How does a normal immune system work?
Frits van Rhee, MD, PhD, FACP: A normal immune system is very complex and has many roles. It defends us against invasion from viruses and bacteria which we can acquire from other people or the environment. And we also get infected during our life with viruses which were dormant in our body. And our immune system even kills off developing cancers. For instance, it is well known that when you’re older, you are more prone to develop cancer than a young person. And one of the reasons for that is that our immune system slowly worsens over time when you get older. So our immune system is a very important part of our body protecting us against infections and also protecting us from developing cancer.
How can cancer “fool” the immune system?
Frits van Rhee, MD, PhD, FACP: In the case of myeloma, it’s important to realize that myeloma cells, or plasma cells—and myeloma cells are plasma cells gone wrong—are actually part of the immune system. And, for instance, when you get myeloma, you lose your normal plasma cells, and the normal plasma cells don’t produce antibodies, so your antibody levels become very low. That opens you up to infection. Also, the myeloma cells alter the environment in which the myeloma cells live, in the bone marrow, and the immune cells in the environment of the myeloma become suppressed. The myeloma in itself also has other effects on the immune system—it makes the immune cells less effective, and even populations of the immune cells increase, which have a regulatory function and dampen down the immune system. So there are overall multiple effects on the immune system which are adverse and which are mediated by the myeloma.
How does CAR T-cell therapy work on a cellular level?
Frits van Rhee, MD, PhD, FACP: What you do when you receive CAR T-cells is that, first of all, your normal immune cells get collected from your bloodstream. For that purpose, you get connected, on one occasion, to a machine which removes some blood, spins your immune cells down, and returns the remainder of the blood. It’s very similar to a stem cell collection, which you don’t need any growth factors beforehand or any chemotherapy beforehand. So it’s what we call a steady state collection and takes one or two hours, and the procedure is very simple. Then the cells get sent off to a manufacturing facility. And in the facility, the cells get genetically altered. So they’re altered so that the immune cells will recognize the myeloma cells, proliferate, expand, and become highly activated to kill the myeloma cells. So prior to receiving the CAR T-cells, the patients get what we call the lymphodepleting chemotherapy, which means that two drugs are given for three days to dampen down the patient’s own immune system so that the CAR T-cells have room to expand. So there’s three days of chemotherapy and then two days rest, and then the CAR T-cells get infused, just like a platelet or blood transfusion. And then the infused cells start to expand in the patient, they seek out the myeloma cells, and kill the myeloma.
Can you describe the logistical process of CAR T-cell therapy and what the patient experience is like?
Frits van Rhee, MD, PhD, FACP: From the logistical aspect, there is the practical item of getting insurance approval. The immune cell collection, or apheresis, needs to be scheduled. Then the patient undergoes the apheresis, the immune cells are collected, they send off, and it can take four to six weeks before the cells come back. During that period of time, sometimes further treatment is given to lower the amount of myeloma in the body. That has two purposes. One, to make the CAR T-cells more effective because there are fewer myeloma cells to fight, and there are also fewer side effects when the tumor burden is less. After the lymphodepleting chemotherapy and the infusion of the CAR T-cells, the chemotherapy will render the counts temporarily low. And once the cells start to really expand and attack the myeloma cells, sometimes the patients develop fevers, so the immune cells go into overdrive and release substances which can cause fevers and night sweats, and sometimes even drop the blood pressure. So that’s an important side effect of CAR T-cells, and patients are carefully monitored for that.
Sometimes only some TYLENOL® is necessary, but there’s also drugs available, like there is an antibody available called ACTEMRA® (tocilizumab), which neutralizes one of these substances called interleukin 6 (IL-6), which causes these fevers and is very effective at treating the cytokine release syndrome (CRS). Sometimes there are also some neurological side effects, such as confusion and other neurological side effects, which are often only temporary. So overall, when you ask a patient who’s on CAR T-cells and a transplant, if you ask them what was more tougher, the vast majority will say that a transplant is tougher than CAR T-cells.
How likely are adverse effects with CAR T-cell therapy, and do you think they outweigh the benefits?
Frits van Rhee, MD, PhD, FACP: A significant number of patients, the majority, will get some form of fever, what we call cytokine release syndrome, and usually the fevers are not severe, and the majority of patients don’t require the drug called ACTEMRA® (tocilizumab) to dampen down the cytokine release syndrome. Some of the neurological toxicities are mostly self-limiting as well, and those are the principal side effects of the CAR T-cells. So there are some other side effects as well, which are much rarer, but overall the benefits of CAR T-cells far outweigh the risks associated with it. And CAR T-cell therapy is quite safe in centers which are experienced with it.
