• info@icbcongress.com
• English
• Persian

• Login

Create Free Account

INTERNATIONAL CONGRESS OF

CancerGenetics

• Precision CRISPR-Cas9 Targeting of PD-1 in T Cells for Enhanced Immunotherapeutic Response in Solid Tumors : A Systematic Review

• Asma Yazdani,¹ Negar Sherafat,² Tina Haghi,³ Afshin Amari,^4,*
  1. Student Research Committee, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, IR Iran.
  2. Student Research Committee, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, IR Iran.
  3. Student Research Committee, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, IR Iran.
  4. Department of Immunology, School of Medicine, Ahvaz Jondishapur University of Medical Sciences, Ahvaz, Iran
  
  
  
• Introduction: The Programmed cell death protein 1(PD-1) receptor is a crucial inhibitory receptor on the surface of T cells, playing a pivotal role in tumor immune evasion by suppressing the function of these cells. Tumor cells exploit this inhibitory pathway to establish an immunosuppressive environment within the tumor microenvironment, thereby diminishing the efficacy of therapeutic responses. One of the major challenges in treating solid tumors is the expression of PD-1 on T cells, which leads to the suppression of anti-tumor immune responses. In recent years, CRISPR-Cas9 technology has emerged as a promising strategy for enhancing immunotherapy in solid tumors by knocking out the PD-1 gene in T cells. The aim of this study is to systematically review the research on enhancing therapeutic responses in solid tumors through the genetic modification of the PD-1 receptor using CRISPR-Cas9 technology.
• Methods: This systematic review was conducted in accordance with the PICO criteria, and aligned with the study’s objectives, following the PRISMA guidelines. A comprehensive literature search was performed for studies published between 2020 and 2024 across major databases including PubMed, SCOPUS, Web of Science, SID, and Magiran, as well as via the Google Scholar search engine. Boolean operators and Medical Subject Headings (MESH) terms such as "Solid Tumor," "Immunotherapy," "PD-1," "CRISPR-Cas9," and "T Cell" were employed. Two independent reviewers screened the retrieved articles based on predefined inclusion and exclusion criteria. Following a critical appraisal of study quality, 10 articles were included in the final analysis out of an initial pool of 118 records.
• Results: Studies employing CRISPR-Cas9-mediated targeting of PD-1 in T cells reported gene-editing efficiencies ranging from 70% to 95%, leading to a marked enhancement of antitumor responses. Nevertheless, precise metrics regarding improvement rates or sensitivity indices were not explicitly delineated in several studies. Edited T cells demonstrated a 2- to 3-fold increase in the production of interferon-gamma (IFN-γ) and interleukin-2 (IL-2) and exhibited over 80% cytotoxic capacity under in vitro conditions. In vivo models demonstrated tumor regression rates of 60% to 70%, compared to 20% to 30% observed in control groups. Multiplex gene editing resulted in the concurrent downregulation of multiple inhibitory molecules such as PD-1, LAG-3, and TIM-3, thereby enhancing T cell persistence without inducing significant toxicity. Although some clinical trials yielded limited objective responses, tumor-infiltrating lymphocytes (TILs) with PD-1 disruption showed a substantial increase in cytokine expression. Additionally, CAR T cells engineered to lack PD-1 exhibited greater proliferation, reduced exhaustion, and improved tumor-targeting capabilities.
• Conclusion: CRISPR-Cas9-mediated genetic editing of PD-1 in T cells constitutes an advanced and promising approach to augment immunotherapy against solid tumors. By abrogating immune checkpoint-mediated suppression, this technology significantly enhances the antitumor functionality of T cells while maintaining their physiological activities and minimizing off-target effects. However, several challenges remain, including dependency on error-prone non-homologous end joining (NHEJ) repair pathways, variability in homologous-directed repair (HDR) efficiency, and limitations in the effective delivery of editing machinery. Moreover, the potential for unintended genomic alterations necessitates further rigorous investigation. Future directions should focus on improving the precision and efficiency of gene editing, minimizing adverse effects, and employing combinatorial strategies to target multiple immune pathways simultaneously. Furthermore, extensive clinical trials are essential to comprehensively evaluate the long-term safety and therapeutic efficacy of this approach. In summary, provided that technical and clinical challenges are adequately addressed, this strategy holds considerable promise as a safe and effective modality for personalized treatment of solid tumors.
• Keywords: CRISPR-Cas9/ PD-1 / Immunotherapy / Solid Tumors/ T cell