Welcome to the Party, CAR T
A new cancer treatment, one unlike any other therapy, has just received a key approval from an FDA expert panel. Called “CAR T cell therapy,” this method is not a drug, but rather uses your body’s own cells to fight off cancer. The pharma company Novartis looks to be the first to bring this revolutionary new medicine to market, after what has been a tight race between Novartis, Kite Pharma, and Juno Therapeutics. With final approval likely on October 3rd, we will soon be constantly hearing about this treatment in advertisements and social media. Most importantly, legitimate hope will be given to many cancer patients who once had few options.
But what exactly is a CAR T cell? What makes it so different from other therapies? That’s what this guide is for. Below, we’ll review the science that makes this technology possible, talk about its applications, and discuss the numerous limitations, risks, and drawbacks of the treatment.
Immunotherapy
The human body has an entire network of cells, molecules, and receptors whose main purpose is to fend off disease. The immune system has long been known to ward off invasive microbes, and medicine has been harnessing this power for centuries. Vaccines work by training your immune system to fight off microbes it usually cannot. More recently, the immune system has been found to play a critical role in many diseases. From Alzheimer’s to diabetes, from arthritis to allergy, the immune system has been found to interact with the body in many ways. It has also been discovered that the immune system plays a critical role in cancer. The immune system can work to detect cancerous growths and eradicate them; it also may be tricked, hijacked, or manipulated by cancers to serve their own ends.
The branch of medicine now concerned with using the immune system to combat cancer is called “cancer immunotherapy.” This field has grown rapidly over the past couple decades, and it has led to some important therapies, such as checkpoint inhibitors. CAR T cells are the newest immunotherapy. But they differ from traditional cancer drugs in several ways.
Most cancer therapies either use a drug (small-molecule chemicals, antibodies) or radiation to target cancerous cells. They attempt to target features of cancerous cells that our normal cells do not have: rapid growth, chemical markers, etc. But CAR T therapy is not a drug at all. Rather, it involves taking your own immune cells, genetically modifying them, and reinserting them in your body. The modifications to these cells allow them to hunt down and kill cancer more precisely and efficiently than other therapies (at least in theory).
T Cells
T cells (the T comes from thymus, where they come to maturation) are one of the most important cells of the immune system. T cells use receptors, found on their membranes, to communicate with other cells and coordinate an immune response. Other cells are able to take pieces of molecules (antigens) and present them on their membrane receptors. T cells have the ability to monitor and check the receptors of those cells to see if their antigen comes from a microbe, virus, or unhealthy cell. In this way, T cells can constantly patrol for infection and infected cells. Each individual T cell has only one kind of T cell receptor (TCR), but the TCRs are different on each T cell. Between all of these diverse receptors, many antigens can be recognized. Once T cell receptors have identified an unusual antigen presented by another cell, they can kill the infected cell or signal for more help. This means they could be an important tool for fighting cancer; they can recognize that something’s wrong, and they can help eradicate the disease.
Cancer cells often display molecules on their surfaces that are different than those of normal cells. If a T cell receptor could be designed to recognize these abnormal molecules, it is possible that they could kill the cancerous cells while leaving normal ones unharmed. Not only would the receptor on the T cell have to specifically recognize the abnormal molecule, it would also have to initiate a signal that will result in killing the cancerous cell. Scientists, through lots of experimentation, have finally put this idea in the clinic.
CAR T cell stands for “chimeric antigen receptor T cell.” The “chimeric” means that they are a molecular combination an of artificially constructed part with the naturally occurring parts of the receptor. This allows scientists to recognize a specific molecule according to their artificial design, while keeping the natural signalling ability.
In the above image, you can see the differences between a CAR (left) and a normal T cell receptor (right). A cell typically has to present the antigen to the T cell using a special protein called an MHC. But with the specially designed CARs, T cells can recognize an antigen located directly on the surface of the target cell. The “ligand binding domain” on the CAR is the part specially engineered to recognize molecules on the surface of cancerous cells. The CAR also includes a spacer (the black line between the blue part and cell), a trans-membrane domain (the squiggle going through the membrane), and a signalling domain inside the cell. You’ll notice that the regular TCR has many more components in the membrane. Those are costimulatory domains, which are necessary to activate the receptor. A CAR doesn’t need as much extra input from the environment to do its job. The two receptors have another part in common: the part labelled zeta (ζ). This is the domain which initiates a signalling cascade within the cell, eventually leading to the immune response.
Once a CAR T cell is activated by the cancer cell it comes into contact with, it can activate a variety of deadly mechanisms that will kill the malignant cell, while leaving healthy cells unharmed.
How It’s Made: CAR T Cells
Manufacturing CAR T cells is a tricky and intensive process. First, T cells are taken from the blood of the patient. It is important that the cells belong to the patient; using another person’s would result in the patient rejecting the T cell transplant. The T cells are removed from the blood, and the rest of the blood is returned to circulation.
The part of the CAR that recognizes the cancerous antigen is developed as a monoclonal antibody. This monoclonal antibody is a protein made in mice that can specifically recognize and bind to a target of interest.
Next, the monoclonal antibody must somehow be inserted into the T cells, in order to be expressed as a surface receptor. To do this, scientists use a virus. Many viruses have the ability to inject their DNA into a cell, where it eventually fuses with the host’s DNA. Scientists hijacked this function to insert the DNA for the receptor. They replace some of the virus’s DNA with the DNA that encodes for the monoclonal antibody, effectively integrating it into the T cell genome. This technology is called a viral vector.
Being exposed to the viral vector is not enough to activate the T cells. In the human body, other cells and molecules normally help to turn on T cell functions. Outside of the body, this process is mimicked by more monoclonal antibodies attached to beads or by artificial Antigen Presenting Cells (aAPCs). This can also control the differentiation of T cells into different subtypes.
