What is CAR T-cell therapy? CAR T-cell therapy is one of the most advanced forms of cancer immunotherapy that we can now offer to patients. People have been telling us for decades, how can we just activate the patient's own immune system to fight cancer instead of giving very toxic chemotherapy agents and other types of agents that can give a lot of side effects and are usually not curative. CAR T-cells have revolutionized this. They represent our ability to take lymphocytes from the patient that are part of their immune system, activate them using genetic modification, which is really one of the most technically complicated procedures that have went into medicine in the past few years, and infuse them back to the patient in a way that may kill kilograms of tumor cells with a single infusion. And what's amazing about CAR T-cell therapy is that we now have about a decade of experience with CAR T-cells in a variety of diseases, and we have patients who are in remission for nearly 10 years. So we do think about it as a curative approach for certain diseases. They have been extremely successful in a variety of lymphomas, and we already have three types of CAR T-cells approved by the FDA for lymphoma and certain types of leukemia that are common in children. And we now can be happy to say that we have the first CAR T-cell approved in myeloma. So that is a dramatic advancement of the field, and we hope that we will see this working out in other diseases as well. As of April 2022, there have been two CAR T products approved for myeloma, Abecma and Carvicti. CAR T-cells are genetically engineered T-cells that are now programmed to fight cancer. In simply saying, our immune systems are supposed to fight foreign infections, bacteria, virus, even a cancer antigen. In patients with multiple myeloma, the immune system is paralyzed, and the cancer cells are also very smart to evade this immune destruction. So what CAR T is, by a technique called leukophoresis, we isolate the lymphocytes, the main arm of the immune system, and then in the laboratory with the help of our cell biologists, introduce a transcript, a construct that puts the gene for the receptor that will go now back to the multiple myeloma cells and attack them. And that's what is called chimeric antigen receptor T-cells. Now those vary from tumor to tumor depending on the target antigen. For multiple myeloma, we are making a BCMA construct. And after the cells are produced, patients are given three to four days of mild form of chemotherapy called lymphodepletion. And then in our institute, we are admitting our patients and then infusing the CAR T cells. Now if you remember the video game Pac-Man from your childhood, before if you think about the lymphocytes being benign, naive, living harmoniously with the cancer and not really doing anything, and now with the introduction of this genetically engineered T-cells equipped with the CAR T receptor, they are like Pac-Man. They are going to go out and seek out those cancer cells that bear that BCMA and release chemicals and toxins to kill those cancer cells. And that can cause actually some of the reactions that we see after CAR T called cytokine release syndrome or cytokine-related encephalopathy. And of course we have medications to counteract that. But the results are phenomenal in patients with relapsed refractory multiple myeloma. This CAR T technology is now paradigm changing. CAR T cell therapy is chimeric adenogen receptor T cells. And we actually, that involves taking a patient's own immune cells, a type of immune cell called lymphocytes, out of their body and modifying, changing them so that they are really educated against the tumor cells. So we know that there are certain features on tumor cells, myeloma cells, that are unique to those cells and those are the things we want to target. We want to take the patient's own T cells or their lymphocytes out of their body, modify those cells in the lab basically, and then grow them up and put them back into the patient where they will actually expand just in some ways like they might if you had your immune system encounter an infection. But here it's not an infection. Here they're encountering the tumor marker, the myeloma marker that is now seen as the enemy by those cells. And those cells then expand and attack and destroy the tumor cells. So we're really harnessing what we understand, the power of the immune system, and using the T cells as cancer attack dogs to go after and destroy the myeloma cells. And the goal is to do it in a very specific way, which is why we pick certain targets like BCMA, B cell maturation adenogen, has been a favored target for myeloma because we know it's on those cells and it's not on normal cells really very much so that we can safely selectively target the disease. Well CAR-T stands for chimeric antigen receptor T cell therapy. What that involves is the chimera was this mythologic beast that was part lion, part serpent, part goat. So you have three animals in one organism. And so in this case what's happening is a new molecule that's not part of that lymphocyte repertoire is being introduced into the T cell. And a T cell is a type of lymphocyte. And what's happening is this molecule or receptor is targeting something. So you target your antigen, you've hijacked the T cell's machinery to have it go attack something expressing the molecule of interest. And it binds to that cell expressing that molecule and it kills it. Now you have to target something that the person could live without for a period of time because you can live without your B cells because you can get gamma globulin. B cells make antibodies after you get a vaccine and you can get immunoglobulin infusions, which is a blood product but it's purified from plasma. And those can suffice to help you fight off infections because you're getting somebody else's immunoglobulins. So that's a very important concept because if you, for example, targeted certain molecules that are expressed on your neutrophils and also on acute myeloid leukemia, you could wipe out the leukemia but you'd wipe out all your neutrophils and that would be bad because now you don't have them to help fight off infections. So that was a very long process there but what you now have is a T cell. You take it from the patient, it gets sent to a laboratory, this vector is put into the T cells. It has this anti-CD19 or anti-BCMA. That gets expressed in the T cell surface. They're grown up and then aggregated together and then sent back to the center or if it's done on site for infusion into the patient. The patient received what is called lympho-depleting chemotherapy and what this does is it knocks down the patient's own T cells to create a little space to allow these new T cells to be infused in so they have a little bit more selective advantage in terms of growing up because the other T cells have been suppressed usually by two drugs, fludarabine and sacophosmin. Then the T cells go into the patient and then they are growing up and they can do a couple of things. They can attack the tumor and if there's a lot of it, something called tumor lysis syndrome can occur where all of a sudden the tumor is being rapidly killed off by these T cells that are now attacking them. The other is there's something called cytokine release syndrome where in addition to attacking the tumor, the immune system gets massively activated and that will lead to a lot of inflammation and some toxic side effects. And then lastly there's a CNS or central nervous system toxicity which can lead to damage to the brain at least in terms of cognitive behavior, understanding what's going on, not being able to follow commands of a variety of things. And these are treated. They need to be aggressively treated. The CNS toxicity is treated with high dose steroids. The cytokine release syndrome is treated with a drug called tociluzumab.