ASH 2024 | The prevention of antigen escape in B-cell lymphomas treated with bispecific antibodies

This was an abstract that came out of science done at the School of Medicine at Mount Sinai and came out of work we did in my lab along with the lymphoma immunotherapy program. Bispecific antibodies have been absolutely transformational, a potent and pretty well-tolerated immunotherapy for multiple types of B-cell lymphomas and now we see it for other tumor types as well, myeloma, leukemias, even prostate cancer and some others. So that is fantastic; it’s not all good news; there is a little bit of, you know, concern, and that is that when some patients relapse, a proportion of the relapse without the target, so in the case of these bispecifics, like glofitamab and epcoritamab, without CD20 present on the cancer cells anymore, we call this antigen escape. Antigen escape has been described with CAR T-cells, not too common with most CAR T-cells, maybe 20%-ish after CD19 CAR T-cells for lymphoma, so you know, common but not very common. The first maybe four studies showing how common antigen escape is for B-cell lymphomas after bispecific antibodies, extremely high; they range from 38 to 80% antigen escape, but probably it’s around 50%-ish. 50% of the relapsing patients no longer have the target available, and that is impactful for those patients. Many of our therapies are targeting CD20, so we can no longer give rituximab plus lenalidomide, any other CD20-targeted therapy. So it’s a big deal. We’d like to understand why it’s occurring. There have been some good studies about that already, but this was an opportunity we had to perform; we call it flow-enriched single-cell RNA sequencing. So if we look at lymphoma specimens prior to any therapy at all, we can find these rare subpopulations that are already CD20-negative even before the therapy. Sometimes they’re 0.1%, sometimes they’re 0.5%. And so a brilliant postdoc in our lab, Ivan Odak, who has worked very hard on this for now some many, many, many months, enriched using flow cytometry and sorting these rare cells, and then we characterize them using single-cell RNA sequencing, and the surprising, for me, I think for most of us, a surprising punchline was that some of these CD20-negative cells are not just randomly CD20-negative; they are CD20-negative because they’ve started a different differentiation program. They started to differentiate towards plasma blast/plasma cell, they’re really plasma blast-like cells, so they’re no longer very B-cell-looking, they’ve lost CD20, they started to downregulate other B-cell features and started to upregulate many plasma blast features like XBP1 and BLIMP1 and even surface markers like CD138 and another surface marker, SLAMF7. So this is all interesting, but it might also be actionable because if you were going to antigen escape and avoid CD20 attacking, maybe we could already use some FDA-approved therapies like elotuzumab, which is a SLAMF7-targeted antibody. Perhaps we could give CD20-targeted therapy and a little bit of SLAMF7-targeted therapy to prevent this antigen escape problem. So it’s pretty early, it is preclinical work, but it’s really with an actionable translational approach that we could take to the future to try to prevent antigen escape, prevent relapse, help our patients to have durable remissions.

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