CAR-T Therapy: Redefining the Future of Medicine
For decades, medicine has relied on drugs that act passively, modulating symptoms or supporting the immune system indirectly as opposed to actively hunting down diseased cells.
In recent years, however, this limitation has been overcome by a modern and more personalized approach to treatment: Engineered Cell Therapy (ECT). The most common form of ECT is Chimeric Antigen Receptor T cell (CAR-T) therapy, which has proven to be highly successful in treating blood cancers. It operates with much higher precision than chemotherapy, making it a strong contender in becoming a mainstream form of cancer treatment. CAR-T therapy also shows promise in treating various autoimmune diseases that have previously been deemed untreatable. While CAR-T therapy is still new and developing, it holds exciting possibilities for the future of medicine.
The National Library of Medicine describes how the patient’s very own immune cells are what serve as the treatment in ECT. Medical experts are able to collect immune cells from the patient, genetically engineer them to enhance their ability to attack targeted cells, and then infuse them back into the patient. These cells then bind tightly to the target cells and multiply rapidly. Once binded, they release cytotoxic molecules that kill these target cells, which are then cleared out by the body’s normal immune system. In addition to releasing cytotoxic molecules, engineered cells can also release cytokines. These are signaling proteins that recruit more immune cells to join the attack. Unlike more passive therapies, engineered cells can respond to the presence of target cells by expanding in number, and some can persist long-term to provide ongoing support against disease recurrence. Since the effects of ECT can last longer, patients' lives are less disrupted by frequent hospital visits.
As explained by the National Cancer Institute, a form of ECT called CAR-T therapy has been most commonly used in cancer treatment, particularly in those that affect B cells such as certain leukemias and lymphomas. In CAR-T therapy, a type of immune cell called a T cell is genetically modified to better recognize and attack cancer cells. They do this by adding a special antireceptor called a Chimeric Antigen Receptor (CAR) to the T cell. This helps it recognize specific proteins on cancer cells, multiply, and in some cases stick around long term to fight recurring cancer. CAR-T therapy has shown to be highly targeted and much more precise than chemotherapy. Because of this, damage to healthy cells is reduced, leaving patients feeling less burdened by numerous side effects.
Professor Ida Su, an expert in chemical and biomolecular engineering and a Ph.D. graduate of the University of Washington with postdoctoral research at the Georgia Institute of Technology, shared her insights on the future of this treatment. I expressed my interest with Professor Su about preventative measures towards a severe side effect of CAR-T therapy called Cytokine Release Syndrome. As discussed earlier, CAR-T and other types of engineered cells release cytokine proteins into the bloodstream to activate immune cells. While this is beneficial in strengthening the attack, an abundance of these proteins can lead to an inflammatory immune response called Cytokine Release Syndrome. Symptoms of this condition include fever, low blood pressure, and possibly organ dysfunction in severe cases. When asked about how this treatment is being managed, Professor Su described how researchers are studying ways to make CAR expression transient. “The CAR expression can be controlled by the promoter”, she explained. “When the patient takes a small molecule drug, it will turn on the promoter and drive CAR expression. When you don’t want CAR expression, you take the small molecule and the CAR will be degraded, so the T cell won’t express the CAR”. Professor Su also mentioned that another possible solution is using mRNA to encode CAR. Since mRNA degrades over time, the CAR expression will be transient as well. With regulated CAR expression, T cells won’t get an activation signal. This reduces the amount of cytokine secreted and prevents cytokine release syndrome.
Another drawback to CAR-T therapy is its steep cost. “One big challenge is the manufacturing challenge”, Professor Su explained. Extracting and engineering the patient’s T cells is a very complex and time intensive process, resulting in its high cost of around 300,000 dollars. A possible solution to this is In Vivo cell engineering, which Professor Su described by saying “Instead of taking T cells out of the body and manipulating them, can we make this process happen in the body?”. The process of In Vivo cell engineering begins with the injection of a particle of virus into the patient. The particle will search for T cells and deliver CAR to them, allowing them to express CAR and do their job in killing cancer. An alternative strategy is using a donor’s T cells as opposed to extracting them from the patient. This would allow CAR-T to become a generalizable shelf treatment as opposed to being highly personalized, reducing the cost.
CAR-T has been shown to work well with blood cancers, as in leukemia, comparably to treating solid tumors. While speaking with Professor Su on expanding CAR-T therapy to treat more types of cancer, she explained that “We first need to understand why CAR-T cells don’t kill solid tumors”. The biggest challenge is that the microenvironment of the solid tumor is very immunosuppressive. “When the T cells go there, they cannot function because they are exhausted,” Professor Su described. In order to combat this, researchers are looking for ways to engineer T cells to secrete the proteins that can better resist the tumor’s immunosuppressive microenvironment. Another possible solution is to upregulate the proteins that CAR-T cells can recognize. Tumors downregulate these proteins, so upregulating them will allow T cells to better recognize and kill the cancer cells.
Engineered Cell Therapy is still a very new approach in the world of medicine, with FDA approvals for CAR-T therapies specifically dated back to 2017. While this form of care is still developing and may have its drawbacks, it has the potential to change many lives and the modern medicine we’re familiar with. Engineered Cell Therapies will increase the precision of treatments, reducing collateral damage to healthy tissues in comparison to other forms of treatment such as chemotherapy. When asked about how Engineered Cell Therapy could fit into the broader landscape of modern medicine, Professor Su said “I can see this becoming applicable to diseases beyond cancer”. CAR-T has shown promise towards treating autoimmune diseases such as lupus, transplant rejection, and HIV. If there are antibodies that can recognize the viral protein, CAR can be engineered to recognize the cells infected by the virus. “I think it comes down to the question, do you want to pay that much to treat an infectious or autoimmune disease?” Professor Su described. “If we can reduce the cost, make engineered cell therapy as cheap as antibody drugs or small molecule drugs, then this could really make engineered cell therapy broadly benefit a large patient population”. As ECT improves and becomes more accessible, it has the potential to redefine what we consider treatable, offering new hope to millions fighting cancer or autoimmune diseases.
