Novel Agents in Acute GvHD


Experts discuss new and exciting agents and combinations that are on the horizon for patients with acute GvHD.


Corey Cutler, MD, MPH, FRCPC: Hannah, what is catching your eye? What are the novel clinical strategies or trials out there that are testing novel agents in acute graft-vs-host disease?

Hannah K. Choe, MD: A big one right now is the MTC TN trial, the 2002 trial looking at T-Guard, which is a combination of two antibodies that are ricin A conjugated and immunotoxin conjugated CD3 and CD7. It’s a very limited course of treatment. It’s given within 2 weeks through infusions. It essentially knocks out the NK and T-cell populations and then allows for new immune reconstitution to happen so that you’re quickly eliminating the GvHD cause, but then hopefully, allowing a gradual regulation of the constitution to allow prevention of viremia. You’re avoiding, hopefully, the chronic exposure of immunosuppression with a limited course of treatment as compared to, say, ruxolitinib or you’d have to keep them on for much longer.

Corey Cutler, MD, MPH, FRCPC: Yi-Bin, what about alpha-1 antitrypsin as it pertains to steroid-refractory acute GvHD?

Yi-Bin Chen, MD: Probably the biggest area of interest for me right now in acute GvHD therapeutics is a shift away from cumulative immunosuppression and focused on more organ resiliency or healing. Alpha-1 antitrypsin may be part of that. It's a little bit unclear how alpha-1 antitrypsin works, but there were preliminary, at least early-phase studies, done in Boston by your group as well as colleagues in Michigan, showing a high response rate of alpha-1 antitrypsin and steroid-refractory GvHD. The CTN is doing an upfront treatment study for high-risk acute GvHD of steroids plus alpha-1 antitrypsin. Again, it is one of these risk-stratified trials, so it'd be interesting to see the results. Unfortunately, the availability of ruxolitinib has made the conduct of that study and the enrollment difficult, but hopefully we're able to get the study done and see the results. The other avenues focusing on organ resiliency and healing are super interesting. We know that from recent studies looking at mouse transplant models, that the stem cell niche appears to be the first and the most important site of a GI GvHD attack. If you lose those intestinal stem cells, that could be the major reason for why many of our patients don't get better. In the past, we've just immunosuppressed even more and that probably didn't help. There's this whole thought process, and we need to do trials to figure it out. If we're able to preserve these stem cells through various different directions, can we make progress? Some of those are using things like glucagon-like peptide 2, IL22, and even what Doris mentioned in terms of microbiome interventions. Can that sort of preserve the stem cell niche and help us? That's super interesting going forward.

Hannah K. Choe, MD: That's ... too, isn't it?

Yi-Bin Chen, MD: Do you want to talk about the MAGIC trial coming up?

Hannah K. Choe, MD: No, please do.

Yi-Bin Chen, MD: Jamie Ferrara presented data at American Society of Hematology about collaborative findings working with Genentech showing a pivotal role for a protein called, RIP1 kinase, in modulating apoptosis of intestinal stem cells in the GI niche. Next year, in 2023, the MAGIC [Malignant Germ Cell International Consortium] consortium will be conducting a clinical trial in risk-stratified high-risk GvHD of steroids plus a novel RIP1 kinase inhibitor to see if we can prevent this apoptosis and improve the outcomes. Again, by focusing on preserving the stem cell niche.

Doris M. Ponce, MD: I want to add interleukin-22, which you mentioned because we use it in the upfront setting away from steroid-refractory, but it's a side conversation since it's important to highlight that tissue regeneration and the rescue of those intestinal stem cells can make a difference. Our results were positive at the upfront setting, and it's something to consider refractory because it's not only minimizing that inflammatory response that cytokine cascade that is devastating to our patient, but also regenerating damaged tissue.

Corey Cutler, MD, MPH, FRCPC: We've talked a little bit about organ-specific treatment. There are a couple of other things out there. Both Yi-Bin and I have experimented with drugs that target T-cell trafficking to the immune system. We are currently testing a compound called, EQ001, which is a CD6 monoclonal antibody that prevents T-cell activation and targets agents. What else is out there? What are the other exciting and novel things that we're going to use? If there's nothing else, what is your algorithm for what you do for patients who are currently steroid-refractory? Doris, what do you reach for?

Doris M. Ponce, MD: It's the toughest question.

Corey Cutler, MD, MPH, FRCPC: For steroid-refractory ruxolitinib-refractory patients, if you had 1 drug, what's your go-to these days?

Doris M. Ponce, MD: It's a challenging arena because we don't have anything that is FDA approved after that failure so we consider using alpha-1 antitrypsin in these patients. Also, we've been adding into the algorithm we've been using. Human chorionic gonadotropin is an option because the concept for us is that this has been shown to have a regenerative effect in particular in the GI tract and in skin, so we think it could complement alpha-1 antitrypsin. Another option that we have used for some select patients is FMT in steroid-refractory GI graft-vs-host disease. Many of our cases that fall into the category of failing all the way to [ruxolitinib] usually is in the GI tract and some also liver.

Corey Cutler, MD, MPH, FRCPC: Does anyone use extracorporeal phototherapy regularly in ruxolitinib failures?

Hannah K. Choe, MD: Not regularly, unfortunately. These patients are usually very sick, oftentimes hospitalized, difficult to get a line into, and not stable enough, potentially, and at high risk for infection with the line. It becomes very complicated to be able to do ECP [extracorporeal photopheresis]. Also, the benefit of ECP is seen over a prolonged course. Unfortunately, we tend to do alpha-1 antitrypsin in patients that have ongoing infections. We have a clinical trial, a phase 1 study, looking at a BET inhibitor as well in a combination with steroids. Clinical trial is always the go-to here. That's obviously 2002 for the T-Guard study if we can and then, ruxolitinib after that, if possible, and then falling into alpha-1 antitrypsin.

Corey Cutler, MD, MPH, FRCPC: What's your go-to in steroid-refractory ruxolitinib-refractory?

Yi-Bin Chen, MD: We use ruxolitinib in vedolizumab off the bat for steroid-refractory, as I said. Patients who have achieved a partial response and are just not getting better, they’re the only ones that would be candidates for ECP, or extracorporeal photopheresis. They have to have somewhat improved and be stable. The true steroid refractory, as Hannah said, they will not do well with photopheresis. We do have a whole litany of agents that we use in the past that we don't like to use anymore these days because of their immunosuppressive effect. These include things like mycophenolate or etanercept, alemtuzumab, and pentostatin. They're always there, though. I don't think any of us feel good about using them because quite frankly, they didn't work all that well and they caused opportunistic infections. Like Doris, we have done work with third-party fecal microbiota transplantation too so we have that as an option for our patients as well. There are some regulatory hurdles there, but certainly that has worked for some patients. Like Hannah, we always try to have a clinical trial open to be able to offer these patients because quite honestly, there aren't that great options. Even though ruxolitinib is progress-based on the results that we discussed for REACH2, if you look at patients who presented with grade 3 to grade 4 disease and started ruxolitinib on that trial, their durable CR [complete response] rate at day 56 is only about 25%. That tells us that we have a lot of room to improve in the treatment of these patients.

Doris M. Ponce, MD: Anything in addition that you do?

Corey Cutler, MD, MPH, FRCPC: No. It's the same things that you all mentioned. We do reach for alpha-1 fairly regularly. We're not big users of extracorporeal phototherapy in the severe acute GvHD setting. It is a tricky thing.

Transcript edited for clarity.

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