. Moreover, CAR-NK cells may have multiple mechanisms for cytotoxic activity because they can recognize and kill targets via engineered killing capacity as well as their intrinsic killing capacity via natural cytotoxicity receptors [ 46 , 47 ].…”