AACR 2026 | Checkpoint irAEs: immune cell origins and treatment strategies

Absolutely. So the talk that I’m going to be giving for AACR is in a special session that’s focused on immune-related adverse events that occur following checkpoint immunotherapy. So obviously, checkpoint immunotherapy has had a tremendous impact on how we treat cancer, leveraging the immune system to go in and attack cancer instead of going after cancer directly. But what we’ve seen in a subset of patients is that we sometimes will get these off-target side effects that in many ways look like autoimmune diseases or autoimmune-driven pathologies. And we call them immune-related adverse events or irAEs. And these are toxicities that are directly attributed to boosting the immune system, but that immune system having these off-target effects. And so what I’m really trying to focus on in my talk is identifying some of the major research bottlenecks that the field is struggling with. And overcoming some of these bottlenecks, in my opinion, is really important for improving kind of how we assess risk for developing these events, how we diagnose these events, and then how we treat these events. And so the focus of my talk is going to be on this issue of where the immune cells are actually coming from that are causing the problem. And there’s sort of two opposing models. One is that the immune cells that are causing the toxicities are actually already there in those organs in patients at the time that we start treating with checkpoint inhibitors. And that just unleashes those cells in those areas to cause tissue damage. The alternative is that those pathogenic cells were actually not in those tissues at the time of treatment initiation, and rather they are triggered in other parts of the body to migrate into the tissue. And being able to distinguish between whether it’s cells that were already in the tissue or cells that have migrated into the tissue is really important both in terms of how we monitor, but also how we treat. So if it is migration, then monitoring perhaps in the peripheral blood could be really useful because the blood is this major superhighway between things like lymph nodes and spleen and bone marrow and these peripheral tissue sites where we see the toxicity. But if they’re already in the tissue when we start treating, then perhaps monitoring in the blood will be less useful. Similarly, in terms of how we treat, if migration is important, we can think about using the arsenal of immunomodulatory drugs we have to block cells from getting into tissues. The gut is a great example because blocking the integrin alpha-4 beta-7 can be very effective for keeping cells out of that tissue, and there are clinically approved alpha-4 beta-7 inhibitors. But as you could imagine, if the cells are already in the tissue, then blocking migration is going to do nothing. And so really understanding where these cells are coming from is super important. But in our translational studies, actually definitively determining whether or not it’s migration versus residence has been really challenging. And so kind of discussing the challenges there in terms of asking that question, as well as kind of areas of the field that I’m hoping are going to be evolving with preclinical models to be able to kind of address where those cells are coming from. I think there’s still a lot of question marks in terms of whether or not the cells are already in the tissue at time of treatment or if they’re migrating in. And if we can figure that out, then that is going to hugely impact how we monitor and how we treat, you know, in terms of thinking about different biologics we could use or, you know, certain types of immunosuppression or, you know, systemic versus targeted therapy. And so I think answering the questions are really important. And just based on where we’re at as a field, I’m actually going to be kind of presenting more questions that we have than answers in my talk. But I’m hoping that by kind of vocalizing where I see the major research bottlenecks are, we’ll be able to kind of start thinking creatively as a field to try to overcome those limitations.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.