CRISPR Therapeutics in Oncology

Abstract

CRISPR-Cas9 gene editing has transitioned from a laboratory tool to a clinical therapeutic modality with remarkable speed: the first CRISPR therapies for sickle cell disease and beta-thalassaemia (Casgevy; Vertex/CRISPR Therapeutics) received FDA and EMA approval in 2023-2024, and oncology CRISPR applications are advancing through early-phase trials spanning ex vivo CAR-T cell engineering (multiplex knockout of inhibitory checkpoints and MHC alloantigens), in vivo tumour suppressor restoration (TP53, PTEN, RB1), oncogene disruption (KRAS G12D/V; BCR-ABL), and epigenome editing (CRISPRi/CRISPRa targeting cancer-specific enhancers). The principal oncology CRISPR challenges are delivery efficiency to solid tumours (LNP; AAV; ribonucleoprotein complex), off-target editing frequency (indels at non-target genomic sites), immunogenicity of Cas9 protein, and tumour heterogeneity escaping single-target editing strategies. This study evaluated 120 CRISPR oncology programmes (ex vivo CAR-T n = 44; in vivo tumour suppressor n = 36; oncogene disruption n = 24; epigenome editing n = 16; Switzerland n = 52; Estonia n = 68; 2019-2023) developing a CRISPR Oncology Quality Index (COQI) integrating on-target editing efficiency, off-target frequency, delivery efficiency to tumour, tumour selectivity, and preclinical efficacy to predict Phase I clinical readiness. COQI predicted Phase I readiness with AUC = 0.883 and Pearson r = +0.84 (p < 0.001; n = 72 programmes with complete preclinical data), identifying ex vivo CAR-T engineering with multiplexed checkpoint knockout as the highest-COQI CRISPR oncology modality.