Mar 17, 2022

Chimeric antigen receptor (CAR) T cells are a group of engineered T cells that express cancer antigen receptors for immunotherapy. In a clinical cancer treatment, medical staff first start by drawing a patient’s blood, isolating immune T cells, and using harmless viruses or CRISPR/Cas9 technology to deliver genes into the T cells.

These isolated and modified CAR T cells can express cancer antigen receptors after gene editing. With these receptors able to bind to antigens on the surface of cancer cells, CAR T cells can target and eliminate cancerous cells with high specificity.  For personalized medicine, engineered CAR T cells are cultured and multiplied in the laboratory before being reinfused back into the patient’s body to treat their specific cancer.

Limitations of CAR T Cells

In recent years, a number of CAR T-cell products have been approved for clinical use, and have achieved great success in the treatment of some hematological tumors. However, existing CAR T therapies still have some limitations. For example, CAR T-cells can only kill cancer cells with a specific marker, and once cancer cells stop making that marker, the target is lost, rendering the treatment ineffective. In addition, CAR T cells also have problems such as self-depletion, off-target toxicity, inhibition by cancer cells, and difficulty in breaking through the tumor microenvironment during the treatment process.

SEAKER Cells for Better Cancer Treatment

In late 2021, a research article published in the journal Nature Chemical Biology showed a major breakthrough in addressing CAR T-cell limitations. In this study, David Scheinberg and his colleagues from Sloan Kettering Cancer Center designed a new pro version of CAR T cells, which they call Synthetic Enzyme-armed Killer (SEAKER) cells. These cells can activate drugs directly in tumors, killing tumor cells containing cancer markers as well as those without markers nearby.

In the study, the researchers developed a small molecule precursor drug by linking a chemical cancer drug with another chemical that "inactivates" its function. After the prodrug is injected into the bloodstream, it gets into the blood circulation and naturally goes to the tumor site where it can be activated by genetically engineered T cells (SEAKER cells) producing an enzyme that cuts and activates the prodrug.

In vivo studies of mouse tumor models showed that SEAKER cells, together with the prodrug, effectively reduced tumor size and exhibited better anticancer activity than conventional CAR T cells. Moreover, exhausted SEAKER cells can still activate therapeutic drugs that will not be suppressed by cancer cells.

In addition, the study showed that SEAKER cells were able to work with various precursor drugs and cleaving enzymes, demonstrating that the SEAKER system is an entirely new engineered drug platform with broad therapeutic promise in fighting tumors, autoimmune diseases and infections.

GenScript helped to produce and purify theRecombinant Proteins involved in this research.

Reference

• [1] Gardner, Thomas J., et al. "Engineering CAR T-cells to activate small-molecule drugs in situ." Nature chemical biology (2021): 1-10.

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