Sub-Journal of "Science": Is the new design expected to equip CAR-T products with "enhancing agents"?

Text|Pharmaceutical Mission Hills

At present, chimeric antigen receptor T cell (CAR-T) therapy has shown strong efficacy in hematological tumors, but there are still many patients who may progress or relapse after the initial remission of the disease
.

If the corresponding antigen is expressed at a low level in tumor cells, then CAR-T therapy may be ineffective

How to enhance the effect of CAR-T products? Recently, Science Signaling published a study in which the scientific team from the Fred Hutchinson Cancer Research Center took inspiration from T cell receptors (TCRs) and designed New CARs with higher antigen sensitivity have been developed, and they have shown better anti-tumor activity in mouse models of lymphoma, leukemia and breast cancer
.

Screenshot source: Science Signaling

Researchers believe that this new technology can be integrated into the structure of existing CARs, which is expected to create CAR-T products that can also work on tumor cells with low antigen expression
.

The concept of TCR-T was proposed earlier than CAR-T
.

CARs were originally designed to mimic TCR signals.

In this study, the researchers compared the signal transduction differences between CAR-T cells and natural TCRs, and found that some key T cell signaling proteins (including CD protein complexes) did not undergo specific cell signaling processes to activate CAR.
Changes
.

In this regard, the researchers designed two new types of CARs that bind to the domains of CD3-epsilon or Grb2 (growth factor receptor binding protein 2)
.

The results of in vitro experiments showed that compared with traditional CARs, T cells with new CARs showed stronger antigen sensitivity and higher activation levels

The research team also tested whether CAR-T cells with new CARs can better control tumor cells with low antigen expression in living animals
.

The data shows that in the mantle cell lymphoma mice expressing low levels of ROR1 (receptor tyrosine kinase-like orphan receptor 1), although it is not statistically significant, CAR-T designed using two new CARs Cells provide stronger anti-tumor effects and longer survival time than traditional CAR-T cells

In the same low-level expression of ROR1 in a mouse model of breast cancer, the researchers found that traditional CAR-T cells did not exhibit anti-tumor effects
.

In contrast, mice that received the two new CAR-T products had significantly lower tumor burdens than mice that received traditional CAR-T products

▲The new CAR design enhances the antigen sensitivity of CAR-T products (picture source: reference [2])

It is worth mentioning that the Fred Hutchinson Cancer Research Center is one of the pioneers in the field of CAR-T research
.

Juno Therapeutics, a subsidiary of Bristol-Myers Squibb (BMS), is derived from this research center, and the technology of Breyanzi, a CAR-T product targeting CD19, also originated from this

I look forward to more early research results that can be smoothly translated into the clinic, so as to develop more innovative therapies that benefit patients

references:

[1]Improving CAR-T cell therapy with more sensitive tumor identification.

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