CAR T-cell therapy

Surgery, chemotherapy and radiation are among the most common methods of treating cancer, but immunotherapy is attracting an increasing amount of research attention, encouraged by recent technical breakthroughs. We take a closer look at two of the major areas of research, checkpoint inhibitors and CAR T-cell therapy, that could help boost the body’s defences against cancer

The idea of immunotherapy dates back to the late 18th century, when Edward Jenner produced the first vaccine to prevent smallpox, and researchers continue to develop new methods of stimulating the immune system as a way of treating disease. By harnessing the power of the immune system and exploiting the specific properties of cancer cells, researchers hope to develop effective, long-lasting immunotherapies that combat tumours and protect against disease.

The idea of immunotherapy may have a long history, but it is only relatively recently that technical breakthroughs have brought new cancer therapies closer to practical realisation. For example, the PD-1 protein (Programmed Cell Death 1), a molecule that plays a major role in regulating the immune system and in cancer immune evasion, was discovered in the early ‘90s, laying the foundations for the development of a new class of drugs, the PD-1 inhibitors.

These drugs fit broadly within the wider category of ‘checkpoint inhibitors’, which remove so-called ‘brakes’ within the immune system that can hamper the response to cancer cells, and so enable the immune system to pursue cancer more aggressively. Checkpoint molecules play an important role within the immune system, helping prevent an overly aggressive immune response; in the case of PD-1 almost acting as an off-switch to prevent T-cells from attacking other cells.

This helps maintain a healthy balance in normal, healthy individuals, yet researchers have found that cancer cells can use these checkpoint molecules to evade the immune system. Building on research advances, scientists are now looking to turn the tables by developing drugs that block the activity of these checkpoint molecules, which has the effect of enabling the immune system to go after cancer cells more aggressively.

Some positive results have already been gained from the use of these drugs. PD-1 inhibitors like Pembrolizumab and Nivolumab have been shown to be effective in treating several different types of cancer, including kidney cancer and some types of head and neck cancers, while Atezolizumab can be used to treat bladder cancer and is currently undergoing further clinical trials as a therapy against certain types of solid tumour.

There is a high level of interest in this research among physicians, patients and investors, yet some researchers have urged caution, suggesting that further investigation is required before immunotherapy techniques can be more widely applied. One major concern is that by allowing the immune system to attack cancer cells more aggressively, the checkpoint inhibitors also enable it to attack healthy organs, causing potentially serious side-effects.

These include fatigue, nausea and appetite loss at the less severe end of the scale, through to more serious problems affecting a number of organs, including the lungs, kidneys and liver. Work is ongoing into how this potential toxicity can be limited or even reversed, but much remains to be learned in this area. Clinical trials are ongoing for several different checkpoint inhibitors, while researchers are also looking at combination trials, where two drugs are used simultaneously.

A second major area of cancer immunotherapy research is CAR T-Cell therapy, in which T-cells from the patient’s own blood are collected and then genetically engineered to enhance the immune system’s ability to recognise and kill tumour cells. The re-engineered T-cells have a specific type of receptor on their surface called a Chimeric Antigen Receptor (CAR), which now allow the T-cells to recognise an antigen on targeted tumour cells.

These modified cells can eventually be re-infused into the patient, with the hope that the T-cells will then multiply and attack cancer cells with that specific antigen. At the moment, CAR T-Cell therapy is only available to patients participating in a clinical trial, but the early results of trials on patients with blood cancers have been positive, leading to a great deal of optimism among researchers about the long-tern prospects for using this approach more widely.

It is important to place these early trials in context however, as so far studies have only been conducted over relatively short time-frames, and participants will need to be followed for a longer period to really build a deeper understanding of the long-term efficacy of the treatment. One important attribute is that the CAR T-cells may remain in the body long after the infusion has been completed, guarding against the recurrence of the disease, but there is more to learn in this respect.

There is also a wider acknowledgement of the existing limitations of CAR T-Cell therapy and the side-effects of this approach. The vast majority of patients treated with CAR T-Cell therapy experience flu-like symptoms, such as a high temperature and muscle pain, while the treatment can also have more serious side-effects, among the most concerning of which is cytokine-release syndrome (CRS), in which there is a rapid and massive release of cytokines into the bloodstream.

This can have serious effects beyond the emergence of flu-like symptoms, with some patients experiencing delirium, confusion and seizure while undergoing treatment. The patients with more severe disease are the most likely to experience these serious side-effects, and researchers are investigating ways to reduce these side-effects and manage them effectively.

The results from recent clinical trials are encouraging in this respect. Trial investigators have reported that the side-effects of CAR T-Cell treatment are relatively mild for most patients, and can be managed with standard drugs, while it was found that those patients who experienced a more severe reaction could be treated with etanercept and tocilizumab, two drugs which helped manage the toxicity of treatment.

An acknowledgment of these side-effects has to be balanced against the side-effects of more conventional treatment when assessing the efficacy of immunotherapy as a method of treating cancer. While the use of immunotherapy is not completely without risk, standard treatments like radiation and chemotherapy also have side-effects, and some researchers have suggested that immunotherapy would in fact be less toxic over the long-term.

A great deal of research attention is now focused on immunotherapy, with many clinical trials ongoing into both CAR T-cell therapy and checkpoint inhibitors. Some therapies are already available; the Food and Drug Administration (FDA) in the US has so far cleared four checkpint inhibitors for use by adults; Yervoy, Keytruda, Opdivo and Tecentriq, while several more are in the pipeline, and data continues to emerge on the efficacy of CAR T-cell therapy.

The early results show significant promise in this respect. Studies show that CAR T-cell therapy could be an effective treatment option for patients with acute lymphoblastic leukemia (ALL) who had suffered a relapse following treatment with more conventional therapies. Research into the use of CAR T-cell therapy on other blood cancers, including chronic lymphocytic leukemia (CLL) and some types of non-Hodgkin lymphoma (NLL) have also shown positive results.

This research is being undertaken in both the public and private sectors, with a great deal of interest among investors in biotechnology companies. Clinical research company Juno therapeutics raised $304 million when they went public in December 2014, and the company is currently involved in several trials aiming to bring CAR T-cell therapies to the clinic.

Recent research suggests that immunotherapy could be used in treatment against more than two dozen cancers, and potentially more, with new drugs showing significant and extended effectiveness against even rare and previously intractable tumours caused by viruses. Viruses and other pathogens are thought to be responsible for more than 20 percent of all cancers, reinforcing the wider potential of immunotherapy.

While there is still a great deal left to learn, Louis Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center, believes immunotherapy will be a central element in cancer treatment in future. “We are in the midst of a sea change in how we are treating cancer,” he said. “We’re really seeing the fruits of many years of research into what drives cancer and how it interacts with the immune system to defeat it and survive.”