Michael Bishop, MD

 Let’s talk about how we’d manage patients who get transplanted. The first issue we’re presented with after a transplant, when they develop symptoms and signs of acute GVHD [graft-vs-host disease]. I’m wondering, Mike, how you initially manage your patients with acute GVHD.

 It’s the same thing I learned when I was a fellow. The first 3 treatments for graft-vs-host disease are steroids, steroids, and steroids. I still think corticosteroids form the foundation. For acute graft-vs-host disease, most of the time they’re going to be on a calcineurin inhibitor. We’ll add corticosteroids, and we’ll do 1 to 2 mg/kg. I might make that even 0.5 mg/kg, and it will have to do with the organ involvement and the severity.

If I have somebody with grade 2 cutaneous graft-vs-host disease, I may use 0.5 mg/kg. If I have somebody with rip-roaring GI [gastrointestinal] and hepatic graft-vs-host disease, I’ll definitely use over 1 mg/kg, and I’ll usually use 2 mg/kg to try to begin the process. I’ll be thinking very quickly. One thing that’s underappreciated and comes back is early intervention. I’ll be looking for the steroid-refractory patients. At that point, I’ll be looking to add an additional agent. Most commonly it will be ruxolitinib. Ruxolitinib has changed our management of acute graft-vs-host disease. We have to make sure we identify those steroid-refractory patients as soon as possible.

 I agree. As I was referring to initially, early intervention—there’s a prophylactic treatment, there are preventive therapies, and there are treatment-related approaches. To intervene too late is a problem because once you get a lot of tissue damage, then you get the circular circuits of inflammation that are hard to stop after awhile.

 In that context, John, do you use biomarkers? For early intervention do you do biomarker studies on your patients for early identification of patients at risk for acute graft-vs-host disease?

 We haven’t generally. Obviously in select clinical trials, we do. We’ve come a long way with biomarkers, but they’re still not mainstream. What is the best day to get these biomarkers, which is the most predictive? James Ferrara and John Levine would provide some better insights than either you or I could. But there’s still debate about whether it’s at 7 days or at 21 days. The timing for these biomarkers as the most predictive for severe GVHD is a little debatable at this point.

Videos

Michael Bishop, MD, leads the discussion on approaching the first-line management of acute GVHD and the importance of early intervention for patients at risk for the disease.

Frontline Management of GVHD

 Let’s discuss some of the factors that contribute to the risk of GVHD [graft-vs-host disease], Mike. Let’s get away from the esoteric biology and tell the audience what you think the major risk factors of acute and chronic GVHD are.

 Our understanding of graft-vs-host disease has significantly changed in the last 20 years. A lot of that has to do with a biology that’s described. We always think about graft-vs-host disease, both acute and chronic, as a T-cell disorder. You take out the T cells, and there’s less graft-vs-host disease, both acute and even chronic.

But you emphasize B-cell biology. We didn’t have a good understanding of that, but the important role that B-cell biology plays, particularly chronic graft-vs-host disease, is very important.

Even our understanding of T-cell biology is relative to chronic graft-vs-host disease and our understanding of T-regulatory cells. The loss of T-regulatory cells plays an important role, which you were talking about with immune dysregulation. Having this further understanding about T-cell and B-cell biology has helped us define the underlying mechanisms that lead to both acute and chronic, and you couldn’t have said it any more eloquently. But it also explained a lot about what happens clinically. Why don’t we see a lot of acute lung graft-vs-host disease? Why don’t we see other forms of muscle and other organ involvement? It has to do with all this biology. That has to do how we define clinically acute and chronic graft-vs-host disease.

Unfortunately, in many ways we’re seeing more chronic graft-vs-host disease. That’s for a variety of reasons, which is good. One is patients are able to live longer from the acute phases of allogeneic stem-cell transplantation. Our supportive measures have become significantly better, so patients are living longer to develop it. Just as you described, immune suppression starts to pull off, we can see graft-vs-host disease.

We’re treating an older population, and they’re more prone to the development of graft-vs-host disease and, as you talked about, thymus involution. Their thymus gets very involuted, and there’s a difference between what we see in children, what we see in young adults, and what we see in older adults. Then our donor sources have significantly increased.

