下一代 T 细胞免疫疗法采用 CRISPR 碱基编辑和先导编辑：挑战与机遇

T cells can be reprogrammed with transgenic antigen recognition receptors, including chimeric antigen receptors and T cell receptors, to selectively recognize and kill cancer cells. Such adoptive T cell therapies are effective in patients with certain haematological cancers but challenges persist, including primary and secondary resistance, a lack of efficacy in patients with solid tumours, a narrow range of targetable antigens, and time-consuming and complex manufacturing processes. CRISPR-based genome editing is a potent strategy to enhance cellular immunotherapies. Conventional CRISPR-Cas9 systems are useful for gene editing, transgene knock-in or gene knockout but can result in undesired editing outcomes, including translocations and chromosomal truncations.

Base editing and prime editing technologies constitute a new generation of CRISPR platforms and enable highly precise and programmable installation of defined nucleotide variants in primary T cells. Owing to their high precision and versatility, base editing and prime editing systems, hereafter collectively referred to as CRISPR 2.

0, are advancing to become the new standard for precision-engineering of cellular immunotherapies. CRISPR 2. 0 can be used to augment immune cell function, broaden the spectrum of targetable antigens and facilitate streamlined production of T cell therapies.

Notably, CRISPR 2. 0 is reaching clinical maturity, with multiple clinical trials of CRISPR 2. 0-modified cellular therapies currently ongoing. In this Review, we discuss emerging CRISPR 2. 0 technologies and their progress towards clinical translation, highlighting challenges and opportunities, and describe strategies for the use of CRISPR 2. 0 to advance cellular immunotherapy for haematological malignancies and solid tumours in the future.