EHA 2026 | Novel insights into the B-cell receptor in high-grade B-cell lymphoma

We used to think about the B-cell receptor as an essential determinant of most B-cell tumors. And this is also the reason why we actually treat patients with drugs that are hitting the B-cell receptor complex, like polatuzumab vedotin, which targets a component of the B-cell receptor. And so we were pretty intrigued when we started measuring the level of expression of the B-cell receptor in various types of tumors. And we realized that in high-grade B-cell lymphomas with MYC and BCL2, the tumors had very frequently lost the expression of the receptor, which is pretty unusual for tumors that arise from mature B-cells. So we went on and tried to study the mechanisms that are responsible for the loss of the receptor. And we recognized that this comes back to a fundamental mechanism that works in immunology, namely tumors can reactivate the recombinase genes, which are important for editing the B-cell receptor. And in these tumors, this process occurs very frequently and unexpectedly at high frequency. And through the process of recombination, you lose the B-cell receptor expression by losing the immunoglobulin light chain expression. And so these tumors now live without a B-cell receptor. They adapt to that, probably selecting alternative mutations. And this is a highly aggressive tumor, life-threatening. So the question was, can we predict which patients will develop these tumors? Can we identify precursor cells when the tumor is still not so aggressive in a way that we could try to treat the patient before it develops this aggressive tumor? And we know that high-grade lymphomas derive from indolent tumors very frequently, they are called follicular lymphomas. And so we started looking at patients who had a clinical history of follicular lymphoma preceding this life-threatening high-grade lymphoma. And we started screening them for the expression of a marker, the recombinase genes, which usually are associated with the aggressive phenotype. And we recognized cells, a rare fraction of cells in follicular lymphoma, that had already expressed the RAG genes. And these are, we believe, the precursor cells that eventually will evolve into a highly malignant tumor. So we are now very interested in understanding the biology of these cells, what are the mechanisms that drive an indolent follicular lymphoma with RAG expression, driving them into something that becomes much more aggressive. 

You know, the treatment of aggressive lymphomas in first line implicates also the use of new drugs targeting the B-cell receptor like polatuzumab vedotin. And so it’s a concern from our point of view of actually having tumors like the ones I described, but also diffuse large B-cell lymphoma, a fraction of them we discovered, they lose the B-cell receptor. So it would be very important at the beginning when you diagnose a disease of this type to actually screen the patients for the expression of the receptor and eventually go with treatment alternative to the treatment with polatuzumab vedotin if you realize that the target is not there anymore. So we started in our institute, in my research program, to actually screen these tumors with drugs that could eventually kill tumors that have lost the B-cell receptor. And we have already identified a number of them that could be potentially provided as second-line treatment to patients that eventually will resist the treatment with polatuzumab vedotin.

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