So, you have multiple myeloma, or you know someone who does (or how else did you end up here?). Chances are you have heard of CAR T (pronounced car — like a Ford — and the letter T — like Sesame Street). What is CAR T exactly and how does CART fit into multiple myeloma treatment?
What Is CAR T?
Let’s start with the basics. Officially, you capitalize the CAR in CAR T because it is an acronym, or abbreviation if you prefer, for chimeric antigen receptor. So, CAR T cell therapy is chimeric antigen receptor T-cell therapy.
Moving on from science terminology, CAR T-cell therapy is a type of immunotherapy. Immunotherapy is when you use the body’s own immune cells to treat their cancer. Assuming this all worked perfectly, this is very much a Star Trek level treatment. Unfortunately, we’re still working out the bugs.
How Does CAR T Work?
T-cells are the body’s immune system workhorse. When you get regularly sick, like with a cold virus, or something like Covid, your body mounts an immune response to kill the invading cells. Time for a quick science review for you biology majors, or introduction to the human body immune system for you non-science majors.
The body has white blood cells. Consider these the security guards. Their job is to look for trouble. White blood cells patrol the body, but they mostly hang out in lymph nodes which filter and trap germs. These are like the security shed, or security camera room. If the white blood cells see something, they sound the alarm and the guards start pouring out of the security rooms into the night find more intruders.
Pathogens such as viruses and bacteria have antigens on their surface. Anything that triggers the immune response is called an antigen. (Psst. That’s the A in CAR T.)
If the body has seen this intruder before, either by previous infection, or from a vaccine, the body’s B-Cells will recognize the antigen and produce antibodies. These antibodies are specifically designed to attach to this specific type of antigen.
Antibodies do not destroy infectious cells on their own. Rather, antibodies signal that the cell they are attached to is bad and must be destroyed. For analogy purposes, a soldier popping smoke to mark a target, or pointing a laser where the bomb should fall is acting like an antibody.
T-cells kill the pathogen floating in body, but also the cells that have been marked by antibodies. In this way, the body kills not only the virus, but also the infected cells that the virus is hiding inside. T-cells also release cytokines which further regulate and control the body’s immune response.
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Immunity works when some of the B-cells and T-cells transform into memory cells and get stored in lymph nodes. If the same antigens appear in the body again, these B-cells and T-cells begin the process of destroying it immediately before enough cells can be infected for the virus to get a foothold in the body.
What Does CAR T Do To Immune System
OK, so here we go. Remember when we talked about B-cells marking virus infected cells with antibodies? The important thing to remember is that the T-cells don’t recognize the virus infected cells, they recognize the antibodies that are stuck to the infected cells by B-cells.
The way this works is that T-cells have a receptor on them that is the mirror of the antibody. (Receptor is the R in CAR T.) Think of this like puzzle pieces. The T-cell puzzle piece will only match up with the matching antibody pieces. This way the T-cell kills the right cells (infected) without killing the wrong cells (healthy ones).
All that is left to understand is “chimeric.” I don’t have any analogy that will help here other than to say that in medicine, chimeric means any organ or tissue that contains cells with different genes than the rest of the organ or tissue. In our case, that will be deliberately modified genes on T-cells, but let’s not get ahead of ourselves.
How Is CAR T Made?
Now that we know all the puzzle pieces, let’s figure out how they make CAR T and why it is such a promising treatment for myeloma.
Cancer cells are mutations of the body’s own cells, as such, the white blood cells don’t really notice them. Cancer cells are not foreign, just broken. That’s why your body doesn’t fight back against cancer inside your body.
However, if you could somehow mark cancer cells as bad the immune system would attack them. You could do that by having a B-cell match and attach to cancer cells generating antibodies. (That might work someday, but that is not CAR T.)
The other thing you could do is get T-cells to think that a protein on the surface of cancer cells is an antibody. So, when the T-cell matches and attaches to that protein on the cancer cell it will kill it.
Basically, if we genetically modified T-cells (making the chimeric), with an antigen (the surface protein) receptor that matched the cancer cells, then the T-cells would attack those cells and generate a further immune response to follow up. Chimeric Antigen Receptor T-cells (CAR T).
How Well Does CAR T Work on Myeloma Cancer?
The catch is that while the altered T-cells are efficient killers, the body isn’t making that kind of T-cells, so the only ones that can attack the cancer are the ones you put back into the body. In other words, you have to flood the body with modified T-cells and hope they find all (almost all) of the cancer cells.
