CAR T-cell Therapy: A type of treatment in which a patient’s T-cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T-cells are grown in the laboratory and given to the patient by infusion.
If you keep up with medical-related news, you’ve very likely heard of the term “CAR T-cell therapy” by now. Indeed, you may even be one of the numerous individuals who’ve reached out to NBTS already to ask about this emerging type of immunotherapy technique, and its possible use in brain tumors. CAR T-cell therapy has become the new “hot topic” in cancer research and news, garnering features in every major publication from TIME magazine to The New York Times, and receiving the coveted distinction as the American Society for Clinical Oncology’s “Advance of the Year” for 2017.
So, what is this new type of treatment grabbing all the headlines in science and health news?
Type of Treatment
CAR T-cell therapy – short for chimeric antigen receptor T-cell therapy – is a type of immunotherapy (or sometimes classified as a “gene therapy”). More specifically, it is part of a class of immunotherapies called “adoptive cell immunotherapy” (also sometimes referred to as “adoptive cell transfer” or “adoptive cellular therapy.”) Adoptive cell immunotherapy, is a type of treatment used to help the immune system fight cancer by collecting a patient’s own immune cells, expanding and enhancing them in the laboratory, and then re-injecting them into the patient. This increases the number of immune cells that are able to kill cancer cells. There are a number of adoptive cell immunotherapy approaches, but CAR T-cell therapy has raced to the top of the pack, in terms of excitement.
CAR T-cell therapy uses a patient’s own T-cells, which have been genetically “re-programmed” in a laboratory to fight cancer cells. T-cells are removed from a patient, armed with a new protein that allows them to recognize cancer, and then are given back to the patient in large numbers to identify, find, and destroy the cancer cells.
T-cells are a type of white blood cell often referred to as “hunter” cells and the “workhorses” of the immune system, for the pivotal role they play in attacking diseased cells within the body.
The immune system monitors our body, watching for “invaders” or foreign substances, molecules, or cells they do not recognize as normal or healthy. The typical way that the cells of our immune system – T-cells included – recognize things that don’t belong in the body is by scanning for specific proteins on the surface of those cells. These proteins are called “antigens” (and are the “A” in “CAR”) and act as targets or markers for the immune system to go after. Immune cells like T-cells have their own proteins on their surfaces called “receptors” (the “R” in “CAR”) that can grab, or bind, onto foreign antigens and trigger an attack against them.
Antigens, are highly specific and need the right corresponding receptor to allow binding (think of a lock, and how it requires the right key to be opened). Therefore, if the immune cells don’t have the right receptor they cannot “see” the antigens marking a diseased cell. Thus, if immune cells like T-cells don’t have the right receptor, they can’t find cancer cells’ antigens to attach and help destroy it. And because cancer is a corruption of, or breakdown in, our bodies’ own normal processes, and not a foreign invader like a germ, bacteria, or virus, our immune system often doesn’t have the right receptor to recognize them as bad.
In CAR T-cell therapy, the T-cells that are extracted from the patient get engineered in the lab to sprout a synthetic, or man-made, receptor that allows them to identify antigens that cancer cells produce. These modified T-cells are referred to as “chimeric” (the “C” in CAR), meaning they are not naturally-occurring. The receptors are the CARs – Chimeric Antigen Receptors – and the new cells in full are the CAR T-cells. Since different cancer types have different antigens, each CAR T-cell is made for that specific target found on cancer cells, but not normal cells. The new CAR T-cell can now seek out and destroy cells that have the tumor-specific antigens on them.
While CAR T-cell Therapy is considered a “new” approach to cancer treatment, the research behind it has been in the works for decades, going back nearly 30 years to the early 90’s when scientists began exploring new techniques to engineer cells. Further, the history of immunotherapy as a theory, or concept, for potential cancer treatment dates even farther back to the turn of the 19th century, when doctors first noticed that some cancer patients who developed infections had spontaneous improvement in their conditions, indicating that perhaps the activation of the body’s innate immune system could play a role – if triggered correctly – to fight cancer.
CAR T-cell therapy really began to pick-up steam and grab attention about five years ago, when early clinical trials of the approach in certain blood cancers showed remarkable results in certain patients. In fact, NBTS covered updates on CAR T-cell research for glioblastoma back in both our 2015 and 2016 recaps from Annual Meetings of the Society for Neuro-Oncology.
