Cancer operates stealthily, overtaking body systems via hijacking formerly healthy cells, and propagating endless, devastating effects throughout the body. Until recently, there was slim hope for the body itself to recognize and eliminate the assailant cells. However, with the emergence of chimeric antigen receptor T-cell therapy, or CAR T-cell therapy, cancer’s undoing may be on the horizon. This novel treatment is a form of immunotherapy that takes a patient’s immune cells, genetically engineers them and infuses them back to destroy the cancer cells. The very cells that have mutated to ravage your body can be combated, not by an exterior energy like radiation or foreign agents like those contained in chemotherapy, but by your own modified immune cells: your unique “living drug”. It almost seems like somethingout of a science fiction novel about the far future, where therapies for diseases are made in bioreactors and patients’ immune systems are upgraded to fight aggressive invasion. But this is the basis for immunotherapy, a treatment where the “immune system can be stimulated or enhanced to attack the malignant tumors”. Now, after the development of CAR T-cell therapies and FDA approval of two of them, this future seems to be nearing ever closer.
The story of immunotherapy is one that emerges at the turn of the 20th century in 1891: the product of a bold investigation by Dr. William B. Coley. The investigation began after he came across the curious case of Fred Stein. Stein, after being afflicted by a bout of bacterial skin infection, had walked out the doors of NewYork Hospital free from the vestiges of a metastatic, recurring cancer. Coley investigated whether Stein was still alive and the search proved favorable: he found a healthy, tumor-free Stein, and living evidence for a potential cancer therapy. Galvanized by Stein’s triumph over cancer, Coley went on to treat cancer patients with otherwise persisting cancers by injecting bacteria into them. After seeing shrinkage of malignant tumors, he eventually concocted a variety of mixtures of bacteria all housed under a single name: Coley’s Toxins. His findings were unprecedented but also controversial, and as radiation therapy began its dominance over cancer therapies, Coley’s Toxins and immunotherapy faded from the limelight (3). Yet, in 2018, immunotherapy once more dominates headlines of cutting-edge cancer therapies. Although far from ideal, it seems Coley’s bacteria and his idea of enhanced immune systems resisting cancer were the prelude to a promising field of cancer therapy.
More than 100 years after Coley’s initial trials, in 2017, the FDA approved two immunotherapies: the first CAR T-cell therapies. Scientists at Washington University School of Medicine have contributed to the emergence of the therapy and its approval through research and clinical trials. Dr. Amanda Cashen, an oncologist specializing in bone marrow transplantation and leukemia, is part of the CAR T-cell therapy team at Siteman Cancer Center in WUSM. Cashen remarks, “At Siteman, we use a CAR T product called Yescarta that is approved for treating diffuse large B-cell lymphoma which is the most common kind of non-Hodgkin lymphoma”. Just a few miles down the road, this therapy is being administered to patients with no standard treatment options left, giving their engineered T-cells a chance to battle cancer, and in some occasions, to completely overcome it (2).
CAR T-cell therapy is a procedure much like the process that developed it in the first place: rooted in the collaboration of patients, doctors, researchers and pharmaceutical companies. First, a sample of T cells, a type of immune cell responsible for killing pathogen infected cells, is obtained from the patient through pheresis, a process of drawing blood that can extract just the T-cell containing white blood cells (1). The T-cells are taken to a specialized pharmaceutical company and are engineered via viruses, which insert genes encoding CAR’s into the T-cell genome (4,5). In the case of currently used Yescarta, Cashen explains, “the CARs target CD19, a marker in the lymphoma cells”. The CAR’s give the T-cells a newfound ability to recognize surface marker proteins, like CD19, on certain cancers. After modification, the T-cells are expanded in number and shipped back frozen to the hospital (1,4). Upon receiving the cells, Cashen explains, “We treat the patient with three days of chemotherapy … meant to suppress the patient’s immune system which helps CAR T-cells proliferate” and then “the CAR T cells are thawed out and infused through an IV line”. Back in the patient, the modified T-cells become a legion of replicating warriors, seeking out and eradicating targeted cancer cells previously unseen by the immune system. Furthermore, recent studies suggest the CAR-T cells may continue their work even after initial attack of cancer cells to truly become a “living drug”, continually rising to the occasion of destroying cancer cells as they form.
There is rightly much anticipation regarding CAR T-cells, but like all innovative therapies, there are complications dispersed throughout the production process as well as some adverse effects. Cashen suggests that “figuring out highest risks for these toxicities, finding them early, and treating them aggressively are very important to make CAR T a safe therapy”. One such toxicity, cytokine release syndrome (CRS), is an immune response provoked by chemical messenger cytokine’s release, and is a hallmark side effect of the therapy. It affects patients with flu-like symptoms and in severe cases, death. Recent studies have shown potential in blunting CRS by decreased dosage of CAR-T cells, infusion broken up over several days and drugs for mitigating responses (1,4). There is also the matter of cost and time. Right now, Cashen notes, “This therapy is very expensive” and “manufacturing of CAR T-cells takes two to three weeks, so that creates a delay of when the patient can be treated”. Many patients with aggressively growing cancers may not be able to afford either the cost or the time needed for the therapy.
For the meantime, CAR-T cell therapy is for those who have failed all standard therapies. But now that its effectiveness has become clear, Cashen adds that “it does make a lot of sense to use it sooner to prevent relapses or treat patients before their lymphoma becomes so aggressive”. In the future, CAR T-cell therapy could be used to treat a variety of cancers for patients in a variety of stages, paving the way for an immensely promising path to curing cancer. It is important to see, however that the continuing development of CAR-T cell therapy for many cancers will present multifold, complex challenges. It will most likely be the focus of researchers to inhibit treatment related toxicity by understanding the precise mechanisms of how CAR T-cells destroy cancer cells. Ideally, the therapy cost would also be lowered significantly and the process would be streamlined for a more efficient manufacturing process. For now, CAR T-cell therapy should be lauded as the marvel that it is: a truly groundbreaking therapy that, by harnessing the power of the human immune system, has the potential to reverse the deadly impacts of cancer.