Managing HIV- and Natalizumab-Associated PML

Dr. Justin Abbatemarco talks with Dr. Irene Cortese about recent advances in the treatment of progressive multifocal leukoencephalopathy (PML), focusing on immune-based therapies like virus-specific T cells and immune checkpoint inhibitors.

Read the related article in The New England Journal of Medicine.

Disclosures can be found at Neurology.org.

Show transcript:

Dr. José Merino: This is José Merino, editor-in-chief of the Neurology Family of Journals. The Neurology Podcast provides practical information to neurologists and other clinicians to help them provide better care for their patients. Thanks for listening, and have a great week.

Dr. Justin Abbatemarco: Hello and welcome. This is Justin Abbatemarco with the Cleveland Clinic here with Irene Cortese to discuss an update on progressive multifocal leukoencephalopathy treatment in light of a New England Journal of Medicine correspondence, Resolution of PML After Treatment with Virus-Specific T Cells and HCT. Irene directs the Experimental Immunotherapeutics Unit at NINDS. Hello and welcome.

Dr. Irene Cortese: Hi, thank you for the invitation to join you today.

Dr. Justin Abbatemarco: It's a pleasure to have you on and to talk about this expanding space in rare disease. And maybe if we could start off, can we just take an overview on how PML usually presents and why does it remain so difficult to treat?

Dr. Irene Cortese: PML, or progressive multifocal leukoencephalopathy, is an opportunistic infection of the brain that is caused by the JC virus. And most of us carry this virus lifelong and without any symptoms, and it really only causes disease when the immune system is significantly compromised and loses the ability to keep it in check. And so when that happens, the virus can gain the ability to infect oligodendrocytes, and this can lead to the rapidly progressive demyelinating infection called PML. These lesions that develop in PML are typically located in the white matter, and they are most often multifocal. And this leads to the clinical manifestation of a combination of cortical and subcortical symptoms that evolve over weeks to months. And, unfortunately, if immune competence can't be restored quickly, then the disease is fatal within just a few months. And so that's really the core of the problem here, is that there is no effective direct antiviral treatment. And the only thing that works is restoring the immune system ability to control it, but that's often very difficult to do. When it's even possible, it's frequently just not even fast enough. And so you can see this even in situations where you'd think that we'd have an advantage, for example, in HIV-associated PML, where we do have effective antiretroviral therapy. Even there, restoring immune competence can sometimes just take too long relative to how quickly PML progresses. And so on top of all that, PML is really quite rare and is also remarkably heterogeneous because it can occur in very different patient populations from HIV to hematological malignancy to genetic immune deficiencies. And this rarity and heterogeneity really make both the diagnosis difficult and also treatment development quite difficult.

Dr. Justin Abbatemarco: It's such a interesting story, and these different backgrounds really present different challenges. But at these last few years, this has been a success story in some way because we've seen so much effort and research into this rare disease space, which is encouraging. We mentioned this at the top, but there are immune checkpoint inhibitors that have at least been trialed for this T cell exhaustion to see if we can boost the immune system, and then more recently with your work around allogeneic-specific T cells to help clear the infection. What have you taken away from those updates?

Dr. Irene Cortese: The biggest takeaway is that these two approaches, checkpoint inhibitors and Virus-Specific T Cells, have really transformed the way that we think about PML. So for decades, our only option was really to try to reverse the underlying immune suppressive condition and just hope that the immune system caught up in time. And now we have these two active strategies to try to speed this process up. Importantly, both these strategies have validated the same core hypothesis that even without a direct antiviral agent, we can improve PML outcomes by restoring effective antiviral immunity. And that said, each of these approaches has real limitations. So first of all, they don't work in all patients. And we have best estimates of success rates somewhere in the 50 to 60% range overall. With checkpoint inhibitors, the fundamental issue is that you're trying to unleash an immune response that has to already be there in some latent or exhausted form. For example, in patients with very advanced immune compromise where the T-cell compartment is essentially absent, there's just nothing left to invigorate, and so checkpoint blockade is really unlikely to help. And even when they do work, there is a real risk of exacerbating underlying autoimmune disease as well as the risk of leading to immune reconstitution inflammatory syndrome, or IRIS, where inflammation in the central nervous system of this immune system waking up and attacking the infection can actually lead to severe morbidity and even death in some patients. Virus-Specific T Cells have a whole different set of limitations. These are mostly practical and logistical at this point. Access is really the big one because there are only a handful of centers worldwide that can manufacture Virus-Specific T Cells. And so this just isn't something you can easily do everywhere or quickly. And also, biologically, every virus-specific T-cell product which is made from a different donor is essentially a different drug. And so it's really hard to predict how any given cell product will actually behave in a given patient. I should also mention that for both these approaches, they truly are still experimental. We don't have any controlled studies, and so most of what we're working from is really retrospective series and case reports. And we definitely have no head-to-head data. And so while we apply general principles estimating residual immune capacity or weighing the risk of exacerbating immune-mediated adverse events, we're really making individualized judgment calls rather than following an evidence-based algorithm.

