IMS 2026 | Single-cell antigen & TCR mapping to investigate tumor-reactive T-cell responses in multiple myeloma

We were really intrigued to try to understand what part of the T-cell repertoire is important in actively preventing myeloma evolution and growth. And we know that there’s an erosion of the T-cell repertoire in patients as they develop their disease. And we see some repair of that with the various therapies that we’re using. And the question is, what are really the drivers? We were asking about this in the context of patients undergoing transplant and a personalized cancer vaccine that we developed. But it also has echoes in some of the other areas like CAR T-cells and bispecific T-cell engagers, where, again, you see the emergence of certain T-cell populations that seem to be protective and create durable responses. And we wanted to ask, what are they actually recognizing?
So one of our first observations was that when we looked at our patients on our trial, and these are patients who underwent autologous transplant and were randomized to either receive a vaccine and standard maintenance or the maintenance alone, we saw that those patients who developed clonotypic expansion of their effector T cell compartment had much better responses. And so there was a high correlation of CR and to some degree VGPR in those patients who had that kind of fingerprint in terms of their TCR pattern versus those patients who didn’t really respond well. And then we sort of asked the question, well, if there’s clonotypes that are emerging and they have some dominance, what’s their nature? We were able to show, using single-cell technologies, that there were shared TCRs across the different patients, suggesting that maybe there were very specific targets that could be highlighted as ones that we should go after when we’re trying to build immunity. And then we sort of did the work of trying to understand, are these neoantigens or shared antigens? Are they specific to that patient’s myeloma? Were they created by mutations? Are they high affinity? Or are they more T cells that we think of in the repertoire outside of cancer? And so in order to do that, we first analyzed the tumor cells themselves, tried to understand what peptides would come from their mutations that would potentially be immunogenic, and going through a computational algorithm, we came up with our list, we looked at the ones that were shared, we ran them against a compass database for another form of validation, and then developed these dextramers, which would bind T cells that recognize those very specific peptides, and started to now see that there were very specific neoepitopes that were recognized in patients, and some of them represented T cells that were undergoing expansion. So that suggested to us that whether it was lymphopoietic reconstitution after the transplant or the vaccine itself was inducing a neoantigen response and that seemed to then be associated with patients who may have more deeper responses. And so now we have to see over time what will that mean.

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