IMS 2025 | The role of the immune system as a mechanism of resistance to T-cell engagers in multiple myeloma

Today I’ll be talking about the role of the immune system in resistance to T-cell engagers. We have been treating a lot of patients with bispecifics and with excellent results and we continue to see advancement of their use in earlier lines. With this, the problem that we are trying to understand and address is how the patient’s immune systems play a role in limiting the efficacy of the bispecifics and what we can do to overcome it. So the first mechanism I spoke about yesterday was immune editing by the innate immune system on antigens that are targets of bispecifics. And this has been well described by several groups for BCMA. Our group has focused on another target, GPRC5D, and found that there is immune editing in about half of the patients, at least, that happens. When this happens, the antigen is lost. And this is extremely important to know because more therapeutics are being developed that can be given sequentially against the same target. So, a patient might get a GPRC bispecific first and then a CAR-T after that. And knowing whether the target antigen is still expressed or not is very important. So towards this, one of our fellows, Tarek Mouhieddine, has developed an assay with our pathologists that can readily identify the protein expression in bone marrows done routinely in most offices and academic institutions and even private practice. So this assay helps us determine whether the antigen is present or not. And we show in our data that the higher the expression, the better the patients do in terms of depth of response and duration of response. And in fact, at progression, patients actually lose the antigen. And this is seen in up to 80% of patients that we profile. Particularly important is extramedullary disease where myeloma happens outside of the bone marrow. The second mechanism that I spoke about was regulatory T-cells that can inhibit the function of our endogenous T-cells that are very important to cause bispecifics to kill myeloma. And studies have shown that higher levels of these cells, both at the onset of treatment as well as later on, actually can have prognostic impact. What is less recognized is that a subset of these cells express CD38, which is the target for anti-CD38 antibodies. And now combination studies where daratumumab, for example, is given along with the bispecific, can actually reduce these regulatory T-cells and allow the normal T-cells to do their function. In fact, in conjunction with the Janssen translational scientists, we have shown that the degree of depletion of these CD38 expressing regulatory cells correlates with the duration of remission from these combination therapies. So this is one mechanism that can be overcome with the current therapeutics and will be increasingly useful as patients get treated with bispecifics. The third and most interesting mechanism that we have been working on is a new molecule called S100A8/A9 that is a damage-associated protein that is secreted by the body whenever there is severe inflammation. And we see it increasing after CAR-T and bispecifics. And actually, the degree of expression of this protein in the blood, as measured by ELISA, directly is a biomarker for the duration of response for both bispecifics and CAR-T. It’s a very powerful biomarker. The way these molecules work is that they are our body’s endogenous system to dampen the T-cell activation that is happening after CAR-T and bispecifics. And in conjunction with Dr Amit Verma’s lab at Montefiore and Roshan Therapeutics, we have actually used a blocking antibody to this molecule that completely reverses in vitro the killing function of both CAR-T’s and bispecifics and are now using it in vivo and animal models and hope to take it to clinical trials.

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