Strategies used to Prevent T-cell Exhaustion in Myeloma | Hermann Einsele, MD, FRCP | IMS 2024

Yeah, good afternoon. My name is Hermann Aizler. I'm based in Würzburg. I am the director of the Department of Internal Medicine 2, where we treat a lot of myeloma patients and we have a large program on CAR T cells and bispecific antibodies, so the new T cell based therapies. We have learned that also T cells, like patients, sometimes get exhausted. The question is, how much does this exhaustion play a role in the efficacy of these modern T cell based therapies like bispecific antibodies and CAR T cells? What we now know is that these T cells, when they are exhausted, they are less effective as CAR T cells and they are less effective when stimulated by bispecific antibodies. So there is some concern and some strategies how we can prevent T cell exhaustion to make these T cells fitter and more effective. And I think that has been nicely shown with studies in which CAR T cells were given earlier. So for example, in CAR T6 or in CARMA, CAR T cells were given after a medium of six lines of prior therapy. Now in CAR T4, T cells are given after one, two or three lines of therapy, so much earlier. So the T cells were fitter and we could already see in the results that these fitted T cells are more effective. So whereas in CAR T2 at one, the overall response rate was about 87 to 90 percent, it went up to 99.4 percent in the CAR T2 at four trials. So doing T cell therapy earlier with less exhaustion makes T cell fitter and we believe that the same is going to happen also with bispecific antibodies. And another strategy is to add on substances that improve the function of T cells. That is, for example, giving cell moths or imides like pomalidomide, lenalidomide with a T cell engager or the CAR T cells to improve their function. So I think we are all fascinated about the fantastic results we have with the T cell engaging therapies like CAR T cells and bispecific antibodies. But T cell exhaustion is an issue and but we have strategies to improve it. And I think we can be very hopeful that in the future these new treatments will become even more effective than they are today. So the question came up, why are T cells exhausted? So for example, if you have a typical viral infection which clears off after seven days, T cells are active for seven days without any problem. Now if a tumor is in a patient and the tumor slowly grows, the T cells that are specific for the tumor cells have contact with the tumor cell for a long time period and this long time exposure makes the T cells being exhausted.