How long do CAR-T cells work?

How long do CAR T cells work? What are things that are stopping CAR T cells from working in myeloma? That's a very good question. For how long can CAR T cells work and what is the durability of the remissions? We've seen very, very good success in lymphoma and in acute lymphoblastic leukemia, which the most common leukemia in children and young adults. Those were simply some of the first diseases that CAR T cells were used in. That's the reason we have such long-term follow-up. The first few patients who got CAR T cells successfully about a decade ago actually had chronic lymphocytic leukemia. Some of those patients are alive today and without disease. The first girl who got CAR T cells for acute lymphoblastic leukemia is now more than nine years out of therapy and in a complete remission without any subsequent therapy. In myeloma, we simply don't have that degree of follow-up. CAR T cells in myeloma entered the field only about five years ago. The larger trials to look at large patient populations, trials that include more than 100 or 150 patients on them, were just initiated about three or four years ago. We have only that degree of follow-up and we know that there are patients with myeloma that have remained in remission for more than two years. How many would be as fortunate as that? We don't know yet. Whether we're going to have patients who are completely cured of their myeloma, I think that's an open question that we don't have an answer for yet. We can be very happy with the results right now because patients treated with CAR T cells from myeloma so far have been highly treatment refractory. We've so far been treating patients who've had seven, eight, nine lines of therapy and have been refractory to all approved agents, which is why they went on these clinical trials. In those patients, we've seen remissions up to two years and again, anecdotally longer than that. We are now seeing a whole generation of clinical trials that are looking at CAR T cells at earlier lines of therapy. We have a trial that is looking at patients who only failed one or two lines of therapy. Very soon, we will be opening trials here at Columbia that would look at CAR T cells as first line therapy. There is some thought that the CAR T cells will simply work better if you use them earlier in the course of treatment. It's quite possible that just by using them earlier in the course of the disease, we will see these longer and much more durable responses. What causes CAR T cells to stop working? So CAR T cells only live for a certain time period before they kind of peter out after having done their job. They get tired and exhausted and they can die. So they've done their job in the initial couple of months or three months and then they slowly decline in terms of their number and activity. This is where the discussion around memory T cell phenotype comes into play. What are the strategies we can utilize to make these T cells live longer? Is memory T cell phenotype or promoting CAR T cells towards that phenotype? Is it going to lead to better T cell persistence? Can we utilize checkpoint inhibition to make them live longer? All of those questions are being asked in various studies.