Fast forward to 2017, and the first two CAR T-cell therapies were approved by the FDA. In September, a CAR T-cell therapy called Kymriah (tisagenlecleucel) was approved for some children and adults (up to 25-years old) with acute lymphoblastic leukemia (ALL) that has relapsed. Then just a month later, in October 2017, use of Yescarta (axicabtagene ciloleucel) was approved for certain patients with large B-cell lymphomas, who’ve failed two or more standard treatments. In trials for the lymphoma drug, an astounding 50 percent of patients saw their cancer disappear completely, and stay gone.
How Does it Work?
The process for this treatment takes some time – anywhere from approximately a week to a few weeks, depending on the laboratory a patient’s medical team is working with.
First, the T-cells must be extracted and isolated from a patient’s blood. To do this, patients go through a process called apheresis. Similar to a dialysis procedure, patients must sit, lie, or recline in a bed or chair and remain still for a few hours while blood is removed through one IV line and then returned through another. After the white blood cells are extracted, T-cells, specifically, are separated, sent to the lab, and genetically altered to produce the CAR. Researchers use a “viral vector” to deliver genetic material into cells, which instructs the T-cells to grow the needed receptor. This makes them CAR T-cells. Since a large number of CAR T-cells are needed for the therapy to be effective, it can take some time for the lab to create, grow, and multiply enough of them.
Once they have enough new CAR T-cells, they are frozen and delivered back to the patient’s medical team. The doctors then thaw and subsequently infuse the CAR T-cells back into the patient through an IV line. With guidance from their engineered receptor, these CAR T-cells seek to recognize and launch a precise attack against the cancer cells that harbor the antigen target on their surface.
Potential Use in Brain Tumors
Because of their ability to induce some dramatic survival improvements in blood cancers, the CAR T-cell therapy approach is now also being studied for brain tumor patients – beginning in the area of highest unmet medical need, and the most aggressive brain tumors, glioblastoma.
Currently, researchers are trying to identify antigens to target in glioblastoma for which CAR T-cells can be engineered and produced. There are various antigens being explored across the glioblastoma research landscape, but the three that are likely furthest along are the markers: EGFRvIII, HER-2, and IL-13Ra2. These are antigens often found on GBM cells, but not healthy brain cells. There are currently clinical trials for CAR T-cells targeting each of these antigens, though all are in the early stages of evaluation.
One of the more recent updates we have is from a small (10 patients) phase 1 trial of CAR T-cells for EGFRvIII, published last July (and also the trial we reported interim results for after SNO 2015, mentioned above). Phase 1 trials’ primary purpose is to ensure no major safety issues, and thus this study was not designed to truly determine if there would be survival benefit at this point. However, the trial did show that, in these patients, there were no major safety concerns observed that would prevent this approach from moving forward in larger and later-stage clinical trials. That said, the trial’s leaders did believe, based on what they observed, that moving forward more will need to be done to make this approach truly effective in a difficult tumor-type like glioblastoma.
“This trial showed that there is a need to target additional antigens in glioblastoma, as well as overcome the immunosuppressive environment that the CAR T-cells encountered in the tumor,” said Dr. Marcela Maus, one of the trial’s leaders. (NOTE: other pilot studies, have seen anecdotal cases of glioblastoma patients responding really well to CAR T-cell therapy).
This reflects a sentiment that was expressed by a number of other leading experts in brain tumor immunotherapy at the NBTS 2017 Scientific Summit. This was what we wrote in our Summit recap, just this past November (#12 on the list):
“…The field [needs to] figure out how to better deliver CAR T-cell therapy to brain tumors and keep the modified T-cells at the tumor long enough for maximum effect…Brain tumors tend to live in an environment that is very hostile to T-cells. If researchers can find a way to get these modified T-cells to the tumor in big enough numbers, the chance of this type of treatment approach working in neuro-oncology will increase significantly.”
Further, one of the original pioneers of CAR T-cell therapy, Dr. Steven Rosenberg of the National Cancer Institute (NCI) outlined some of the challenges in applying these treatments to complex “solid” tumors like glioblastoma:
“Researchers estimate that the overwhelming majority of [solid] tumor antigens reside inside tumor cells, out of the reach of CARs, which can only bind to antigens on the cell surface…Early reports from…trials [targeting solid tumor antigens, including EGFRvIII] have not reported the same success that’s been seen with blood cancers…Another key obstacle with solid tumors…is that components of the microenvironment that surrounds them conspire to blunt the immune response. So success against solid tumors may require a ‘super T-cell”…that has been engineered to overcome the immune-suppressing environment of many advanced solid tumors.”
