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

SIMPLE SUMMARY: In recent years, innovative immunotherapy-based treatments have paved the way for a new approach to hematological malignancies. Instead of conventional chemotherapy, T cells have been genetically engineered to detect—and engage their cytotoxicity against—tumor cells, and their success story is astonishing. However, many setbacks—including insufficient efficacy, deficient autologous source, heavy side effects, and a hefty price—limit their use. A promising alternative could be chimeric antigen receptor NK cells, which possess interesting cytotoxicity and minimal graft-versus-host disease risk. In this article, we review the possible sources, the development techniques, the potential advantages, and the challenges faced in the field of chimeric antigen receptor NK cells. 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.