Study advances CAR T cell therapy targeted at cancer

Cancer immunotherapy involves the activation of cells in the patient’s own immune system to fight tumor cells. Chimeric antigen receptor (CAR) T cell therapy is one of the most important recent developments in immunotherapies focused on cancer.

CAR T cell therapy involves the extraction of T cells from the patient for genetic alterations: a CAR T cell is directed toward the cells through a viral vector, supporting the T cells to better recognize and destroy tumor cells. When the required surface structure in the patient’s cells is identified by the antigen receptor cells, they begin to multiply and destroy the target cells.

CAR T cell therapy was first introduced in Finland in 2018, and the form of treatment has been used to help patients suffering from lymphomas and leukemia.

To date, the use of CAR T cell therapy on solid tumors has been quite challenging: for example, it is difficult to target the therapy at only the tumor when the type of cancer is not linked with any particular surface structure.

In many types of cancers, a specific protein is abundantly present on the surface of the tumor, but since the protein also exists in low numbers in normal tissues, CAR T cell therapy is incapable of distinguishing between the levels of target proteins. This is the reason why genetically altered cells can rapidly attack healthy organs and cells, possibly resulting in lethal side effects from the treatment.

A research work, recently reported in the Science journal, has identified a new way to apply CAR T cell therapy to even solid tumors: Finnish and American researchers collaborated together to find a new method of programming CAR T cells so that they destroy only the cancer cells, without affecting the healthy cells containing the same marker protein as that of cancer cells.

New technique based on ultrasensitive identification of HER2 cells, further investigation underway

HER2 is a protein typically associated with ovarian cancer, abdominal cancer, and breast cancer, among others. This protein can even occur in large numbers on the tumor cell surface because the expression of the HER2 protein can be multiplied in tumors due to gene amplification.

The novel CAR T cell engineering technique designed by the team is built on a two-step identification process of HER2 positive cells. And because of this technique, the team was able to generate a response in which CAR T cells destroy only the tumor cells in the cancer tissue.

Our solution requires the preliminary identification of the surface structures associated with the cancer When the preliminary recognition ability that induces the CAR construct is adjusted to require a binding affinity that is different from the affinity used by CAR to direct the killing of these cells, an extremely accurate ability to differentiate between cells based on the amount of target protein on their surface can be programmed in this two-step ‘circuit’ which controls the function of killer T cells.”

Kalle Saksela, Professor of Virology, University of Helsinki

Additional studies for using the new CAR T cell engineering technique are already underway. Anna Mäkelä, a postdoctoral researcher who works at Professor Saksela’s laboratory, is supervising a project sponsored by the Academy of Finland that studies the use of CAR T cell therapy on different types of cancers and their surface structures.

We are very excited about these results, and we are currently developing the technique so that it could be used to treat ovarian cancer. As the work progresses, the aim is to apply the technique itself and the targeting molecules of CAR constructs even more broadly to malignant solid tumors. Our goal is to develop ‘multi-warhead missiles’, against which cancer cells will find it difficult to develop resistance.”

Anna Mäkelä, Postdoctoral Researcher, University of Helsinki

Source:
Journal reference:

Hernandez-Lopez, R. A., et al. (2021) T cell circuits that sense antigen density with an ultrasensitive threshold. Science. doi.org/10.1126/science.abc1855.

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