Shifting their focus to acute graft versus host disease, panelists reflect on evolving treatment strategies and novel therapeutics.
Corey S. Cutler, MD, MPH, FRCPC: Now that we’ve talked about what’s critical in chronic GVHD [graft-vs-host disease] and what’s coming up in the future, why don’t we jump back to acute GVHD? Yi-Bin, why don’t you tell us what you think is exciting in the world of GVHD both with prevention and therapies on the horizon.
Yi-Bin Chen, MD: Let me talk about therapy first. I think we have made looking at acute GVHD, especially with a lower GI [gastrointestinal] tract, a focus of our research. From the treatment perspective, as we mentioned already, it’s doing more clinical trials to refine the role of biomarkers. A big reason for why our clinical trials in acute GVHD in the past have possibly, shall I say, failed, meaning not showing progress, has been that we’ve enrolled everybody with this disease of acute GVHD, and that probably was too heterogeneous a group with different biologies. To be able to use biomarkers to risk-stratify patients, to do high-risk trials where we use steroids plus another agent, and then do low-risk trials where, as Corey mentioned, we are using no steroids and using a less harmful agent, that may lead the way to progress here in not treating everybody the same. I think the big shift away from global immunosuppression and focusing on organ resiliency is going to move us in the right direction.
If we look at the most modern models of lower-GI GVHD, the earliest site of attack appears to be the intestinal stem cell niche. And if your intestinal stem cells are destroyed, it impairs your ability to heal and to have, what Corey had mentioned, this re-epithelialization of the GI tract. So if your stem cells are gone, no matter how many T cells you eliminate, there’s no immune system left. You cannot heal; you’ll basically succumb to infections from having no mucosal barrier. The trials that are being done are to focus on the preservation of intestinal stem cells, including agents such as IL-22 [interleukin-22] and human chorionic gonadotropin by our colleagues at the University of Minnesota in Minneapolis. We will be opening a trial using glucagon-like peptide-2 to preserve more intestinal stem cells as well. All these things are targeted toward preservation of the intestinal stem cells and that’s in addition to our work in trying to shape the microbiome.
It’s really fascinating. When we all started our careers in treating acute GVHD, therapies were immunosuppression, immunosuppression, immunosuppression, and now it’s a little bit––well a lot––of immunosuppression. But what we’re adding on is more protecting intestinal stem cells or shaping the immune system, and going forward, again, who knows what’s going to happen, but these are the ongoing trials that we’re focused on to try to improve the care of these patients. For GVHD prevention, moving on from tacrolimus and methotrexate is proving to be difficult. We’re waiting on the results of the Progress trials, specifically the Progress III trial [NCT03959241]which should read out hopefully very soon, to show us whether in the reduced-intensity setting that a posttransplant cyclophosphamide-based platform can be proved to be superior from a variety of perspectives compared with tacrolimus and methotrexate.
But progress continues in other ways such as, as we mentioned, the approval of abatacept, and where does that fit in? We haven’t mentioned at all the graft manipulation strategies that exist, including conventional T-cell completion, the work done by our colleagues at Stanford University in California with the Orca-T technology, the naïve T-cell depletion platforms that have been shown. And these are all a bit more complicated in terms of having a laboratory that can perform these manipulations, but in these small trials that have been presented, the results are very, very impressive, and we look forward to participating in larger trials to really generalize and see if these results can hold. As Corey mentioned, we completed a study using itolizumab added to tacrolimus-methotrexate, and our own institution has parallel trials using the prolonged use of early ruxolitinib, adding it to tacrolimus-methotrexate as well in preventing acute and chronic GVHD. I think it’s just a really exciting time for us; I think we have a lot more tools or toys, shall we say, and ongoing investigation. I think it’s on us to be able to collaborate and figure out how to best incorporate all these findings.
Corey S. Cutler, MD, MPH, FRCPC: I agree, there are tons on the horizon, and even on the therapeutic side when patients escape these novel preventive strategies. Alpha-1-antitrypsin has become part of our usual armamentarium here at our center for steroid-refractory disease that might also be refractory to ruxolitinib on the basis of the trial that we did with a group at Michigan State University in Lansing and that is being tested now in a prophylactic strategy as well.
We’re testing the Equillium compound itolizumab, which probably impairs T-cell activation and T-cell migration. There are a couple of other things out there that are being tested. And again, our ability to provide supportive care, provide antifungals and antibacterials, and really support the patient through their acute GVHD to allow them to heal has also improved outcomes, and we know in fact that outcomes are improving over time.
Transcript edited for clarity.