Our Science

The Power of the TCR

Our complex immune system evolved to defend the body from pathogens such as bacteria and viruses, but it can also be harnessed to fight cancerous and pre-cancerous cells. Its most potent weapons are T cells, which can track down abnormal cells and eliminate them through the utilization of T cell receptors (TCRs) – clusters of proteins on every T cell that identify specific antigens displayed on the outside of cells.

Once a TCR has identified a cell that needs to be eliminated, it binds to it through the coordinated action of the TCR and the αβ-TCRs recognizing their associated tumor antigens, specifically only when presented on human leukocyte antigens (HLA), cell-surface proteins responsible for the regulation of the immune system. Then, the TCR sends up an alarm – catalyzing a highly complex and broad signaling cascade that leads other T cells to activate and multiply, ultimately killing the abnormal cell and protecting the body against similar threats in the future.

The TCR is composed of eight parts or subunits. Two of them recognize other cells – TCR-α and TCR-β. The remaining six are proteins that each play unique and critical roles in T-cell signaling (i.e. CD3γ/CD3ϵ, CD3δ/CD3ϵ and CD3ζ/CD3ζ). They are not redundant or interchangeable – each of the TCR subunits makes distinct contributions to the activation and regulation of T cells, and only the combination of all the TCR subunits can optimally activate and control all functions of T cells.

In essence, T cells are the key to cancer immune surveillance.

TRuC-T Cells: Engineered for Maximum Impact

We engineer our TCR Fusion Construct T cells (TRuC-T cells) to recognize cancer cells as biological threats through a three-step process. First, after receiving cells from patients, we identify a cancer antigen recognition domain, or a “homing device”, tailored to recognize that patient’s specific tumor antigen and fuse it directly to a TCR subunit. Then, we use a lentiviral vector to transfer the genetic information for the TRuC construct into that patient’s own T cells where it naturally integrates into the native TCR complex. We then re-administer these engineered T cells equipped with the new homing device back into the patient, giving them the ability to detect and destroy cancer cells. Upon antigen engagement, these T cells harness the entire TCR to produce a more powerful yet controlled T cell response against cancer.

Many engineered T cell therapies are only able to use one subunit or two of the eight parts of T-cell receptors, while others are restricted to a patient’s HLA subtype (an immune identifier analogous to blood type). In contrast, our engineered T cells use all the parts of the TCR and work across all HLA types to produce a powerful yet precise defense against cancer that can persist in the hostile, immunosuppressive microenvironment of solid tumors. In both preclinical and clinical studies, we have seen these properties translate into more durable responses with potentially fewer adverse events for patients with cancer.

These emerging data are very encouraging when we consider that other types of cell therapies such as CAR-Ts have struggled to show efficacy against solid tumors and have high rates of severe side effects in some patients, including cytokine release syndrome and neurotoxicity. Other forms of engineered TCR-T cells have limitations as well – specifically, each one can only be used in patients with one of several specific HLA subtypes, limiting their use and increasing the time and cost of patient enrollment.