The first human trial of CRISPR-based cell therapy

The first human trial of CRISPR-based cell therapy clears safety concerns as new treatment for late-stage lung cancer

In a study recently published in Nature Medicine, Lu et al. examined the feasibility and safety of using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-engineered, patient-derived T cells to treat late-stage lung cancer.

• Gene-editing therapy holds great promise in treating a wide range of human diseases from cancer to genetic disorders. The introduction of the CRISPR technology, due to its simplicity and intrinsic programmability,² has revolutionized the gene-editing field, and quickly surpasses both zinc-finger nuclease and transcription activator-like effector nuclease to become the method-of-choice for therapeutic gene editing.³ However, due to potential off-target effects, the safety of CRISPR-based therapy remains controversial. In a study recently published in Nature Medicine,¹ Lu et al. examined the feasibility and safety of using CRISPR-engineered T cells to treat late-stage lung cancer. They demonstrated very low off-target editing rates and no severe treatment-related adverse events (AE), thus supporting its general safety for clinical use.¹
• Non-small cell lung cancer (NSCLC) accounts for 83% of all lung cancer and is the leading cause of cancer-related death worldwide. Currently, immune checkpoint inhibitors targeting either PD-1 or PD-L1 have become part of the standard treatment for late-stage, PD-L1-expressing NSCLC with no molecular drivers. To determine whether PD-1-edited autologous T cells can be a viable alternative to antibody-based immunotherapy such as pembrolizumab in cancer treatment and to examine the general safety and feasibility of CRISPR-based cell therapy, Lu and colleagues conducted the first-in-human trial of CRISPR-edited, PD-1-ablated T cells in patients with advanced NSCLC. In total, 12 patients received transfusion of edited T cells and were monitored for up to 96 weeks for treatment-related AEs.
• To generate PD-1-ablated T cells, the authors electroporated plasmids encoding Cas9 and guide RNAs (gRNA) targeting the second exon of the PD-1 gene into patient-derived peripheral blood mononuclear cells (PBMCs). The transfected cells were expanded ex vivo for 17–40 days before being reinfused into patients in a dose-escalation study (Fig. 1). The editing efficiency and in vivo persistence of edited T cells were monitored by next-generation sequencing (NGS) of mutations at the PD-1 locus in infused cells for up to 1 year. The authors observed relatively low levels of editing efficiency (median = 5.81%) in infused cells, which may be related to the use of older-generation plasmid-based gene delivery system instead of the newer more efficient ribonucleoprotein method at the time of the study. As a result, edited T cells did not persist long term in most patients.