EHA 2026 | Distinct tumor microenvironment archetypes underpin response to glofitamab in DLBCL

So bispecific T-cell engagers, they have been very successful in treating refractory/relapsed diffuse large cell lymphoma. And more recently, they have shown to be highly effective in the first line setting when combined with chemotherapy. So one example is the COALITION clinical trial that was carried out in Australia, which combined the T-cell engager glofitamab, which targets CD20 on the tumor cells and CD3 on the T-cells, with R-CHOP or Pola-R-CHP. So the results of the trial look very promising and are now published in the Journal of Clinical Oncology. So despite the success of the clinical trial, a percentage of patients still don’t respond to therapy. So we wanted to understand why they don’t respond to therapy. So we leveraged the clinical trial samples that we had access to from the COALITION clinical trial to investigate that further. So what we identified was that not the number of T-cells within the tumor microenvironment of these patients mattered the most, but the proximity of these T-cells to tumor cells. So, for example, in responders, they had increased numbers of T-cells in very close proximity to the tumor cells. And non-responders, they had tumor-dominated archetypes. That is, the distance between the tumor cells and the T-cells in non-responders was greater than in responders. So what struck us was not that just the number of CD8 T-cells in proximity to the tumor cells was associated with better responses, but also the number of CD4 T-cells in proximity to the tumor cells was associated with better outcomes. So we know that CD8 T-cells, they can kill via direct cytotoxicity, via perforin and granzyme. However, the role of CD4 T-cells is less clear. So CD4 T-cells, they can be polarized into pro- or anti-inflammatory immune subsets, which can have pro- or anti-tumor activity. So what we found was that the CD4 T-cells, they could differentiate into potent cytotoxic CD4 T-cells. So we made use of in vitro model systems and what we identified is that the killing capacity of the CD4 T-cells was comparable to CD8 T-cells and that the CD4 T-cells could kill via perforin and granzymes the same way that standard CD8 T-cells do. And because the B cells, the tumor cells arise from B cells, which are antigen-presenting cells, what we wanted to address was which molecules on the surface of the tumor cells, apart from CD3 engagement, could be important for the efficient differentiation of cytotoxic CD4 T cells. So what we identified was that major histocompatibility class 2, so antigen presentation on MHC2, and also the presence of adhesion molecules was essential for differentiation of cytotoxic CD4 T cells, especially when CD20 expression on the tumor cells was low. When we went back to the patient samples and we compared the baseline tumor microenvironment, we could already see that non-responders, they had lower levels of some of these molecules as well. And when we look at the non-responders and compare the paired sample biopsies between baseline and at relapse and disease progression, we could see that those patients have further down-regulated some of these molecules, which suggests that they may be involved as mechanisms of resistance to the drug. So in summary, what we identified is that the overall number and proximity of the T cells to the tumor cells is associated with better responses to glofitamab combined and combination therapies in the first-line setting, that CD4 T cells contribute to the response by differentiating into cytotoxic CD4 T cells, and that a molecule such as major histocompatibility complex class II and the presence of adhesion molecules are essential for this differentiation, and the down-regulation of some of these molecules may be associated with mechanisms of resistance. This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.