Although CAR T-cell technology is 30 years old, understanding its efficacy as a cancer therapy is in its infancy
Last year, the US Food and Drug Administration approved Kymirah, the first-ever treatment that genetically alters a patient’s own cells to fight cancer therapy. Kymirah is based on three decades of immunological research that caught the attention of the oncology field after performing well in small-scale clinical trials. Kymirah is a ‘living drug’ derived from the patient’s own blood. From this blood, T cells (an immune cell subset with direct cancer-killing ability) are purified in the lab before being genetically engineered to express a chimeric antigen receptor (CAR). This CAR molecule is designed with an extracellular antibody-like domain fused to an intracellular signalling domain which enables T cells to simultaneously detect cancer cells whilst boosting T cell activity. These engineered T cells are then expanded in number before being infused back into the patient. A successful treatment will see CAR T-cells further expand in the body while homing in on and killing the cancer they have been designed to target.
This first CAR-T cell therapy registration is an extremely exciting breakthrough, which has the potential to change the lives of many cancer patients. For example, one study showed that 83% of participants taking Kymirah were cancer free after 6 months. However, it is important to bear in mind that treatment with Kymirah and alternative CAR T-cells are not without risks. Trials with other CAR T-cell therapies under development have experienced serious side effects, such as cytokine release syndrome caused by a hyper-reactive immune response that can be deadly.
Due to Kymirah being a ‘personalised medicine’ the number of people set to benefit is small. However other companies such as Kite Pharma and Juno Therapeutics [recently acquired by Celgene] are working on similar treatments, so the number of providers of this bespoke medicine may increase. With further development and an increased understanding of immunoncology this type of immunotherapy is set to expand the number of indications that CAR-T cells can treat, including solid tumors, which are challenging environments for immunotherapies to penetrate. The ultimate goal would be to find the right conditions for an off the shelf ‘living drug’ that requires one dose to clear disease. This can only come through continued investment and research.
CAR T-cells up close
There are several variants of CAR T-cells in development but third generation receptors all have common components including an extracellular targeting element, transmembrane spacer, 2 co-stimulatory domains and a signalling domain. The exterior portion of the transmembrane protein is an antibody-like domain designed to optimally bind to specific antigens that are overexpressed and ideally uniquely produced on the target cancer cell. The tumour antigens are also recognised in their intact form, in that they don’t require processing and presentation in the context of MHC, which will help to alleviate the risk of immune escape. The combination of a stimulatory and co- stimulatory domain stitched into one receptor improves proliferative responses following antigen binding and prevents anergy, enabling T cell persistence. Although CAR T-cell technology is 30 years old, understanding its efficacy as a therapy is in its infancy. Many unknowns are yet to be explored. Can effectiveness and safety be boosted? Which are the best antigens to target? Which of the plethora of co-stimulatory domains are optimal? How can we best engineer and expand isolated T cells? Finally, and most importantly of all, can an ‘off the shelf product’ ever be created to negate the need for time-consuming and expensive personalized therapy?