How is CAR-T Cell Therapy Different from Standard Chemotherapy?
FDA approved the first gene therapy treatment in the US recently in August this year. This new therapy called the CAR T cell therapy, uses body’s genetically engineered immune system to hunt and kill cancer cells. Named “Kymriah” by Novartis, this therapy was approved for treatment of an aggressive type of Leukemia (specifically Acute Lymphoblastic Leukemia) in children and young adults up to 25 years of age who did not respond to other treatments. The basic idea of T-cell therapy is to remove a patient’s white blood cells and then add a molecule to the cells which can stick onto cancer cells, lock-and-key style. The cells are then returned to the patient.
Dr. Carl June was on CureTalks earlier this November and gave the listeners a spectacular insight into treatment, side effects and trials on CAR-T cells. He also explained how CAR-T cell therapy was different from standard chemotherapy.
It is radically different. The therapies that we have had until recently are either surgery or radiation or a combination. And both of those are non-specific therapies, and they work by killing cells but they also kill normal cells, which leads to the side effects. With immune therapy it is precisely targeted at just the cancer cells, there are not those off-target effects. Off target effects are when the therapy is killing cells but it’s not helping you get better. So chemotherapy has many side effects and symptoms such as nausea and vomiting, to very severe issues which can involve liver failure, heart failure, bloody diarrhea and so on. Those are off target effects and they actually don’t help you get better from the tumor.
On target effect is – side effects related to actually when you are killing the tumor. So those happen, you know, when the patient is actually benefiting from the therapy. And the first one we found with our CAR-T cells (CAR- by the way stands for – Chimeric Antigen Receptor – and basically that means, it is a T cell that’s been modified. The word chimera is used because its from Greek word – “Chimeric Beast” – which is a fusion of 2 different animals in the greek mythology), the T cell that is a fusion of 2 cells in the natural immune system – which is the B cell. B cells normally make antibodies, which we use in our defense against viruses and infections. The T cells normally just kill cells, but does not make antibodies. So a CAR-T cell takes the best world really, of a T cell and a B cell. The T cell can be a killer cell of tumor cells, but also has now – antibodies in it. Then that is how we can direct it to kill tumor cells.
The first on target effect we found from CAR-T cells is very high fever. In our first adults, we have a fever of 106 degrees, that would last for several days, and there is no infection. We now call this cytokine release syndrome or CRS. It only happens in patients who are getting better. The fever happens when the tumor is killing, I mean when the CAR-T cells are killing the tumor cells. It is a violent reaction. It can last up to a week. We now have ways to manage it. We learnt a lot about CRS. As I mentioned it has high fever, usually higher in children than in adults, probably because children’s immune system is more robust. We have also learned that if we treat patients earlier, when they don’t have as much tumor, there is less CRS.
So our first patient, the first 3 that were reported, that were treated in 2010 were adults. By the scan that were done they had between 5-7 lbs of tumor each. When their tumor got ablated by the CAR-T cells, it was violent. They had fevers which lasted – in one case – 2 weeks, until the tumor was all gone. The patients recovered and they were completely fine. There was no long term side effects from that. So that’s an on target side effect is Cytokine Release Syndrome. It can be severe in patients with high tumor loads. Up to 1/3rd of the patients go to ICU, but the fatality rate from this is less than 1%. In the trial that Novartis did to get the FDA approval of CAR-T cells for leukemia for patients between age 3-25, 48% of the patients had Cytokine Release Syndrome, but there was no fatalities.
Both chemotherapy and targeted therapy are two effective methods for cancer therapy. The difference is that chemotherapy can also kill the normal cells when eliminating the cancer cells. On the other side, the normal cells can survive the targeted therapy, when the growth of cancer cells was limited. Chemotherapy drugs effectively target processes that cancer cells need to grow and divide, such as the ability of the cancer cells to replicate their DNA. However, many normal cells, like the cells that line the digestive tract, also need to replicate.
In short, though chemotherapy drugs are particularly toxic to cancer cells, they also damage healthy cells. The use of standard chemotherapy therefore produces many, and often severe, side effects. Furthermore, these side effects sometimes prevent patients from being able to take high enough doses to fight the cancer most effectively.