ERIC 2024 | Challenges in developing immunotherapies for CLL compared to other hematologic malignancies

Yeah, this is a very important and crucial question. As most of you know, cell therapies have changed the landscape of how we treat, especially hematological malignancies. It works very well in B-cell-derived malignancies like aggressive lymphoma, acute leukemia. However, the results are not as good in CLL. So immune checkpoint inhibition does not work that well, but also CAR T-cell therapy does not work that well. And I think metabolism and the microenvironment in general plays a crucial role in this. We know for example that T-cells are very much exhausted, the T-cells that are found in CLL patients, so they are actually the backbone of the CARs that you produce at the end. So when your backbone, when your product is not fit enough, it will not work. So in this case we know, metabolically at least, that they cannot adapt that well, that they cannot turn on their metabolism that well, that they have defects in the mitochondria, you know, the most important organ of the metabolism, which of course contributes to probably the poor results that we see. On the other hand, we also know that there is a very potent microenvironment that can impact immune responses in a negative way. And for CLL cells, we know that there are fibroblasts that are reprogrammed by the CLL cells to act immunosuppressive. We know that the myelocyte compartment is shifting towards promoting tolerance, but in this case tumor tolerance. So all these factors, in addition to the metabolic alterations we see, contribute to I would say not as optimal immune responses.