Potential Side-Effects and Other Considerations
Like any cancer treatment, CAR T-cell therapy can cause serious – even fatal – side effects. Some of the most worrisome safety issues seen to-date in human trials and treatment with CAR T-cells are a syndrome known as cytokine release syndrome (CRS), which can lead to dangerously high fevers and major drops in blood pressure, and neurological symptoms like brain swelling (edema). Some of these symptoms have even caused companies developing CAR T-cell therapies to halt or pause development.
However, these issues appear limited and often reversible (as noted by the acceptable safety results reported above from the glioblastoma CAR T-cell EGFRvIII trial), and researchers and doctors are beginning to learn how to better manage and treat these side-effects. In fact, a drug called Actemra (or tocilizumab) was identified and is now often used to treat CRS.
Prices for these cutting-edge new treatments to-date have been set very high. For example, the cost for a complete course of Kymriah has been set $475,000 (before insurance). This continues a trend in high-pricing models for new cancer immunotherapies and is an issue any patient considering these treatments needs to discuss with their medical team and insurance providers.
As noted above, tumor-specific antigens in cancers like glioblastoma are not as easy to identify as some blood cancers. For example, one of the lead antigens for glioblastoma CAR T-cell therapy, EGFRvIII, is only found in about 30% of glioblastoma patients. Therefore, only those with this specific mutation would likely receive (or even be eligible) for this CAR T-cell treatment.
Efficacy and Durability
Even in the trials with the best results of CAR T-cells in blood cancers that led to the approvals noted above, not every patient responded to the therapy.
“There is definitely room to improve,” said Dr. Terry Fry of the NCI, who has been involved in much of the work with CAR T-cell therapy and blood cancers. Even those who experience a complete response, up to a third will see their disease return within a year, Dr. Fry said. Many of these disease recurrences have been linked to ALL cells’ no longer expressing the target antigen over time, a phenomenon known as antigen loss.
It’s still early stages for our understanding of if, and how, CAR T-cell therapy can work for brain tumors. Early clinical trial results to date have demonstrated the feasibility of this approach – and that it certainly warrants more investigation – but also potential limitations and challenges. While some remain skeptical that the CAR T-cell therapy approach can be applied as successfully in brain tumors as it has to date in blood cancers, others remain hopeful and speak of a “cause for optimism,” that the hurdles to making CAR T-cell therapy successful for brain tumors don’t appear to be insurmountable and are many of the same issues the field is working on for other solid tumors.
Among the items that need to be addressed are: more antigen targets – and targeting multiple antigens in combination – T-cell persistence (how long the engineered T-cells stick around the tumor to marshal the immune attacks), and combining CAR T-cells with other forms of immunotherapy and anti-cancer treatments to improve its effectiveness.
Thus, in the case of CAR T-cell therapy for brain tumors, in many cases, the bad news is also the good news. That is, the bad news is that in the neuro-oncology field we are still in the “early days” of understanding if and how we can harness this approach that’s proved potent for certain blood cancer patients – thus there is a long way to go and much more work to be done. But the good news is that researchers are just starting to imagine all the possibilities for improving CAR T-cell therapy efficacy. The field is continually improving the understanding of how we could make this treatment a reality in brain tumors, and the research that needs to be done to get there. At a very rapid rate for scientific research, the cancer research field, in general, has made remarkable strides in CAR T-cell development. For example, advances have already been made in the engineering of T-cells to improve the CAR T-cells’ ability to multiply after infusion into the patient (called expansion) and survive longer in the circulation (persistence) from the early days of experiments with this approach, as well as cut down significantly on the time it takes to produce CARs in the lab. They’ve also generated testable hypothesis on the types of combinations that might be needed to overcome hurdles to more (and more durable) responses to this treatment approach and, again, improved in handling potential side-effects of the treatment. The course of research on CAR T-cell therapy is, indeed, encouraging.
If you are interested in participating in CAR T-cell therapy trials currently happening in glioblastoma – or simply learning more about them and the options – please speak to your medical teams and/or visit the NBTS Clinical Trial Finder (trials.braintumor.org) to identify opportunities to discuss with your doctors.
Resources/Sources & Further Reading