Inborn Errors of Immunity in LGL Leukemia

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Jar Maciejewski, Chair of the Translational Hematology and Oncology Research Department. He was previously a guest on this podcast to discuss bone marrow failure and cytopenias program, and that episode is still available for you to listen to. He's here today to talk about inborn errors of immunity that underlie clonal T-cell expansion and large granular lymphocyte leukemia. So, welcome back.

Jaroslaw P. Maciejewski MD, PhD: Oh, thank you very much, thank you for the invitation.

Dale Shepard, MD, PhD: So, remind us a little bit about what you do here at Cleveland Clinic.

Jaroslaw P. Maciejewski MD, PhD: Well, essentially, I see patients and physician scientists who has laboratory and program in genetics, and these days you cannot be specialists in everything, even in hematology, within this, we have people who see my, if you wish, shtick is bone marrow failure. And it can be seen in broader or in narrower terms. Usually bone marrow failure is seen in the context of pediatric disease, but indeed adults have bone marrow failure, and in fact, myelodysplastic syndrome, which is disease on the borderline between bone marrow failure and leukemia, by many is considered a bone marrow failure as a primary, depending who is speaking, and to whom, and what is the purpose of a particular application. So, immune bone marrow failure or bone marrow failures in adults, we are talking about acquired bone marrow failures, are essentially immune-mediated, and the question is only what is the mechanism of this particular group of diseases?

And I think in general, most of them are mediated by T-cells. And one of the very unique forms of bone marrow failure is large granular lymphocytic leukemia, which has this model character, because in this, if you wish, glorified lymphoma, but essentially it's a clonal expansion of cytotoxic T-cells, we have a lot of cytopenias that are immune-mediated. And despite of a lot of laboratory work, the best evidence that this is an immune disease is that when we apply immunosuppression, we can achieve remissions. So, this is a pretty good. You know, we try to be more rational over years, since the laboratory, but still the reason we know that most of the idiopathic aplastic anemia or LGL is immune-mediated disease is because we have success of immunosuppressive agents. But if you have something that is mediated by immune system, everybody thinks that it's due to hyperreactivity, right?

A sort of allergy, if you wish, but mediated by T-cells. And so, the whole line of investigation for the last 30 years was to find the hyperimmune trait, a sort of hyperresponsiveness. But more and more, we realized through genetic studies mainly is that, it might be the opposite, and in fact, many of the autoimmune diseases stem from maladaptive compensation of immune deficient trait, which are referred to inborn errors of immunity. And the way it generally works is that, let's say if we have a defect to clear a particular pathogen because of mild production of antibodies, then the other branch of immune system, non-cellular immune system, steps in, and it's overreacting or overcompensating, producing the disease. And this is how we envision pathogenesis of LGL leukemia, which is essentially a lymphoma of cytotoxic T-cells, that originally we have an unclear infection and the stimulus to produce clonal responses that eliminate this particular trigger persist so the proliferation at certain point become autonomous.

So, but you ask why this infection persists? And here is the key, it's not because they have a hyperimmune trait, because in this case, we would delete the antigen, it's an inability to clear the autoantigens and therefore you have a persistent T-cell response that leads into all this adverse reaction. So, in this particular paper, we noticed that a lot of patients with LGL leukemia have either hypoglobulinemia, have hypo IGA, or have other defects. And then when we systematically then sequence these patients for the presence of this, we realize that these are not necessarily hyperimmune traits, but the hypo-immune rate, this proverbial inborn error of immunity, are extremely prevalent in this group of patients. So, you would ask, why do you find them in older folks and not in kids? Because mainly these are very weak genetic traits. So, these could be carriers of otherwise recessive traits, and we think that the recessivity is defined based on presentation in childhood, but the carrier actually is not free of risk. As sort of like in BRCA2, right?

That while we think that the presence of LGL is protective, how do we know whether it's protective in somebody who 30 years later get leukemia? Maybe he wouldn't have gotten the disease or the breast cancer or so on. So, these are often recessive traits, or these are dominant traits or diseases mediated by dominant traits, but atypical variants. So, not the canonical variants that produce severe disease in childhood, but genetic variants that it takes extremely long time, if you wish, to percolate.

