Chimeric antigen receptor (CAR) T cell therapy represents an incredibly promising cellular immunotherapy approach for treating cancer that takes advantage of unique capabilities of T cells, an important part of our immune system. These T cells—hundreds of billions of which circulate through our bodies at any given time—are capable of recognizing and eliminating cells that have become damaged, infected by viruses, or have turned cancerous.
Our normal T cells usually do a good job of protecting us from threats, but they aren’t foolproof. Fortunately, CAR T cell strategies can make these already powerful immune cells even more effective against cancer. We invited Michel Sadelain, M.D., Ph.D., a CAR T pioneer at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, to join us on our “Cancer Immunotherapy and You” educational webinar series for patients and caregivers to discuss, “What’s Next in CAR T Cell Therapy.”
At MSKCC, Dr. Sadelain serves as the director of the Center for Cell Engineering, director of the Gene Transfer and Gene Expression Laboratory, and the Stephen and Barbara Friedman Chair. In addition, Sadelain is a member of the CRI Clinical Accelerator Leadership and the recipient of the 2012 William B. Coley Award for Distinguished Research in Tumor Immunology.
Here are some of the topics we discussed with Dr. Sadelain during the webinar:
HOW CAR T CELLS ARE DIFFERENT FROM NORMAL T CELLS
While our T cells are capable of recognizing an almost limitless variety of target molecules, one of their main limitations is that these molecules—also known as antigens—must be displayed on a cancer cell’s surface in a very precise way in order for T cells to engage and attack them. If a cancer cell’s target antigen isn’t displayed within the context of the major histocompatibility complex (MHC), then it will essentially be invisible to a T cell, even if that same antigen is presented abundantly on the surface of the cell.
CAR T cells, in contrast, don’t have this limitation, due to their CAR (chimeric antigen receptor), which is basically a synthetic construct that is made by fusing the antigen-binding portion of an antibody to a normal T cell “ignition” switch. That way, when the antibody portion binds an antigen on a cancer cell, it sends an activation signal to the CAR T cell that stimulates its activity.
Through these engineered receptors, CAR T cells can target antigens on the surfaces of cancer cells, even if they aren’t displayed in the context of the MHC system. This gives them added flexibility when it comes to the types of antigens and cancer cells they can target.
HOW CAR T CELLS ARE MADE
In general, there are currently two primary sources of T cells that will be turned into CAR T cells: from the patient (autologous) and from a donor (allogeneic). In both cases, transforming these normal T cells into CAR T cells that target specific markers requires the delivery of genetic instructions into these cells, most commonly via viral vectors but, more recently, genome editing tools such as CRISPR-Cas9 have also begun to be used. The newly inserted genetic code causes the T cells to develop into CAR T cells, which are then expanded in number before being re-infused into patients, where they can get to work seeking out and eliminating cancer cells.
Recently, Dr. Sadelain was able to treat patients successfully with CAR T cells that were made from donor-derived cells called induced pluripotent stem cells, demonstrating the feasibility of this allogeneic approach. Additionally, a number of academic institutions and pharmaceutical companies are developing other allogeneic-based CAR T cell therapies.
There are a number of advantages allogeneic CAR T cells have over autologous. They don’t have to be made from scratch each time but instead can be produced from readily available, “off-the-shelf” batches of cells awaiting genetic instruction. This would also allow for a higher level of quality control and production consistency than is seen with the variability of patient-derived T cells. Also, since the donor-derived cells are plentiful, patients with compromised immune systems who may not have sufficient numbers of T cells on their own may also benefit.
WHY CAR T CELLS ARE CALLED “LIVING DRUGS”
Unlike most drugs, which are inanimate molecules that leave the body soon after treatment has ceased, CAR T cells are living cells. Many versions of CAR T cells are now also equipped to expand over time and alter their activity as well as increase their numbers after the patient’s course of treatment has ended, with the goal of providing durable benefit to patients.
“This is very different from any drug, which from the second that you take it, it becomes degraded, requiring that you take the drug again,” Sadelain noted. “But this [CAR] T cell is a living drug… capable of expanding as long as there is tumor antigen to be found.”
CAR T CELLS IN THE CLINIC
As of September 2019, the U.S. Food and Drug Administration has approved two CAR T cell therapies for the treatment of cancer patients. Both these treatments—axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®)—are autologous products and both are designed to target the CD19 antigen that is expressed by most B cell cancers. Both treatments are approved for subsets of patients with relapsed or refractory large B cell lymphoma, while Kymriah is also approved for subsets of children and young adult patients with acute lymphoblastic leukemia (ALL).
In addition to these approvals, a variety of CAR T cell therapies—both autologous and allogeneic—are being evaluated in clinical trials for a number of cancer types, including other subtypes of leukemia and lymphoma as well as brain cancer, breast cancer, lung cancer, multiple myeloma, ovarian cancer, and others.
IMPROVING CAR T CELL THERAPY’S EFFECTIVENESS
Despite the impressive initial response rates in leukemia and lymphoma patients who have been treated with the currently approved CAR T cells, about half these patients will have their disease relapse within a couple years. This can be due to two reasons.
The first is that the leukemia cancer cells can “ditch” the target antigen—CD19—so they no longer express it, which prevents the CAR T cells from recognizing and eliminating them. To address this issue, researchers have developed CAR T cells to target multiple antigens—for example, both CD19 and CD22—to prevent this “escape” by leukemia.
