Abstract
Genome editing technologies not only provide unprecedented opportunities to study basic cellular system functionality but also improve the outcomes of several clinical applications. In this review, we analyze various gene editing techniques used to fine-tune immune systems from a basic research and clinical perspective. We discuss recent advances in the development of programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases. We also discuss the use of programmable nucleases and their derivative reagents such as base editing tools to engineer immune cells via gene disruption, insertion, and rewriting of T cells and other immune components, such natural killers (NKs) and hematopoietic stem and progenitor cells (HSPCs). In addition, with regard to chimeric antigen receptors (CARs), we describe how different gene editing tools enable healthy donor cells to be used in CAR T therapy instead of autologous cells without risking graft-versus-host disease or rejection, leading to reduced adoptive cell therapy costs and instant treatment availability for patients. We pay particular attention to the delivery of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral damage and increases therapeutic effectiveness. Finally, we review creative innovations, including immune system repurposing, that facilitate safe and efficient genome surgery within the framework of clinical cancer immunotherapies.
Highlights
Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
Natural killer (NK) cell lymphocytes play an important role in the innate immune system due to their ability to kill a variety of target cells, including cancer cells, and can rapidly respond in a thymus-independent manner without previous recognition of the antigen [78]
A new system, in which endogenous T-cell receptors (TCRs) and human leukocyte antigens (HLAs) molecules on allogeneic T cells are eliminated, leading to a reduction in graft-versushost disease (GVHD) and rejection by the transplant recipient’s immune system, has been developed. These off-the-shelf–based therapies are of special interest to patients who, due to previous treatments or disease progression processes, have T cells deficient in either number or quality
Summary
The remarkable progress made in GE tools in recent years has made it possible to engineer different immune cell types for FIGURE 1 | Representative scheme of the different genome editing tools used to improve the immune system. The replacement of the APOBEC1 component in BE3 with natural adenine deaminase Escherichia coli TedA led to the creation of the first adenine base editor ABE which was followed by ABE1.2 After several target mutations and optimizations, the ABE7.1 base editor was released This was followed by the latest version ABE8 with its base editing facility for HSPCs and human primary T cells [33]. Cells previously considered behavior of different immune cells to be fine-tuned by deleting highly resistant to genetic modification can be gene-edited or enhancing endogenous gene expression and by inserting new very efficiently using these new technologies. This enables the genes in safe harbor loci. We review recent advances in GE methods that have been successfully applied to different immune cell types
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