Dr. Justin Abbatemarco: And could you talk about those Virus-Specific T Cells? It's not something we use commonly in neurology. How do those work? And have they been used in other spaces successfully that we've been able to maybe apply some of those principles here?

Dr. Irene Cortese: Yeah. So Virus-Specific T Cells were really first developed in the transplant setting, and they were essentially a way to bridge patients immediately following myeloablation. And in the period of time it took them to fully immune reconstitute a brand new immune system, it was a way to protect them from the common viral infections mostly that can develop in this time period and that led to such high morbidity and even mortality. And so the way this is done is that you basically take healthy lymphocytes from a healthy donor, and you can train them in vitro by ex vivo expansion and stimulation to basically become professional killers of the particular virus of interest so that, at the end of this expansion period, you basically have a enriched antiviral product that can be adoptively transferred to the patient recipient. And they may not last for a very long time, however, they can, especially with repeated infusions, provide the necessary immunity to bridge until definitive immune reconstitution is achieved. And so the initial experience with Virus-Specific T Cells was really against the various viruses that are so common in the post-transplant setting, like CMV, EBV, adenovirus, and also BK virus, which is a cousin, let's say, of the JC virus. And over time, the process for manufacturing Virus-Specific T Cells has become more and more streamlined. And so back as in 2015, 2017, we started to realize that perhaps these types of cell products might even be used to treat an acute infection and not just to administer in the setting of a planned transplant. And so essentially we've done exactly this, basically copied these manufacturing methods from the transplant world to make Virus-Specific T Cells against the JC virus and can then use them to treat PML. I should mention that BK virus is very similar in structure to the JC virus. And for that reason, what we learned early on when we started to apply Virus-Specific T Cells to the treatment of PML was that we could actually use Virus-Specific T Cells that were made against BK virus and successfully treat PML. More recent years, groups have been manufacturing JC virus-specific BST, but those BK Virus-Specific T Cells can still be used to treat PML.

Dr. Justin Abbatemarco: That's really incredible. And it's so cool when we borrow things from these other fields to help inform rare diseases within neurology space. Maybe it's a perfect segue into the cases report in New England Journal of Medicine where you had two cases with inborn errors of immunity. You've utilized the strategy and then stem cell transplant. Walk us through those cases. What did you see? What did we learn from these that we can apply more broadly?

Dr. Irene Cortese: Our paper really told the story of our experience of treating these two young men. Both of them had developed PML in the setting of an inborn error of immunity. One of them had DOCK8 deficiency, and he also had Sézary syndrome as a comorbid condition. And the second patient had a CD40 ligand deficiency. And for both these patients, we basically adopted the same strategy, which was to first try to gain control of the JC viral infection. And once that infection was actually under control, then we went ahead and proceeded to definitive treatment of their underlying genetic immune deficiency, which was transplant in their setting to correct the real root problem that they had. And what I think was perhaps most instructive in this experience is what happened after transplant in both cases. So transplant obviously involves a period of renewed immune vulnerability, and that's exactly when we feared that the PML might come back, even though we had been able to gain control, at least temporarily, using this adoptive transfer Virus-Specific T Cells. Fortunately, in these two cases, that didn't happen. And in fact, patient one actually developed IRIS shortly after engrafting with worsening neurological symptoms and also imaging that showed active inflammation, which responded well to steroids. And he's now years out with no evidence of PML or his prior malignancy, which was also treated by the transplant. The second patient's course was complicated by cryptogenic organizing pneumonia, or COP, which can happen in the post-transplant setting, and did require steroids. And this did cause a transient uptick in the JC viral copy number in the spinal fluid, but this resolved once the steroids were tapered. And this patient also is now several years out with only mild residual neurological deficits. So it's important that for both these patients, the transplant donors, in addition to undergoing collection for the transplant itself, they also underwent a collection to make extra rescue Virus-Specific T-Cell products that we had on hand just in case the PML relapsed post-transplant, which of course was not, in the end, needed. And so basically, the overall strategy for both these patients was sequential and deliberate. First to establish virus-specific immune control, and only then proceeding to the definitive but higher risk step of transplant with the safety net available in case virus reactivated during that post-transplant period.

Dr. Justin Abbatemarco: The complexity of these cases, though, and the successful outcome is just incredible. And again, we don't always treat these level of patients, but most neurologists will see PML during their career. How do you think this helps inform this broader field of PML treatment in your mind?

Dr. Irene Cortese: For me, these two cases really crystallized the idea of immune facilitation as a bridge rather than as a standalone endpoint. For example, in these two patients, Virus-Specific T Cells could not have led to a definitive cure because the underlying immune defect was still there, but they could buy time and control the virus long enough to get to something that could actually fix the underlying problem, which in this case was the transplant. And I'll be honest, proceeding to transplant in a patient with active or recent PML was really frightening. And clearly that is not an option or appropriate at all for the majority of patients with PML. So I guess that the broader lesson here is that Virus-Specific T Cells or potentially other immune-facilitating strategies might serve as a bridge to get us to the point where we either have a way to address that root cause of immune suppression or just buy us the time needed to recover from immune suppressive exposures and perhaps opens up the question of how we might use sequential strategies and combinations of strategies to optimize the care of these patients.