Dale Shepard, MD, PhD: Are there particular gene abnormalities that you found or were there some that you were more surprised to find than others?

Jaroslaw P. Maciejewski MD, PhD: Yeah. The presence of traits that lead to hypoglobulinemia is one, but also short telomeres is another group of interesting, if you wish, hypomorphic inborn error of metabolism. Yeah. So, these are these type of otherwise subtle defects that we detected, and we, sort of demonstrated that these are the ones why the actual T-cell responses overshooting. So, there are many of them and they are by themselves individually not that common, but if you add them together as a group, this explains a big chunk of LGL leukemia.

Dale Shepard, MD, PhD: Can that change the way we think about treatment because the response... So, essentially, we've now found a trigger for why you have the excess, or like you say, hyperimmune condition, but are there ways we can go back and try to fix those abnormalities?

Jaroslaw P. Maciejewski MD, PhD: Well, I think that this is unfortunately therapeutically histrionic relationship between immunosuppression when needed and actually trying to boost the immune system. And one way of doing it, the easiest way, the 100-year-old way is to infuse immunoglobulins. So, in many of this patient, we notice that after immunosuppression didn't work, what happened is the immunoglobulins, when infused, cleared the defect because they helped to eliminate the antigen, and therefore there was not a second trigger for the T-cell expansion to persist. So, I think we have to be judicious and in certain circumstances, it might be smart not to additionally immunosuppress, but in fact, boost the immunity, which seems at the first glance counterintuitive.

Dale Shepard, MD, PhD: So, take away the trigger for the...

Jaroslaw P. Maciejewski MD, PhD: Yes, yes.

Dale Shepard, MD, PhD: ... reason for the hyperimmune system.

Jaroslaw P. Maciejewski MD, PhD: Yes. If we assume that, for example, a certain antibody response is needed to bind the antigen and then eliminate it via ADCC, right? And this antibody is missing, but would be present in polyclonal immunoglobulin, then we provided, we sort of bypass this defect, and helps the cellular immune system, such as NK cell and T-cells to eliminate the antigen, and therefore the trigger does not persist.

Dale Shepard, MD, PhD: Are there other hematologic malignancies where we think this might be a factor?

Jaroslaw P. Maciejewski MD, PhD: Well, the interesting part is that, if you wish, LGL leukemia is like natural CAR T-cells. In the context of solid tumors or certain leukemias, patients who have LGL have actually better outcomes. If you wish, the LGL clones are these guardians or hyperreactive immune police, similarly to CAR T-cells, it's just they are natural. And in these cases, the prognosis of corresponding neoplasm might be better as long as the LGL persists. But obviously at certain point, they either wear out or there is an immune escape. And this is an important lesson of LGL leukemia, is that if otherwise patient is asymptomatic, don't treat it like a lymphoma, less is better. So, if the hands are forced because of pervasive anemia or cytopenia, we treat them, but otherwise they might be there for a reason. They see something you don't see as a doctor with a CT scan or with laboratory test. They sniff out bad guys or viral infection, but in case of tumors, this might be early evolving cancers.

Dale Shepard, MD, PhD: What did you find related to STAT3, which has been shown to be important I guess in this?

Jaroslaw P. Maciejewski MD, PhD: STAT3 is an old story. STAT3 is a very important transcription factor, if you wish, that characterize certain groups of lymphoma. And early on, our group together in collaboration with the Finnish group published in New England Journal of Medicine, that's STAT3, canonical STAT3 gain of function mutation are present in LGL. So, the LGL has been defined by the presence of STAT3 mutation. Now, as usual, things are more complicated than they seem. So, the STAT3 mutation characterize LGL, but there are some LGLs that don't have mutations. And we believe that this is this continuum whereby polyclonal immune response becomes clonally skewed and eventually the most pervasive clone is, if you wish, solidified in its persistence by acquisition of STAT3 or STAT5 mutations.