We’re using more unrelated donors. We’re using haploidentical donors. If you have an older individual, they may be using a brother and sister, or maybe a son or a daughter, as a haploidentical donor. Although we have low levels of relatively—to use the post-transplantation cyclophosphamide—these patients still can develop acute and chronic graft-vs-host disease.

Often the chronic graft-vs-host disease that evolves in these individuals can be severe and very difficult to treat. We’re seeing a lot of the factors that we already knew about in the development of acute and chronic, and probably the most important factor for development of chronic graft-vs-host disease if you did develop acute graft-vs-host disease. We’re seeing this more, and it’s becoming a challenge with us clinically, but for good reasons. The patients are living longer, and we’re able to apply transplantation to a broader audience.

 Would you agree that some of the risk factors for at least acute GVHD have to do with mismatching of donor recipients, that the greater the mismatch between the donor and recipients, the greater the risk of acute GVHD?

 Absolutely, and we know that. We have it from our studies. When we’re doing sex mismatch, when we’re using female donors, when you were talking about the use of an alternative donor that’s not related, the minor histocompatibility antigens—we know that they play an important role. Those are inherited differently from how we inherited HLA [human leukocyte antigen]. Because of that, using a related donor, you have at least a 50% probability if it’s a matched sibling donor; in the haploidentical setting, it’s 25%. It might be a little less, but all the factors—prior viral exposure, prior antigen exposure during pregnancy, and age of donor, which we really hadn’t taken into consideration in the last 20 years. Maybe it’s better to use a 20-year-old volunteer donor than a 68-year-old matched sibling donor for all the reasons that we were talking about in terms of antigen exposure, etc.

 I agree. As you mentioned, the most important predictor of chronic GVHD is the presence of some level of acute GVHD. But you can certainly get chronic GVHD if there’s no obvious acute GVHD, which means a lot of acute GVHD that occurs is physiologically happening, but we don’t clinically notice it.

One part of this acute GVHD stuff that predicts for chronic GVHD, which goes back to the pathophysiology, is that in acute GVHD or subclinical acute GVHD, the donor T cells injure these epithelial cells in the lymph nodes and thymus of the recipient. Those are the cells that can modulate this clonal deletion business. If they’re damaged, and the only thing that seems to damage them is not chemotherapy or radiation therapy but GVHD. That creates a defect in these cells. But the T cells that come out from the stem cells that go into these organs are not appropriately clonally deleted, and the T cells have some level of autoreactivity engage B cells and cause chronic GVHD. The notion of when to intervene to prevent these things is a controversial question. But I would suggest that.

 I want to reemphasize what we said. There’s this spectrum. They aren’t necessarily 2 distinct entities. You may not have seen clinical acute graft-vs-host disease, but there’s an immunologic process going on. Are the embers there from whatever happened before? These new T and B cells emerge from the marrow, not the passively transferred T cells or the passively transferred B cells. There’s a continuum, and that continuum is what happens in that development over time as the new immune system develops.

Expert hematologist-oncologists provide insight on major risk factors for GVHD and associated challenges for treatment.

Risk Factors for GVHD

 My feeling about how to intervene for both of these diseases is that for acute GVHD [graft-vs-host disease]—that initial recognition of the antigen and the expansion of the donor T cells—if you want to prevent severe GVHD, you’ve got to intervene relatively early, not late. For chronic GVHD, the initial defect is occurring early on. The stem cells that become T cells in the recipient are educated in the peripheral lymph nodes and the thymus of the recipient. Even though the thymus is involuted in adults, it still functions a little. That process of clonal deletion, peripheral tolerance, or central tolerance is abnormal because the cells that do that selection have been damaged.

What cells damage those? It turns out those are donor T cells. There’s a lot of evidence in the mouse that the cells that damage the organs, which are responsible for differentiating stem cells into T cells and proper clonal deletion, are the T cells of the donor. You have to prevent the donor T cells from damaging those specialized tissues in the thymus and the peripheral lymph nodes of the recipients. Otherwise, the stem cells that come into the recipient are going to be made, and a lot of autoreactive T cells are going to come out the back end. They’re going to engage B cells, and you’re going to get this autoreactivity and alloreactivity, which we define as chronic GVHD.

My bias is that all these treatments to intervene late in the process of these diseases can only keep a lid on something that’s already 90% out of the bag. That’s the best we can do. That’s what we see in a lot of these treatments. They modify the disease but don’t prevent the disease. If you want to prevent it, you might have to start thinking about earlier interventions. That’s been my pet peeve with testing a lot of the reagents in GVHD. We give them too late, and they have a very minor temporizing effect. With earlier treatments, they may have a bigger effect.

