Improved tumour killing immune cells against brain cancers


Researchers at IGP have demonstrated a mechanism for how cancer killing immune cells called CAR- T cells sometimes are prematurely exhausted and fail to kill the cancer cells. They also present new CAR-T cells against brain tumours that lack this unwanted exhaustion feature. The future aim is to use these CAR-T cells to treat brain cancer. The study has been published in the journal Nature Communications.

CAR-T cells are immune cells that are modified to eliminate cancer cells. The modification includes the attachment of an artificial molecule called CAR to the immune cells. The CAR molecule is designed to bind to a specific structure, a so-called antigen, expressed on the surface of cancer cells. The interaction between the CAR molecule and the antigen leads to activation of the CAR-T cell and subsequent killing of the cancer cell.

Designing an optimal CAR remains challenging and it has been known for a long time that certain CARs are prone to activate the CAR-T cell even in the absence of a cancer cell. This leads not only to activation but also exhaustion of the CAR-T cell. In the new study, recently published in the journal Nature Communications, the researchers have shown which part of the CAR molecule that is involved in this phenomenon.

“Researchers have so far believed that the antigen-independent activation and exhaustion of the CAR-T cells was only related to instability of the structural region of the CAR. In our study we could show that the part of molecule that directly interacts with the target antigen can also affect the stability of the CAR, in some cases leading to antigen-independent CAR-T cell activation and exhaustion,” says Tina Sarén, postdoctoral researcher at IGP and first author of the paper.

The researchers found that the antigen-binding regions in the CAR molecule in certain cases were responsible for CAR clustering on the surface of CAR-T cells, leading to antigen-independent activation. When the CAR-T cells later were exposed to cancer cells they had become dysfunctional and could no longer kill the cancer cells.

“We believe that this can be one reason why CAR-T cells in some cases fail to persist long enough in cancer patients to result in an effective treatment,” says Di Yu, who led the study together with Magnus Essand.

“To get an optimal therapy, you need the best possible CAR molecules. In the paper we also describe a method to screen CAR candidates and quickly discard problematic ones,” Sarén says.

CAR-T cells are often effective when used to treat hematological malignancies but still face hurdles for solid tumours, including brain cancer. In the study, the researchers present new CAR-T cells, directed against an antigen that is often expressed in brain tumour cells. These CAR-T cells do not show any antigen-independent activation and therefore represent a good candidate for future treatment.

“We have started the work to be able to produce our new CAR-T cells at clinical grade. We hope to be able to initiate a new clinical trial for the severe brain tumour type glioblastoma in Uppsala within two years,” Essand says.

More information:

Paper in Nature Communications

Magnus Essand’s research

Last modified: 2022-01-26