To make CAR T treatments, doctors remove the patient’s own blood and filter out the white blood cells, which include T-cells. They add a gene for a receptor that will bind to a protein on the cancer cells. Then they grow millions of T-cells with this added (chimeric) gene. Then they put those millions of T-cells into the patient’s body with an infusion. The flood of T-cells attaches to and destroys cancer cells in body.
As you can imagine, CAR T only works when the T-cells can float through the blood stream finding cancer cells. So, in its current form CAR T only works for liquid cancers like leukemia, lymphoma, myeloma and other blood cancers.
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CAR T Side Effects
There is always a catch.
In medicine, and cancer treatment, the catch is side effects.
The biggest problem is cytokine release syndrome (CRS). When the CAR T cells multiply, they release cytokines into the blood to trigger the rest of the basic immune system. Unfortunately, the basic immune system doesn’t help cure cancer cells. So, those effects are just trouble inside the body.
Typical side effects include fevers and chills, nausea, headaches, fast heartbeat, fatigue, muscle pain and joint pain, and worst of all problems with breathing.
CAR T can also cause some weird nervous system issues like seizures, twitching, loss of balance, and loss of consciousness.
Kinds of CAR T
There are a few different kinds of CAR T. They are named for the way the chimeric antigen is created and shaped.
- Tisagenlecleucel, also known as tisa-cel (Kymriah)
- Axicabtagene ciloleucel, also known as axi-cel (Yescarta)
- Brexucabtagene autoleucel, also known as brexu-cel (Tecartus)
- Lisocabtagene maraleucel, also known as liso-cel (Breyanzi)
- Idecabtagene vicleucel, also known as ide-cel (Abecma)
Can I Get CAR T Treatment?
CAR T treatments are still very new. Doctors are still working out all of the issues and learning to avoid things like CRS. It is possible to do more harm than good with CAR T. So, they do what they always do with new cancer treatments for myeloma patients.
New treatments for multiple myeloma start out as experimental. In order to get them you have to participate in a clinical trial. Once the trials have good enough results they approve the treatment for “multiple relapsed or refractory” myeloma.
The basic idea is this. There are a bunch of myeloma treatments out there right now. So, doctors will start patients on the most basic, or standard, myeloma treatments. Today, that is usually some form of dexamethasone, Revlimid and Velcade, often called VRd.
If that doesn’t work, or if that stops working, then you try the next thing, maybe a stem cell transplant, or adding daratumumab, or… whatever the patient and doctor think might work best.
But, we all know there is no cure for multiple myeloma and eventually it will come back. That is a relapse. Or, if the medicine had been working, but now it isn’t, that is called refractory.
So, when other things are not working, doctors are now approved to use CAR T treatments.
Exactly when you can get CAR T is open to interpretation. My oncologist said that you can basically say you have tried as many “lines” or regimens as you want. It all depends on how you count them. In other words, when he thinks the time is right for CAR T, then we’ll get the paperwork to match the requirements.
They will keep doing this until they have the side-effects figured out and they have thousands of real-world patients that have had success with the treatment. In a few years, new myeloma patients might go from VRd straight to CAR T without ever doing a stem cell transplant or other treatments.
A few years back, daratumumab was approved for use in multiple relapsed or refractory multiple myeloma. As time has gone by and the safety and efficacy of daratumumab has been proven in thousands of real-world patients, it has “moved up” the scale of how soon it is used. Some myeloma specialist doctors are now calling for daratumumab to be part of the first response in some myeloma patients.
All new and experimental multiple myeloma treatments do this. Basically, start with the sickest people who are out of options. Officially, that is something like “have relapsed / refractory myeloma and have tried at least four lines of previous treatment.
If it doesn’t work, well they didn’t have any other choices anyway. If there are side effects, well, they would have died, or gotten sicker with myeloma anyway. Then, you sort of move up: Has tried at least three lines of treatment, and so on.
The Sloan Kettering people have a nice little video explainer that is even more basic than my explanation here.
Will My Insurance Cover CAR T for Multiple Myeloma?
Unfortunately, it always depends on your insurance policy. Even more unfortunately, it often depends on how well your doctor (or their office) submits the request to your insurance company.
As a new, and very expensive treatment, CAR T will need to be pre-approved by your insurance company. Whether or not they cover it will depend on your policy, and what else you have tried, plus how dire your situation. In other words, if you haven’t tried some (all?) of the cheaper drugs, they probably won’t cover it.
The good news is that with FDA approval, at least one CAR T treatment no longer counts as “experimental.”
If you get denied, don’t take no for an answer. File an appeal, and then do it again, and again.