Dr. Justin Abbatemarco: Really appreciate your paradigm of how you think about these cases in treatment, and yet you can have these short-term strategies to bridge patients to have an improved immune response to get this under control. Could we talk about other common examples? So we have natalizumab-induced PML cases, HIV-associated PML cases. How would you think about managing those, so outside of these inborn errors of immunity?

Dr. Irene Cortese: Each PML patient is somewhat unique, and definitely the underlying condition that is driving the immune suppressed state is really critical in mapping out what we need to do. I think of HIV-associated PML or even natalizumab-related PML as being somewhat unique. Because unlike most other causes of PML, we actually do have clear and reliable ways to restore immune competence, so basically antiretroviral therapy in HIV infection or simply discontinuing the non-immune-depleting drug natalizumab in the case of natalizumab-related PML. And so this is obviously a real advantage compared to many of the other underlying conditions where there really is no good way to reverse that immune suppression at all. That said, in some patients, for example, with advanced AIDS and very low CD4 counts, immune reconstitution can still be very slow even when the HIV replication itself is well controlled. And so in a subset of patients, the PML can still really pace the recovery. And so we do sometimes need strategies to bridge that gap. And basically. we would consider the same immune restoration approaches that we've been talking about right now. There is an added layer of complexity here that's a bit more, let's say, unique to HIV-related PML or to the setting of natalizumab-related PML, which is that in both these cases, immune reconstitution is going to happen eventually. And when it does, then many of those patients do experience PML IRIS where the constituting immune response paradoxically worsens the neurological injury by attacking the infected tissue. And so this really needs to be watched for and managed typically with steroids. And certainly this risk of developing PML IRIS needs to be really considered if we are going to use strategies to boost or facilitate immune reconstitution in the setting of HIV infection or natalizumab-related PML. And we just have to be particularly mindful because there's already a very high likelihood of developing PML IRIS independently of getting that extra boost. Comparatively, in the setting of non-HIV-related PML or not in the setting of natilizumab treatment, I think that strategies like checkpoint inhibition and Virus-Specific T Cells have really been game-changing because, historically, these patients had no equivalent to antiretroviral therapy with no reliable path to reconstituting immunity. And we're really hoping that these approaches will start to bring the outcomes that we've seen, for example, among HIV-related PML and in the setting of natalizumab and PML to these other underlying conditions and achieve the same immune control and survival rates that are achieved in at least a substantial portion of these patients.

Dr. Justin Abbatemarco: It's been so exciting. Again, the updates in this field when we really did... We had nothing to offer patients for so long and now to have conversations that are a little bit different. Can I ask you to peer around the corner? What does the future look like in your mind? Do you see other therapies that are potentially at play and maybe right now are there clinical trials that we could enroll patients so that we can help inform the field more broadly?

Dr. Irene Cortese: Yeah. So I think that ways to facilitate and accelerate immune reconstitution have clearly been shown to be a valid strategy. And so what I expect and hope is that in the years to come, we'll learn to harness that better and learn to identify which patients are most likely to respond to particular types of strategies to facilitate immune reconstitution. It's really important, I would say, that patients participate in trials because the field really does lack controlled data and it lacks head-to-head comparisons. And so every patient enrolled in a trial or a well-structured registry is really contributing to how the next patient gets treated. And given just how rare and heterogeneous PML is, we're just not going to advance this field through isolated case reports alone. And so we really do need patients and their physicians to be willing to participate in structured and collaborative research. The Holy Grail is, of course, a direct antiviral agent that would really broaden our ability to treat patients and potentially also continue to treat whatever that underlying condition was that led them to the risk of PML in the first place, so, for example, patients receiving treatment for cancer or patients having an autoimmune disease that requires immune suppression. And so I am hopeful that eventually the direct antiviral will be identified. And along that line, what I can mention is there are certainly clinical trials that are ongoing. At NIH, we have an active natural history study from where we can funnel patients into various experimental treatment strategies, including Virus-Specific T Cells or checkpoint inhibitors. Or right now, we actually do have an ongoing trial of intravenous brincidofovir as a possible direct antiviral strategy. What I hope for the future is that we will find ways to really collaborate and to form national as well as international consortia so that we can accelerate the development of these treatments.

Dr. Justin Abbatemarco: We have things we can do now, and then we can help inform care for our future patients as well. So these are great messages, and I can't thank you enough for coming on. Again, most of these developments have been under your guidance, and we appreciate your leadership in this space and helping to give us this insight into this really rare disease. For folks, they can check out the article. It's in the New England Journal of Medicine, Resolution of TML After Treatment with Virus-Specific T Cells and HCT. Irene, thank you for coming on.

Dr. Irene Cortese: Thank you so much.

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