Chimeric Antigen Receptor (CAR) T-cell therapy has delivered major advancements in the treatment of lymphoid malignancies. However, the FDA approval of two of these therapies, tisagenlecleucel (Novartis) and axicabtagene ciloeucel (Kite Pharma) has highlighted the many barriers to broader access and adoption. These barriers range from high price-points and the unwillingness of insurance companies to cover these treatments, to manufacturing and Quality Control challenges, and the potential for toxicities in patients. We discuss here some of the future solutions to help bring this technology to mainstream medicine, and how flow cytometry is being utilized to help ensure the safety and efficacy of this magic bullet.
Over the last decade there has been a revolution in the development of immune-based therapies and personalized medicine for the treatment of a wide array of cancers. Many of these cutting-edge therapies have been accelerated by immunology research using advanced flow cytometry techniques that enable researchers to decipher the underlying pathways and cell types associated with the therapeutic strategy. Cancer immunotherapy leverages the fact that many cancer cells express tumor specific surface antigens that can be detected by our immune system. Effector T-cells play a key role in this process because they produce substances that kill the pathogenic cells, however prolonged exposure to the antigen, can result in exhaustion of these T-cells. This T cell exhaustion represents a state of dysfunction that is associated with a loss of effector function and proliferative capacity that arises during chronic infection and cancer.
The Evolution of CAR-T Cell Therapy
The development of Chimeric Antigen Receptor (CAR) T cell therapy has been a decades-long road from conception in the 1980s to the FDA approval of the Novartis CAR-T cell therapy, tisagenlecleucel in 2017 that heralded the onset of this multibillion dollar healthcare industry. The initial concept for CAR-T therapy was developed with the construction of recombinant TcRs that replaced the TcR V regions with antigen-specific antibody V regions. The chimeric TcRs retained the normal extracellular C region, the transmembrane segment, and the cytoplasmic signaling domains, and therefore maintained the ability to induce T-cell proliferation, interleukin production and cell lysis. Furthermore, these chimeric TcRs were non-MHC-restricted and universal in the sense that a given chimeric construct could be transfected into T-cells from any individual. T cells expressing CAR have been shown to recognize a wide range of surface antigens, including glycolipids, carbohydrate moieties and proteins (Morello et. al. 2016) and can attack malignant cells expressing these antigens.
The immune system not only has the power to respond to a foreign antigen, but it also has the amazing ability to remember it and then act quickly to a re-exposure. How the immune system accomplishes all of this is under research, but the impact of this knowledge offers great promise in the development of safer and more effective vaccines.
What exactly are epigenetic modifications?
Epigenetics describes any changes in gene expression that occur without alteration in a DNA sequence. Epigenetics is why identical twins tend to become less identical with age- their genomic DNA sequence does not change but the epigenetic landscape that regulates gene expression naturally diverges over time. These changes may be cell or tissue-specific and may be heritable through multiple generations. Even though epigenetic mechanisms primarily function through the nucleus, they can be induced by a range of environmental signals including physiological and nutritional stress, cellular damage, environmental signals, and cell signaling molecules such as hormones. Epigenetic changes can be mediated through modifications of the DNA directly, or of the protein components of the chromatin structure.