Improving Cancer Immunotherapy with CRISPR‐Based Technology

Abstract

cancer immunology. Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) was tested to treat melanoma cancer patients in 1980s. [5] Monoclonal antibodies (mAbs) targeting tumor-specific or highly expressed surface antigens were approved by the U.S. Food and Drug Administration (FDA) for cancer treatment in late 1990s, for example, mAb Rituximab targeting B cell marker CD20 was approved in 1997 for non-Hodgkin's lymphoma and mAb Trastuzumab (Herceptin) targeting highly expressed human epidermal growth factor like receptor 2 (HER2) was approved in 1998 for HER2-positive breast cancer. Cytokines like interleukin-2 (IL-2) that can augment the anti-tumor immune response were also approved in 1998 to treat metastatic melanoma patients. The first FDAapproved cancer vaccine was developed in 2010 under the brand name of 'Provenge' (sipuleucel-T) that works as an autologous dendritic cell-based vaccine for the treatment of advanced prostate cancer. In the following year, the first immune checkpoint inhibitor anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) antibody was approved as a novel licensed drug for treating metastatic melanoma. Therapies with genetically engineered T cells expressing chimeric antigen receptor (CAR-T cell therapy) also stepped onto stage as approved cancer drugs in 2017 with the first one "Kymriah" targeting a B cell antigen CD19 for the treatment of refractory pre-B cell acute lymphoblastic leukemia and diffuse large B cell lymphoma. In addition, there are many ongoing immunotherapy clinical trials that have been showing impressive anti-tumor response and clinical benefits. With these explosive progresses in this field, Science magazine named cancer immunotherapy as "Breakthrough of the Year" in 2013. [6] Furthermore, the 2018 Nobel Prize in physiology and medicine was awarded to Dr. Allison and Dr. Honjo for their contributions to immune checkpoint cancer therapy. Genome editing technology is a fundamental platform for modern biomedical research, which enables people to precisely manipulate the genetic materials in cells or organisms. This technique can be either applied as research tools or ways of therapeutic intervention for gene therapy or engineered cell therapy. Several engineered nucleases such as zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and meganuclease have been designed to fulfill the DNA scissors function for genome editing, however, the editing efficiency, ease of use, timing and cost issues collectively limit

CRISPR screening in cardiovascular research

“…Many researchers have applied CRISPR screening in immune cells to investigate questions in tumor immunology (reviewed elsewhere) ( Li & Fei, 2020 ; Shi et al, 2022 ), but very few studies are linked to cardiovascular diseases. Inflammation plays a prominent role in the development of cardiovascular diseases such as atherosclerosis which involves inflammation-induced endothelial dysfunction and interplay between blood vessel cells and inflammation-related immune cells (e.g., monocytes and macrophages) ( Henein et al, 2022 ).…”

Intercellular CRISPR Screens Enhance the Discovery of Cancer Immunotherapy Targets

“…Additionally, genome-wide CRISPR screening is being used for immunotherapy as well. For example, pooled CRISPR screening in immune or cancer cells has been used to evaluate immune cell function regulators and identify immunotherapeutic targets (6, 7). Dong et al edited CTLs to identify which gene knockouts increased in vivo tumor infiltration and in vitro degranulation of CTLs (8).…”