Chimeric Antigen Receptor (CAR) NK Cell Therapy in Multiple Myeloma
Chimeric Antigen Receptor (CAR) NK Cell Therapy in Multiple Myeloma
Mehran Masdari,1,*
1. Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
Introduction: Multiple myeloma (MM) is an incurable disease with a collection of enfeeblement hematological disorders with ordinary clinical phenotype that occurs by atypical plasma cells originate from terminally differentiated lymphoid B-cell lineage. Multiple myeloma is the second most common hematological cancer after Non-Hodgkin lymphoma (NHL) and accounts for approximately 1% of all malignancies. Natural Killer (NK) cells are part of natural armament were described as large granular lymphocyte, manifesting 5-20% of circulating lymphocytes in humans which are capable to annihilate unnatural cells without the request for prior confronting.
With the remarkable capability of NK cells to efficiently induce cytotoxicity without prior antigenic stimulation, antigen presentation by MHC class I molecules, and antibody recognition, it is achieved through a complex interplay between inhibitory such as Killer immunoglobulin-like receptor (KIRs) and activating receptors like Natural cytotoxicity receptor (NCR) family. These receptors and their signals involve the release of cytokines, induction of apoptosis, and ultimately the elimination of cancer cells.
Genetic engineering enables the use of synthetic receptors to alter the specificity and function of NK cells. Unlike T-cells, NK cells are considered to be safer effector cells, as they have the potential to avoid serious complications such as cytokine release syndrome (CRS), tumor lysis syndrome, graft versus host disease (GVHD), and neurotoxicity.
Methods: A search was conducted in PubMed and Google Scholar using the keywords “Multiple myeloma”, “CAR-NK Cells” and “Natural Killer cells”. The relevant documents were selected, and a thorough review of the information was completed.
There are various sources for CAR-expressing NK cells to produce large-scale off-the-shelf products. These including peripheral blood mononuclear cells (PBMCs), which typically have a mature phenotype and are easily isolated. Umbilical cord blood (UCB) is advantageous for selecting donors with certain HLA types and less mature phenotype. NK92 cell lines are less cytotoxic and more affordable. Human-induced pluripotent stem cells (iPSCs) demonstrate a mature phenotype and antitumor cytotoxicity.
CAR constructs are typically made up of an extracellular synthetic receptor that recognizes antigens, an extracellular hinge region, a transmembrane domain, and one or more intracellular co-stimulatory domains. The CAR receptor is usually derived from a murine monoclonal Antibody in the form of a single-chain variable fragment (scFv), although it can also be encoded to express a naturally occurring surface receptor that has an affinity for tumor-specific ligands.
Various methods of gene transfer have been utilized in NK cells, including Non-viral delivery methods (e.g. Electroporation and Cell squeezing), Viral-vectors (Retroviral and Lentiviral vectors), gene-editing techniques (like CRISPR/CAS 9 and Transposons), and Surface engineering approaches (e.g. Liposomes).
Results: Chimeric antigen receptor NK (CAR-NK) cells have shown promise as a type of Adoptive NK cell therapy against MM. These cells have the ability to kill myeloma cells, while also being mostly non-toxic to normal tissues.
Thanks to Advancements in gene-editing techniques, new CAR-NK cell products with potent anti-tumor activity have been developed. This can greatly improve the survival rates of cancer patients who have limited treatment options.
As the enthusiasm for innovative immunomodulatory therapies grows, there is a chance for even greater effectiveness in targeting NK cells against myeloma.
With more clinical data expected in the coming years, CAR-NK cell therapies could potentially revolutionize tumor immunotherapy. As a result, the use of allogeneic NK cells as immunotherapy for MM holds great promise
Conclusion: This review describes the principle design of CARs, the main genetic modification techniques, and the potential uses in the treatment of multiple myeloma.
The use of Chimeric Antigen Receptor NK cells for adoptive cellular therapy shows promise and possesses the potential to be developed as readily available “off-the-shelf” products, it offers an interesting strategy to treat MM patients in clinical use.