CAR-T cells have been celebrating a success story in the treatment of various leukemias and lymphomas since last year. In the case of solid tumor diseases, however, they have so far failed because the T cells are unable to penetrate the mantle of macrophages around a tumor site. However, this could now change.
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For CAR-T cell therapy, a patient's own T cells are removed and genetically modified ex vivo. The cells then express a highly specific chimeric antigen receptor (CAR), which enables them to identify tumor cells after infusion of the altered T-cells back into the body and to attack them specifically.
To date, this novel immunotherapy for the CD-19 antigen of some hemato-oncological diseases, such as B-cell lymphomas, has been most successful. After binding of the CAR-T cells to the surface antigen CD-19, a cytokine cascade is triggered, as a result of which the cancer cells are specifically destroyed.
In the case of solid tumors, however, the procedure has so far failed. The reason for this is the dense coats of macrophages and regulatory T-cells, which often envelope the outer tumor areas. The problem, however, is not so much the physical barrier represented by the regulatory T cells and macrophages as their anti-inflammatory cytokine environment.
CAR-T cells of the 4th generation, on the other hand, avoid this problem. These cells, also known as TRUCK (T cells Redirected for antigen-Unrestricted Cytokine-initiated Killing), carry genes in addition to the genetically modified T cell receptor that is responsible for the release of further interleukins, e.g. IL-12. IL-12 is a proinflammatory interleukin and stimulates the release of IFN-gamma as well as serine proteases or cytolytic proteins in T-cells and natural killer cells.
Such proteins and cytokines can soften the immunosuppressive effect of the microenvironment in the solid tumor area, which ultimately improves T-cell activation and tumor cell destruction.
Current research in this context is investigating the use of EGFR-vIII (Epidermal growth factor receptor) as a target protein in glioma, PSMA (prostate-specific membrane antigen) in prostate cancer, or MSLN (mesothelin) in pancreatic cancer. But despite all the euphoria, the use of CARs and TRUCKs is not without risk.
Source:
Van Schandevyl S. & Kerre T., Chimeric antigen receptor T-cell therapy: design improvements and therapeutic strategies in cancer treatment. Acta Clin Belg 2018; 13: 1-7. doi: 10.1080/17843286.2018.1545373