So, diagnostically speaking, STAT3 and STAT5 mutation essentially makes a diagnosis in this context of LGL leukemia. And again, not all LGL leukemia have it, but if you will see it, it's definitely stat three. It does not negate the fact that the original trigger to it was this hyperresponsiveness. If you wish, if you compare it, let's say with colon cancer, where you have the polyps, or you have colitis with a polyclonal stimulation and inflammation, and then there is a narrowing and focusing of the clonal responses to the most pervasive, in the case of colon cancers, this would be an escape of colon cancer cells from the control of immune system based on constant pressure.

And here it's a similar story, that you have a constant stimulation and these clone acquire gain of function of STAT5 mutation in order to persist. Now, prognostically, it's not that important because we and others have shown, following these original pivotal papers approximately 10 years ago, that they are treatable similar way as the other, but the importance is in understanding the pathophysiology of it and the fact that it helps you tremendously in cases where you are not certain. Is it actually LGL leukemia or is it a response to EBV or some other virus, right? And when we find stat three mutations, it's totally clear that this is already at the stage of a clonal disease. So, if you wish low grade lymphoma.

Dale Shepard, MD, PhD: If by identifying these inborn errors, is it possible to come up with a way to predict who might develop an LGL leukemia, do some intervention? Is there something we can do to try to be more mindful and get ahead of things?

Jaroslaw P. Maciejewski MD, PhD: Well, it's a model disease and the age of presentation of LGL leukemia is 60s and 70s, but of course this original information in this fairly well-defined entity led us to pose the same hypothesis in other bone marrow failure syndrome, and the most important of them being idiopathic aplastic anemia. And here again, 100 years of looking for the antigen, which was unsuccessful, and hyperactive genes led us to find out that they are hyperreactive genes. Now, so what are the consequences therapeutically? Of course, it might help us to identify what triggers the original reaction in the first place. So, in order to acquire this disease, which is not endemic and not familiar, but might have triggers that are extraneous, and genetic background, maybe not Mendelian, you have to sort of identify two things. So, patients ask very much questions, and this is every oncologist gets these questions, I get this question as well with leukemias, why did I get it?

And in aplastic anemia, in LGL leukemia and other immune-mediated bone marrow failure is this unfortunate, you know, circumstance where two rare events came together. So, people who have this immune predisposition might go along for a long time and not having anything, in fact, most of them will never have aplastic anemia or LGL leukemia. But in addition to it, if they find this, if they encounter this particular antigen, whether it's a virus or some other pathogen or chemical, then both of these factors explains why these diseases are not common because you have to fulfill two criteria, and in addition to it, it tells you that I would like to know what it is to avoid. Now, on the upside of it is, that this particular trigger, if encountered by you and me, who are not carrier of this genetic, if you wish, trait, it's probably totally benign. So, you need to fulfill sort of a double criteria, but once we know one, then we are going, of course, to focus in this group of patient of what, in addition to immunodeficiency now triggers this hyperreactive response of cellular immune system that is responsible for the damage.

Dale Shepard, MD, PhD: So, you found the first hit. We just don't know what that second hit is.

Jaroslaw P. Maciejewski MD, PhD: The second hit is a problem to find, and you know there are ways to approach it. Needless to say, I'm trying to find it for the 30 years, but there are people who are older in me in this business, so I am not feeling particularly bad about it. But I think this is an important step to see that in these patients... And it's a sort of you know surprising why we didn't come up with this sooner. If somebody has immunodeficiencies and it predisposes him to irregular response to something that otherwise might be benign. So, now we have to look what it could be. Right? And you know this is a subject of work in the laboratory. In terms of the clinic it's that boosting immune system with things like immunoglobulins might be a good idea, in patient refractory to immunosuppression, so you need both. You need to remove the trigger or help to remove the trigger, and if you wish tame the hyperactive immune response.

Dale Shepard, MD, PhD: Well, certainly it's a complex mechanism and you've made an important contribution to sort it out.

Jaroslaw P. Maciejewski MD, PhD: 30 years, yeah.

Dale Shepard, MD, PhD: So, appreciate you joining us and giving us your insights.

Jaroslaw P. Maciejewski MD, PhD: No, thank you very much. Thank you for the invitation.

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