Genetically Engineered T Cell-Mediated Killing

T-cells play a central role in cell-mediated immunity and are found widely distributed within tissues as well is within the tumor environment. Interactions between T-cells and cancer cells result in functional activation and proliferation of T-cells, hereby trying to kill the cancer cells. However, cancer cells have developed strategies to escape and suppress the immune system so they can survive, proliferate and metastasize.

Tumor-specific T-cells can be isolated from some tumors, especially melanomas and viral-associated malignancies, and used as adoptive T-cell immunotherapy. However, tumor-specific T-cells are rare for most types of cancer and consequently difficult to isolate. To be able to treat tumors lacking tumor-specific T-cells, patient's T-lymphocytes could be isolated, ex vivo expanded and genetically modified, followed by re-infusion of the patient.

TCR and CAR T-cell modification strategies

Strategies to genetically modify T-cells include altering the specificity of the T Cell Receptor (TCR) or introduction of antibody-like recognition in Chimeric Antigen Receptors (CARs). Through such modifications, the T-cells gain enhanced antigen specificity and are redirected to successfully target antigens that are expressed by tumors.

The TCR is a multi-subunit transmembrane complex that mediates the antigen-specific activation of T-cells. The receptor is composed of two different protein chains. Binding of the TCR with an antigen expressed by cancer cells involves a T cell surface glycoprotein. After binding of the TCR/glycoprotein complex to the antigen/MHC complex on the cancer cell, the T-cell becomes activated so it can attack and kill the cancer cell. TCR modification of T-cells results in higher sensitivity and specificity towards the antigens presented by cancer cells and thus more effective cancer cell killing.

CARs  are composed of an antigen-binding region, a transmembrane domain to anchor the CAR to the T-cell and one or more intracellular signaling domains. CARs combine antibody-like recognition with T-cell-activating function, hereby requiring co-stimulation rather than one stimulus. However, unlike the TCR, CAR-T cells recognize various antigens that do not need to be processed and presented by MHC molecules and can thus be used in all patients who express the same tumor antigen.