Fred Hutch develops next-generation CAR-T cell therapy with greatly enhanced anti-tumor activity

Author: Bai Lu

Chimeric Antigen Receptor (CAR) T cell therapy has shown strong effects in blood diseases, but if the corresponding antigen is expressed at low levels in tumor cells, CAR-T therapy may be ineffective, and many patients continue to disease after the initial remission Progress or relapse

For example, a single infusion of T cells expressing a synthetic CD19 targeting CAR can completely relieve 90% of acute lymphoblastic leukemia patients and 40%-50% of non-Hodgkin’s lymphoma patients, but a considerable number of patients progress or progress after treatment.

The reduction of antigen expression is undoubtedly a major obstacle to the efficacy of CAR-T cells

Science Signaling Issue 697 Cover Paper: Fred Hutchinson Cancer Research Center uses phosphorylated proteomics to conduct in-depth research on endogenous T cell receptor (TCR) and engineered receptor (CAR) signal transduction, and designed a method for cancer A wider range of effective CAR-T cells for treatment

In order to solve this problem, researchers at the Fred Hutchinson Cancer Research Center explored ways to enhance the effects of CAR-T products.

Researchers believe that this new technology can be applied to existing CAR structures to create better CAR-T therapies that can eliminate tumor cells expressing low levels of target antigens

CAR was originally designed to mimic TCR signals.

The structure and mechanism of CAR (Source: Bangyao Biological)

In this study, Fred Hutch's team compared signal transduction in CAR-T cells with natural TCR

Based on this understanding, the researchers improved the CAR structure and designed two new types of CAR

A) Schematic diagram of CAR with CD3ε sequence; D) Schematic diagram of CAR with GRB2 or GRAP2 SH2 domain (Source: Science Signaling)

In the laboratory dish, the T cells carrying the new CAR exhibited higher antigen sensitivity and higher activation levels than the original CAR T cells

The team also tested whether the new CAR can better control tumor cells with low antigen expression in living animals

Source: Science Signaling

In a mouse model of breast cancer with low ROR1 expression, the researchers found that traditional CAR-T cells did not show anti-tumor effects

Source: Science Signaling

It is worth mentioning that Fred Hutch is one of the pioneers in the field of CAR-T research

Note: The original text has been deleted

Reference materials:

1# Alexander I.

2# Improving CAR-T cell therapy with more sensitive tumor identification (Source: FIERCE Biotech)