The second main reason that CAR T cells sometimes fail to provide long-term protection is that they can become “exhausted,” which can allow any residual cancer cells to proliferate and lead to a full-blown relapse. To address this, several strategies to engineer “exhaustion-proof” CAR T cells are being explored. Additionally, combining CAR T cells with other immunotherapies, especially the checkpoint inhibitors that block the PD-1/PD-L1 pathway that can promote exhaustion in T cells, is a promising approach currently being evaluated in clinical trials.
Both these issues—antigen loss and T cell exhaustion—are just as relevant, if not more so, to CAR T cells in solid cancers, which comprise the vast majority of cancer cases.
Whereas CD19 serves as an effective target antigen because it is expressed almost universally on cancerous B cells, there is no such ideal target on most solid tumors due to the inconsistency of antigen expression across the tumor, referred to as heterogeneity. Thus, a great deal of ongoing work is seeking to identify more suitable targets for CAR T cells in a range of solid cancers
The issue of T cell exhaustion is also much more pronounced in solid cancers. Unlike leukemia cells, which CAR T cells can freely encounter in the blood and bone marrow, solid tumors often possess a hostile tumor microenvironment that can block, deactivate, or repel immune cells. In addition to the strategies to address CAR T cell exhaustion mentioned above, there are several other strategies being studied, such as enhancing the metabolic fitness of solid tumor-targeting CAR T cells.
“So which ones of these [strategies] will work,” asked Dr. Sadelain. “We don't know. These are early days. But clearly, the issue of identifying suitable targets and further refining the design of the CAR T cell to overcome a not-very-friendly tumor microenvironment are the two main lines of work that are going on today in developing CAR T cell therapies for solid tumors.”
OVERCOMING POTENTIAL ISSUES INVOLVING DONOR-DERIVED T CELLS
There are issues that can arise from supplying a patient with donor-derived CAR T cells, however, because the patient’s immune system may recognize the new donor cells as “foreign” and vice-versa. To prevent these CAR T cells from attacking the patient’s normal tissue (a condition known as graft-versus-host disease, or GvHD), doctors can add a CAR to donor T cells that are already equipped to target a virus to which the donor had previously been exposed. As a result, in addition to targeting cancer cells that express the CAR-specific antigen, these T cells will only attack virus-infected cells, and thus would leave the patient’s healthy tissues alone. Another strategy is to remove the natural T cell receptor from the CAR T cells altogether, thus preventing them from attacking anything other than the designated CAR T-directed target.
Preventing the patient’s immune system from rejecting the allogeneic CAR T cells is a little bit trickier. As of now, these donor CAR T cells have only been used to treat patients whose immune systems have been compromised and are thus unable to attack and reject the new cells. However, newer developments, like Dr. Sadelain’s breakthrough with respect to stem cell-derived CAR T cells mentioned above, have paved the way for expanded application of these allogeneic CAR T cell therapies. With these approaches, it’s conceivable that there could be “banks” of stem cell-derived CAR T cells created, and that patients could be matched with the donor CAR T cells that are most compatible with them. This is similar to how organ transplants work, in that the donated organ is more likely to be accepted by the patient’s body if it’s genetically similar to their own, which is why relatives are often considered good potential donors.
“So, if this works one day, then we will have what you called "off-the-shelf” therapy,” said Sadelain. “We will have reservoirs of stem cells or the CAR T cells derived from those stem cells, perhaps in pharmacies that, like today, are the storage area for conventional medicines. Perhaps we will have T cells banked, ready to be used, whenever needed. And the hope here is that, were this to materialize, be effective, be safe, and be cost-effective, this would contribute to lowering the cost of cell-based medicines.”
ADDRESSING THE SIDE EFFECTS OF CAR T CELL THERAPY
There can be serious side effects associated with CAR T cell therapy. One that is particularly important is called cytokine release syndrome (or cytokine storm), which is caused by an “excessive” immune response due to CAR T cell activity. Fortunately, doctors have learned how to recognize and address it, minimizing the risk of harm to patients.
As Sadelain stressed, “The good news is there are drugs that can control cytokine release syndrome, and if you intervene early, you can abate it very quickly. “But we want more than that. We want to make sure that it never happens.”
To that end, Sadelain discussed the development of mouse models that mimic cytokine release syndrome that have helped improve our understanding of the biological mechanisms that underlie it.
“Already this understanding is yielding new clues as to where a drug could be given to prevent the cytokine release syndrome… So I think there is reason to be optimistic that, while cytokine release syndrome is a very real issue today, in the upcoming years… this will become less and less of an issue.”
Michel Sadelain, M.D., Ph.D., is the director of the Center for Cell Engineering, the director of the Gene Transfer and Gene Expression Laboratory, and the Stephen and Barbara Friedman Chair at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City.
Dr. Sadelain’s work provided the foundation upon which the first two FDA-approved CAR T cell immunotherapies were developed. After demonstrating the effectiveness of CD19-targeting CAR T cells in mice, this strategy was applied in the clinic, where it’s provided great benefits so far for both adult and pediatric patients. More recently, Dr. Sadelain has continued to advance our understanding of CAR T cells and reveal important insights that are being used to improve their activity. These include the development of novel strategies to overcome the resistance that can occur as well as efforts aimed at increasing CAR T cell survival and persistence in patients, so that they can provide long-term protection.
This webinar, the fourth in the 2019 Cancer Immunotherapy and You webinar series, is made possible with generous support from Bristol Myers-Squibb as well as Celgene and Cellectis.