Next, the CAR T cells are grown until there are enough of them to fight the cancer. They are then concentrated so they can be re-infused into the patient by an IV. But before they can be infused, the patient must have many of their own immune cells knocked out. This allows a successful transfusion of the new cells into the patient.
This entire process can take about 18–25 days. For many patients, each day waiting is absolutely crucial. Cutting down on the manufacturing time may prove vital to help more patients.
Eye on the Target
One of the greatest challenges for scientists and doctors has been finding suitable targets for this treatment. Few cancers have identifying markers specific enough to work in this context. That is, it’s hard to pick out tumors that have one specific molecule that differentiates them from healthy cells. Often, cancerous cells may overexpress a certain molecule, but healthy cells still have them at low amounts. This could lead to a disastrous attack on normal bodily cells.
The first target that has been successful in clinical trials is CD019. This is a protein expressed on the surface of B cells, another type of immune cell. This allows for the targeting of certain lymphomas and leukemias that occur in B cells. The CAR T therapy that just got a thumbs-up from an FDA committee is CTL019 by Novartis, which will be used for treatment of children and young adults with advanced leukemia. This is the first of a group of CAR T therapies that will help patients with aggressive blood cancers. It has so far blown other treatments out of the water with an 83% complete remission rate. While the initial focus has been narrow as a proof-of-concept, researchers hope to expand CAR T to a greater variety of blood cancers using the CD019 model.
Safety Concerns
With any new medicine, there are always a variety of safety issues that need to be navigated. But with CAR T therapy, there are some special safety concerns that must be carefully evaluated.
- Cytokine Release Syndrome — Also known as CRS, this a whole-body inflammatory response. This syndrome can frequently be initiated when CAR T cells are infused back into the patient. Cytokines are molecules used for immune system communication. Their massive and sudden release has sent many CAR T patients to the ICU. CRS can be treated there effectively with anti-inflammatory drugs.
- Neurotoxicity — Juno Therapeutics had to halt one of their CAR T trials this summer after 5 patients died from severe brain swelling known as cerebral edema. CAR T cells can affect the brain in ways that are difficult to predict, which may limit their application in some areas.
- Additional Cancers — Because the CAR T cells are genetically altered, there is a risk that mutations could occur in them to cause further cancer. While this risk is likely low, and has not yet been observed, it is possible that a new cancer might arise years after having been treated with CAR T cells.
- Viral Replication — Although the risk for this is again low, it is possible that the viral vectors used to genetically alter CAR T cells become replication-competent viruses in the cells. Through mutation, the viral DNA could learn to replicate more virus again, and spread to other cells. This has not been observed and would seem unlikely, since viral vectors are used for many lab techniques.
These potentially lethal side-effects leave investigators wary. Novartis has announced a 15-year protocol that it will use to monitor patients after transfusion. Hopefully, any unforeseen side-effects will be caught by good regulation. So far, the FDA seems to think that the benefits of this treatment outweigh the risks.
Additional Challenges
- Manufacturing — So far, CAR T cells have only been produced for relatively small clinical trials. Will this process scale up to help thousands? Building reliable manufacturing and distribution centers will be key. Companies are currently scrambling to ensure they can effectively produce more CAR T cells. Timing is also important. Will scientists be able to get the T cells back to patients as quickly as possible?
- New Targets and Solid Tumors — The next great hurdle for researchers is to design CAR Ts that will work in different types of cancer. CD22 and BCMA are potential targets for other blood cancers. Targeting solid tumors has so far proven to be much more difficult. Many solid tumors have markers that are also expressed at low levels on healthy cells. A variety of mechanisms are being attempted to help circumnavigate this obstacle. There may be hope for CAR T cells in cancers like melanoma and colorectal cancer. Solid tumors also grow in an environment that suppresses the immune system. This is another impediment to CAR T cells, since the tumor may try to divert or kill them. Combinations with other drugs may help in this endeavor.
- Drug Combinations — CAR T cells may work effectively in combination with a variety of traditional drugs. Testing out these combinations will require many clinical trials, hopefully expanding care to new patient populations.
- Engineering Specific T cells — There are many different subtypes of T cells. Fine-tuning which ones to infuse back into patients will help make CAR T cells more effective and nuanced. There has also been some research toward using stem cells instead of adult T cells, hoping to help with host tolerance.
- Beyond Cancer — Some researchers think that engineered T cells can treat a variety of diseases beyond cancer. Engineered T cells may be able to fight infection, combat inflammatory diseases, and help with transplantation immunology.
This is an exciting time for immunotherapy, and for oncology in general. This is a truly unique type of medicine, one only made possible through recent advances in biology. It represents our ability to use our own body’s natural defenses by augmenting it with new technology. Although CAR T cells are no miracle cure-all, engineered T cells may be able to play an important role in disease therapy in the decades to come.
“Natural forces within us are the true healers of disease.” — Hippocrates
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References:
- “CAR T Therapies Drive Into New Terrain.” Katie Kingwell. Nature Reviews Drug Discovery 16, 301–304 (2017) doi:10.1038/nrd.2017.84
- “Global Manufacturing of CAR T Cell Therapy.” Bruce L. Levine, James Miskin, Keith Wonnacott, Christopher Keir. Molecular Therapy Methods and Clinical Development. Volume 4, 17 March 2017, Pages 92–101. doi:10.1016/j.omtm.2016.12.006
- “Therapeutic T Cell Engineering.” Michel Sadelain, Isabel Rivière, Stanley Riddell. Nature 545, 423–431 (25 May 2017) doi:10.1038/nature22395
- STAT News, Adam Feuerstein
- Endpoints News, John Carroll
- Fierce Biotech, Nick Paul Taylor
- Xconomy, Alex Lash