The problem with earlier treatments is people worry that that would result in a reduction in graft-vs-leukemia. That can be tested only in randomized clinical trials.

Dr John DiPersio discusses an early intervention approach to the management of chronic and acute GVHD.

Role of Early Intervention in GVHD Treatment

My name is John DiPersio, and I’m from Washington University School of Medicine in St. Louis, Missouri, and I’m the chief of the division of oncology and the deputy director of the Siteman Cancer Center at Washington University. I’m going to be working with my colleague Mike Bishop from The University of Chicago Pritzker School of Medicine. He’s the head of the transplant and cellular therapies program at the University of Chicago.

We’re going to be discussing some of our viewpoints of diagnosis and management of acute and chronic graft-vs-host disease [GVHD]. As an introduction, for those of you who take care of patients who are undergoing transplantation, and those of you who have referred patients to transplant centers, you’ve had the opportunity to see how complicated and devastating graft-vs-host disease can be. You’ve probably also been exposed to a number of relatively new treatments that have emerged over the past several years for the management of both acute and chronic graft-vs-host disease.

The way I would describe graft-vs-host disease is that it’s a disease in which the donor T cells recognize host antigens as nonself. When you think about it, what’s the recognition? The recognition is that donor T cells must see some antigen expressed on host tissues that’s different from what that donor T-cell has been developed to see itself. That usually means it’s a different HLA [human leukocyte antigen] antigen and a different minor histocompatibility antigen. Or it’s simply a different minor histocompatibility antigen where the donor and recipient are matched so that the sequence of the HLA of the donor and recipient are the same, and the recipients express a host antigen that’s recognized by the donor T cells. That host antigen is expressed in the context of host HLA, either class 1 or 2.

That minor histocompatibility antigen could be a single nucleotypic polymorphism from any protein— beta-2 microglobulin, albumin. We all have different SNPs [single nucleotide polymorphisms] that we’re born with that are encoded in chromosomes, aside from the chromosomes, and encode the HLA locus, and these protein-specific differences are unique to each of us. Even though you may have a match sib that’s a DNA identical to you at the HLA locus, the minor histocompatibility antigens will be different, and they can be presented in the context of antigen-presenting cells of the host so that the T cells of the donor can recognize them and cause a reaction that results in graft-vs-host disease.

There are many theories about which T cell is the most important and which T cells contribute most of the pathology of acute graft-vs-host disease. To simplify it, acute GVHD is best defined as this allogeneic reaction—donor T cells reacting against host, major and minor histocompatibility antigens in which the T cells are contributing to the illness.

With chronic GVHD, these are passively transferred T cells that have already seen antigen and are primed in the donor. They can see these antigens in the host as nonself. Chronic GVHD is due to T cells again, but instead of coming from the donor T cells, they come from donor stem cells. Normally, when you do a transplant—in a mouse, for instance—the stem cells become T cells. But when they become T cells, they lose their ability to recognize self-antigens. In a recipient animal, those allogeneic-reactive T cells are deleted. It’s called clonal deletion, central deletion, or anergy.

In the context of chronic GVHD, what we think is happening is that some T cells that are normally deleted to the host antigens leak out. They leak out over time. The T cells that are generated from the host, from the donor stem cells, engage B cells and induce this B-cell reaction. You have B-cell proliferation, B-cell activation, and the production of antibodies. Some of those antibodies can result in antibodies that bind to host tissues and cause disease.

To simplify that, acute GVHD—whether it happens a week after transplant, a month after transplant, or 3 years after transplant—is due to the maturity cells that come from the donor graft. Initially, chronic GVHD is due to the T cells that are leaking out of the host from the donor stem cells that are not appropriately clonally deleted. Those T cells recognize a host as nonself, and they engage B-cells, and you get this combined effect of T-cell reactivity and B-cell reactivity, and you get a disease called chronic GVHD. If it’s mostly B cells, autoimmune B cells, and autoimmune antibodies, you get a very pure B-cell–appearing disease like scleroderma, or a patient who has a mixed connective tissue disease.

