Many scientists, physicians, and patients are looking to immuno-oncology as the future of cancer treatment, especially with cutting-edge immunotherapeutic techniques like chimeric antigen receptor (CAR) T cell therapy, which has been called a “living drug.” This phrase refers to the fact that the therapy is derived from the patient’s own living cells. The treatment begins with apheresis to collect T cells from the patient’s body. The remaining components of blood are returned to the blood stream, and the collected T cells are reengineered in a laboratory to generate CARs on their surfaces. The resulting cells are called CAR T cells. CARs are proteins that allow the reengineered T cells to recognize antigens on cancer cells.
In effect, CAR T cells are trained to recognize a tumor as a foreign body to be attacked. The cells are multiplied in the lab and frozen for preservation during the proliferation stage. When they number in the billions, the cells are returned to the hospital, where they are infused directly into the patient. The CAR T cells reintroduced to the body continue to multiply to form a sort of army of attacker cells that recognize and kill the patient’s tumor.
Importantly, CAR T cells introduced in the body remain long after the initial infusions and provide protection against cancer recurrence. For that reason, many researchers believe that the treatment can enable long-term remissions.
Recent Challenges in CAR T Cell Cancer Immunotherapy
Recently, Juno Therapeutics announced that three patients died in a clinical trial for CAR T cell therapy—an event that shocked researchers, oncologists, and investors. Juno Therapeutics is one of three companies competing to bring CAR T cell therapy to the market for the first time. The Food and Drug Administration (FDA) responded by putting a temporary hold on the clinical trial involving the three deaths. According to reports, the deaths stemmed from swelling in the brain. While CAR T cell therapies have had safety issues in the past, the news of the three deaths is an unprecedented red flag for Juno Therapeutics, as well as its two rivals, Kite Pharma and Novartis, both of which have received heightened scrutiny since the announcement.
What has caused the most fear about these deaths is that researchers do not know the exact cause of the swelling, which means they can offer no guarantees that it will not happen again if the trials continue.
While the deaths are a tragedy for the patients’ families and a setback for research, it’s unlikely that scientists will abandon CAR T cell therapy. Already, researchers have collected an impressive amount of data showing how engineered T cells have created lasting remission in patients who were previously very sick. However, this approach to immuno-oncology is only a handful of years old, and individuals are still trying to figure out the balance between safety and efficacy. So far, researchers have only dealt with hundreds of patients. While this number may seem high, they will have to treat thousands of patients before the therapy and any side effects are completely understood.
Researchers leading a Novartis investigation have not noted brain swelling as a major side effect of CAR T cell therapy, and definitely not one that would be fatal. The most common side effects that other researchers have encountered include neurological ones, such as confusion or seizure. In most cases, these side effects can be treated or reversed. Until all the data from the Juno Therapeutics clinical trial is available, scientists can only give educated guesses about precisely what caused the deaths—but they do not think there is yet any reason to abandon the therapy.
Resounding Effects from the Juno Therapeutics Trial
The deaths of the three patients also affected the finances of companies involved in CAR T cell research. Immediately after the news surfaced, share prices for both Juno Therapeutics and Kite Pharma dropped. Obviously, investors are concerned about the effect of the announcement on public perception of the safety of immuno-oncology. The drop in stock prices may also reflect fear that the FDA will tighten its reins on the CAR T cell therapy class, which will slow down research and discovery at all three companies. Already, Juno Therapeutics will experience significant delays, so the same issues may also affect Novartis and Kite Pharma.
However, the deaths may have been caused by Juno Therapeutics’ specific procedures during the trial. Before patients receive CAR T cell implantation, they generally undergo a round of chemotherapy, which kills underperforming T cells to make way for the reengineered cells. According to Juno Therapeutics management, researchers added a second chemotherapy agent to the cocktail administered to patients, in an attempt to amplify results. All three fatalities occurred among the group receiving this new cocktail. The added agent, fludarabine, has been used in other CAR T cell trials without any ties to fatal brain swelling, so further investigation is necessary before any conclusions can be drawn.