No 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 finetune 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.

The use of chimeric antigen receptor (CAR) T lymphocytes in the treatment of refractory or relapsed (R/R) B cell acute lymphoblastic leukemia (B-ALL) has meant a radical change in the prognosis of these patients, whose chances of survival with conventional treatment are very low. The current probability of event-free survival by R/R B-ALL patients treated using anti-CD 19 CART cell therapy is as high as 50-60% at 1.5 years, which is a very important advance for this group of very ill patients. Although most patients (70 to 94%) achieve complete remission (CR), the main problem continues to be relapse of the disease. Most relapses, both in clinical trials and real-world evidence, are due to failure of CAR-T cell expansion or limited CAR-T persistence. However, despite the adequate functioning of infused CART lymphocytes, the tumor cells of an important group of patients manage to evade CAR-T attack, resulting in a CD 19-negative relapse. Several mechanisms have been described that may be able to produce the escape of leukemic cells, such as acquired mutations and alternative splicing of the CD19 antigen, CD19 epitope loss or masking, leukemia lineage switching, and trogocytosis. In the present review, we comprehensively analyze the leukemic cell escape mechanisms, the incidence of CD19-negative relapse reported in clinical trials and real-world evidence (outside clinical trials), and provide an update on the main lines of current research into the prevention of leukemia evasion.