ICML 2025 | LymphoMAPs: using microenvironment archetype profiles to predict CAR-T outcomes in pts with LBCL

So yesterday at the plenary presentation and also published last night in Cancer Cell, David Russler-Germain presented our work doing single-cell profiling of large B-cell lymphoma. This was a collaborative effort between MD Anderson and Washington University in St. Louis and we collectively put together a set of 232 biopsies that we profiled by single-cell multiomics which enabled us to comprehensively profile both the immune and the non-immune microenvironment of a large series of both newly diagnosed and relapsed/refractory large B-cell lymphomas. So by putting together this atlas of different cell types in large B-cell lymphomas we managed to discover three reproducible underlying microenvironment archetype profiles that we call lymphoMAPs. The first profile is largely depleted of T-cells and is characterized by high frequencies of cancer-associated fibroblasts and tumor-associated macrophages. We call that the FMAC subtype. There are two subtypes that have high frequencies of T-cells. One that looks a bit more like a normal lymph node microenvironment characterized by stromal cells like follicular dendritic cells and marginal zone reticular cells that provide a supportive microenvironment for T-cells and so the T-cells are a healthier naive and memory cell phenotype and also CD4 biased and we call that the lymph node archetype. The second T-cell rich archetype is more inflamed, doesn’t have those supportive architectural cells that provide the cytokines for T-cell health and is instead characterized by high frequencies of exhausted CD8 T-cells together with super-activated macrophages. We call that the TEX archetype, short for T-exhausted. So we evaluated these different archetypes and their association with a lot of different clinical characteristics. There’s a lot of detail of those in the paper. What we focused on in the plenary presentation last night was the association with CAR T-cell outcomes. You can imagine based upon the biology of the different microenvironment archetypes and even prior associations between CAR T-cell outcomes and microenvironment for example associations with macrophage compartment that there would be associations with outcome. We saw that in our own data set and also in the ZUMA-1 data set but the largest validation series that we had was the ZUMA-7 data set which was the large Phase III randomized study of axi-cel compared to standard of care chemotherapy with autologous stem cell transplant in second-line large B-cell lymphoma. So we leveraged the existing gene expression profiling data from that study and we developed a classification algorithm that we call Lymphomapper, which is also a publicly available tool now, in order to classify those samples into the three lymphoma microenvironment archetypes. And then we compared the axi-cel arm to the standard of care arm within each archetype. What we found was that while the lymph node archetype patients did very well with axi-cel with a highly significant benefit for axi-cel over standard of care, the FMAC archetype patients which have a T-cell depleted microenvironment did less well but they still significantly benefited compared to standard of care and the TEX archetype that has a highly inflamed microenvironment characterized by exhausted CD8 T-cells had no significant benefit for axi-cel over standard of care. So we’re excited about these findings for a couple of different reasons. One is that we think that this is going to be a useful predictive biomarker for selecting patients that are most likely to benefit from CAR T-cells alone, but also the underlying biology gives us several opportunities in order to intervene in a biologically rational way in order to improve the outcomes of patients in either in combination with CAR T-cell therapy or as alternatives to CAR T-cell therapy and so we’re going to explore this prospectively using lymphoMAPs to select patients into sort of a basket trial in which we’re either combining with CAR T-cell therapy plus for example blocking interferon gamma with an interferon gamma blocking antibody or checkpoint blockade in the TEX archetype.

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