مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
Allogenic CAR-T cell therapy: challenges and perspectives
Allogenic CAR-T cell therapy: challenges and perspectives
Laleh Dehghani,1Fatemeh Roozbahani,2,*
1. Bushehr university of medical science, Bushehr, Iran 2. Mazandaran university of medical science, Department of microbiology and immunology
Introduction: CAR-T cell therapy has emerged as a significant breakthrough in cancer treatments particularly in patients with hematological malignancies who have not responded well to previous therapies. Harnessing the power of the immune system to fight cancer is the basic concept of this treatment. the patient’s T cells were genetically modified to express a synthetic receptor called chimeric antigen receptor. These receptors are designed to recognize certain molecules in cancer cells and eliminate them. Despite being a revolutionary approach, As mentioned above the source of engineered T-cells, are autologous. even though they have demonstrated remarkable clinical success, it is associated with several limitations including severe side effects, manufacturing time, cost, and feasibility issues for patients who lack adequate T-cell population. Allogenic CAR-T cells represent an alternative approach by utilizing healthy donor-derived T-cells instead of patient’s derived ones. This innovative solution allows for wider accessibility and reduced manufacturing time compared to autologous therapies that require a personalized production process.
Despite offering several advantages, allogenic therapy faces its limitations such as graft-verses-host-disease (GVHD). Effective application of this approach is due to overcoming these challenges. In this review, we investigate the viability of allogenic CAR-T cell therapy using double-negative T-cells (DN T cells) as the new cell sources for this novel therapeutic approach.
Methods: To identify relevant studies a comprehensive search of electronic databases such as Pubmed, Scopus, and Frontiers Immunology was conducted. The search terms used were “allogenic CAR-T cell therapy, double negative CAR-T cells(DN CAR-T cells), CAR-T cell therapy, and cancer treatment.” The search was limited to articles published from 2012 to 2023. Studies were only included if they investigated allogenic CAR-T cell therapy using DN-CAR T cells. Studies that focused on autologous CAR-T cell therapy were excluded. Inclusion criteria also required studies to report safety, efficacy, and potential adverse events associated with DN-CAR T cells. The data extracted from included articles were summarized and analyzed to identify common themes across them.
Results: Double negative CAR-T cells are subset of T-cells that lack CD4 and CD8 co-receptors and express a chimeric antigen receptor on their surface. potential usage of these cells as sources for allogenic settings is due to several advantages they possess over autologous sources and conventional CAR-T cells. One of the major limitations of allogenic sources is the risk of GVHD, in which the donor T-cells attack the recipient’s healthy tissues. However, DN T-cells, by lacking CD4 and CD8 co-receptors, that are crucial for T cell activation and subsequent GVHD development, can reduce the risk of GVHD. Based on the prior studies that were conducted on animal models, mice treated with DN CAR-T cells targeting CD19, showed an 80 percent survival rate after 120 days which proved their persistency. Furthermore, DN-CAR-T cells have demonstrated a lower potential for off-target toxicities compared to conventional CAR-T cells. This is attributed to their more limited repertoire of T-cell receptors and reduced expression of activation markers. DN CAR-T cells offer advantages in terms of scalability and manufacturing. conventional CAR-T cells cannot be pooled from different donors due to alloreactivity. However, DN T cells derived from various donors can be expanded in a single culture without losing their functionality. This facilitates large-scale production which is a crucial aspect of the clinical application of allogenic CAR-T cell therapy. In current allogenic approaches with conventional T-cells, genetic modifications such as TCR knockout are conducted to prevent GVHD. Despite the effectiveness of these strategies they complicate the process therefore DN T cells remain an attractive alternative.
Conclusion: Allogenic DN CAR-T cell therapy holds potential value in the future as to date it has minimized the challenges such as GVHD and severe side effects in previous approaches and simplified manufacturing process. Further research and clinical trials should focus on enhancing safety, exploring combinational approaches, and conducting long-term efficacy. By addressing these areas, Allogenic CAR-T cell therapy using DN-CAR-T cells can revolutionize the field of cancer treatment and broaden its application to both hematological malignancies and solid tumors.