If you have more of an inflammatory component, it’s mostly because of T cells that are still around. That’s what’s called an overlap syndrome. An overlap syndrome would be somebody who has a bit of acute GVHD from residual donor T cells that are still reacting to host APCs [antigen-presenting cells] and minor histocompatibility antigen. These new T cells from the donor stem cells are improperly clonally deleted and are autoreactive that engage B cells, and you have this mixed T-cell alloreactivity and B-cell autoreactivity, so you get this mixed overlap syndrome.

That’s the way chronic GVHD and acute GVHD work. We’ve never worked this out completely in humans, but through a number of experimental models in the mouse, this is the best model to think of the physiology of acute and chronic GVHD. When you see someone a year after transplant, and they look perfect, you taper their immunosuppression. They get a very red rash and some diarrhea from those donor T cells that came in from the graft initially and stuck around all that time and were reactivated.

But if someone has an esophageal dysplasia or pulmonary toxicity, that’s most likely because of T cells developed from the stem cells of the donor in the peripheral lymph nodes in the thymus of the recipient, which are improperly clonally deleted and so they engage B cells. The B cells make antibodies, and you get this disease, which is akin to either a mixed connective tissue disease or a sclerodermatous-like illness. That’s chronic GVHD.

John DiPersio, MD, PhD, and Michael Bishop, MD, define acute and chronic graft-vs-host disease (GVHD).

Overview of Graft vs Host Disease (GVHD)

Michael Bishop, MD, a professor of medicine and director of Hematopoietic Stem Cell Transplantation Program at The University of Chicago Medicine, discusses the different settings where chimeric antigen receptor (CAR) T-cell therapy are used.

Bishop thinks CAR T-cell therapy made a significant impact upon patient care. CAR T cells are indicated for 3 main groups of patients. The first is for non-Hodgkin lymphoma and for pediatric and young adult acute lymphoblastic leukemia (ALL), which has FDA-approved agents. More recent approvals have been for patients with mantle cell lymphoma. Physicians are waiting for what they expect to be the first indication for CAR T-cell therapy in multiple myeloma.

Starting with ALL for the pediatric population, CAR T cells have been a game changer, according to Bishop. These young patients have median overall survivals of less than 6 months, but the high response rates with CAR T are enabling them to potentially go on to an allogeneic stem cell transplant and in some cases, be free of disease.

In the non-Hodgkin lymphoma setting, there are now 3 products indicated for advanced B-cell non-Hodgkin lymphoma, which is significant for patients with totally refractory disease. There is this therapeutic option that is potentially curative. Bishop says investigators are seeing patients out to 5 years without any further therapy after receiving CAR T cells.

Michael Bishop, MD, discusses the different settings where chimeric antigen receptor T-cell therapy are used.

CAR T Cells Have Reshaped the Hematologic Cancer Landscape

Michael Bishop, MD, a professor of medicine and director of Hematopoietic Stem Cell Transplantation Program at The University of Chicago Medicine, discusses the investigations of and responses to chimeric antigen receptor (CAR) T-cell therapy in different disease types.

One of the settings furthest along in exploring the use of CAR T cells is non-Hodgkin lymphoma, with about 40% to 50% patients are achieving sustainable complete responses with CAR T-cell therapy. There are still significant areas that can be improved upon for this patient population, according to Bishop.

Another disease type where there is potential opportunity to use CAR T cells is acute lymphoblastic leukemia. Bishop says there has been success for children in this setting, and now there is study for adults that will be reporting out soon called the ZUMA-3 trial (NCT02614066), which investigated brexucabtagene autoleucel (KTE-X19). Other studies are looking at the use of allogeneic CAR T-cell therapy in patients with acute lymphoblastic leukemia.

There are also trials in multiple myeloma looking at CAR T-cell therapy. Bishop feels the results for this patient population appear to be very exciting, with higher and more sustained complete response rates, and there is an opportunity to further improve upon those results.

Michael Bishop, MD, discusses the investigations of and responses to chimeric antigen receptor T-cell therapy in different disease types. 

Michael Bishop, MD | Authors

Articles

Frontline Management of GVHD

Risk Factors for GVHD

Role of Early Intervention in GVHD Treatment

Overview of Graft vs Host Disease (GVHD)

CAR T Cells Have Reshaped the Hematologic Cancer Landscape

Investigating CAR T-Cell Therapy for Use in Different Disease Types