CRISPRand CAR-T are two novel topics. What if the two are combined? It is undeniable that in addition to generating powerful research tools or models, the CRISPR-Cas technology itself has great potential to become drugs or therapies, especially in CAR-T gene editing. In recent years, the field of cancer immunotherapy has developed rapidly, and scientists have quickly applied gene editing technology to it. Currently, a large amount of research has focused on the application of this technology to the development of CAR-T therapy. This article will mainly introduces them from two aspects:universal CAR-T and enhanced CAR-T.

Universal CAR-T

First let's talk about the universal CAR-T. Currently, most of the CAR-T cells on the market are produced using the patient's own T cells. This process is not only time-consuming, labor-intensive, and expensive, but it is also limited by current production capabilities. If scientists can figure out how to generate universal CAR-T cells, such treatments are expected to become more convenient and cheaper. Because these off-the-shelf cells will increase the number of patients who can be treated with a single CAR-T cell product.

However, two issues have become the main obstacles to universal CAR-T, graft-versus-host disease (GVHD) and host rejection. Fortunately, a research team led by scientists at Memorial Memorial Sloan Kettering Cancer Center found that allogeneic donor CD19-specific CAR-T cells kill tumor cells while causing the lowest risk of GVHD . The article was published in Nature Medicine.

Based on such a natural advantage, researchers wanted to use CRISPR to edit CAR-T genes to reduce the antigenicity of CAR-T. Professor Carl June, a pioneer in the CAR-T field, published an article in Clinical Cancer Research, confirming that in vitro and animal model research, CIRSPR was used to knock out TCR (T cell receptor) and B2M (β-2 microglobulin). After a gene related to immunological exclusion, T-cell alloreactivity was reduced without causing GVHD.

Coincidentally, Chinese and British scientists have also discovered that a universal CAR-T can be constructed by knocking out TRAC (T cell receptor alpha constant chain) with CRISPR.

While there is another interpretation of the universal CAR-T, that is, the same T cells can be loaded with different antigens. The concept was developed by scientists at MIT and Boston University. As shown in the figure below, a universal receptor is expressed on T cells, and then this universal receptor can be linked to different target antigens, and an isolated, universal, programmable CAR system is developed for T cell therapy. They named it SUPER CAR-T. In other words, patients with different cancers need only enter the same SUPER CAR-T, and then enter the corresponding antigen (such as lung cancer-specific antigen or lymphoma-specific antigen, etc.), which greatly speeds up the treatment process.

Enhanced CAR-T

In addition to generating universal CAR-T, CRISPR can also improve the efficacy of CAR-T cells by knocking out genes for immunosuppressive pathways or signaling molecules (such as CTLA4, PD1). A more representative example is a CRISPR clinical trial led by Professor Carl June, approved by the Recombinant DNA Advisory Committee of the National Institutes of Health. In this experiment, researchers will use CRISPR / Cas9 to knock out genes encoding PD-1 and genes for endogenous T cell receptors in CAR-T targeting melanoma.