مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
Chimeric Antigen Receptor (CAR) NK Cell Therapy VS CAR-T Therapy in Multiple Myeloma.
Chimeric Antigen Receptor (CAR) NK Cell Therapy VS CAR-T Therapy in Multiple Myeloma.
Mehran Masdari,1,*
1. Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
Introduction: Multiple myeloma (MM) is a heterogeneous, incurable plasma cell malignancy associated with an overproduction of monoclonal gammaglobulin (also known as M protein). This condition represents approximately 10-15% of all hematological malignancies.
MM is also known as Kahler’s disease, most commonly presence of hypercalcemia, renal insufficiency, anemia and lytic bone lesions (CRAB features) with a median age of diagnosis 65-72 years.
Chimeric antigen receptor (CAR) T cell therapy is a remarkably personalized immunotherapy that utilizes genetically modified T cells, primarily CD8+ cytotoxic T lymphocytes (CTLs), along with monoclonal antibodies (mAb). This innovative approach aims to effectively target and eradicate tumor cells independently of human leukocyte antigen (HLA) presentation.
Natural killer (NK) cells used in CAR-NK therapy are crucial components of the innate immune system, possessing cytotoxic abilities similar to CTLs. Additionally, this cells possess synthetic receptors, enabling them to eliminate target cells without the need for prior antigen confrontation.
Methods: A search was conducted in Google Scholar and PubMed using the keywords “multiple myeloma”, “CAR-T Cells”, “CAR-NK Cells”, and “Natural Killer cells”. The relevant documents were carefully adopted, and a comprehensive review of the information was carried out.
CAR constructs in NK cells, which bear similarity to T cells, consist of an extracellular synthetic receptor (Ectodomain) derived from a mAb for recognizing tumor-associated antigens (TAAs). They also include an extracellular hinge region (spacer), a transmembrane domain (a hydrophobic region), and at least one intracellular signaling domain (endodomain), which serves as the functional terminus of the CAR. The activation signaling pathways through the endodomain enhances the elimination of tumor cells. In CAR-T cell therapy, the synthesis of CARs is autologous, involving the collection of the patient’s own peripheral blood mononuclear cells (PBMCs). In CAR-NK therapy, NK cells can be derived from various sources, such as NK-92 cell lines, human-induced pluripotent stem cells (iPSCs), or healthy donors (allogeneic).
CAR-NK cells and CAR-T cells are produced ex vivo through a series of steps including stimulation of T/NK cells, genetically engineering using various system (such as viral vectors, transposon, and CRISPR/CAS 9), proliferation, and finally, the infusion of CAR cells into the body.
Results: The significant advantage of CAR-T cells is their long-term working ability. Compared to other myeloma treatments, a single infusion of CAR-T cells may lead to persistent immunity and strong cytotoxicity. The disadvantages of this therapy are long-term production time, graft versus host disease (GVHD), cytokine release syndrome (CRS), and neurotoxicity. Other side effects of CAR-T therapy include B-cell aplasia and grade III/IV anemias that considered of on-target/off-tumor toxicity (OTOT). In contrast to CAR-T cells, CAR-NK cells are safer effector cells that may abstain or decline adverse effects of multiple myeloma such as tumor lysis syndrome, CRS, GVHD, and other OTOTs of CAR-T therapy. Furthermore, it is cost-beneficial therapy due to the attempt to make off-the-shelf products. Disadvantages of CAR-NK therapy are lack of clonal expansion that would limit clinical utility and obstacles in freezing and storage.
Conclusion: This review provides an overview of the main design of CARs, compares of CAR-T and CAR-NK therapy, discussing their potential application in the treatment of multiple myeloma.
The positive results achieved with CAR-T/NK cell therapies have strengthened the field of myeloma immunotherapy. However, it is important to address the limitations of these technologies through additional research on CARs and finding solutions for the obstacles based by CAR-NK/T cells. By doing so, the treatment of multiple myeloma will become more accessible.