Studying T-Cell Therapy for Potential Lung Tissue Repair with Benjamin Singer, MD

00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. For many patients with severe viral infections that damage their lungs, recovery can be long, difficult, and life-threatening. Current treatments for these patients are mostly supportive therapies, but Northwestern medicine scientists are investigating how to modify our bodies own regulatory T cells to be used as potential cellular therapy to repair damaged lung tissue after a viral infection. In a new study published in the Journal of Clinical Investigation, Northwestern Medicine scientists found a subset of laboratory modified T cells can promote the repair of lung tissue of mice with severe influenza pneumonia. Joining me to talk about this discovery is Northwestern Medicine physician scientist, Dr. Benjamin Singer. He is the senior author of this new paper and the vice chair for research in the Department of Medicine as well as the Lawrence Hicks, professor of Pulmonary Medicine and associate Professor in the division of Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine. Welcome to the show, Dr. Singer. 

[00:01:21] Benjamin Singer, MD: Thanks so much for having me. 

[00:01:23] Erin Spain, MS: Viral pneumonia was in the news quite a bit during the COVID-19 pandemic, so can you refresh our listeners' memories about what can happen to the lungs during viral pneumonia and what makes recovery so difficult? 

[00:01:35] Benjamin Singer, MD: Yeah, I think. Many listeners will remember the COVID to 19 pandemic very well, and the huge numbers of patients that we saw at Northwestern and across the world with severe viral pneumonia due to the virus. SARS-COV-2, but viral pneumonia broadly is something that in the ICU we are very familiar with. There's an epidemic of influenza virus pneumonia every year, and oftentimes we have seen pandemics of virus caused pneumonia due to influenza. And if you think back even in the 21st century, we have had multiple pandemics of viral pneumonia, including the 2009 Influenza Pandemic, the original SARS Viral Pneumonia Pandemic, the MERS Pandemic, and of course, SARS COV to two or COVID-19. 

[00:02:24] Erin Spain, MS: Talk about how these patients are treated today. It's mostly supportive therapies you're able to offer. 

[00:02:29] Benjamin Singer, MD: Yeah. When patients become very, very sick from viral pneumonia and they come into the ICU and need life support to sustain their bodies while their lungs and other organs heal, most of what we have to offer is just that. It's life support. We have a few medications that can help the body clear the virus. And we have very few options that calm down inflammation effectively and safely across viruses, and also have no therapies that we know of that help rebuild the damaged lung tissue. And really that's what we're interested in studying from a research perspective, is how can we help the body rebuild the damaged lung faster so that patients don't need life support for long periods of time. The reason that's important is because patients who require life support for long periods of time are very susceptible to complications. These can be new pneumonias that occur as a consequence of being on a mechanical ventilator. Other complications that can befall patients in the ICU. And we know that those complications are what drive the poor outcomes in patients with severe pneumonia. So again, the idea is if we can rebuild the lung faster, get patients off the mechanical ventilator, off of life support faster, we think that they're gonna do better. 

[00:03:49] Erin Spain, MS: And again, you're a physician scientist, so you're seeing these folks in the ICU. You're going back to the lab and informing your work. Through the patients that you treat. And I wanna talk a little bit about this paper that we're discussing today, and it focuses on regulatory T cells or Tregs. Explain them to me and the role that they play in healing and in human health. 

[00:04:10] Benjamin Singer, MD: Yeah, it's fortuitous that we scheduled the recording of this podcast today, uh, October 6th, 2025. 'Cause there was an announcement from the Nobel Prize Committee that the discovery of regulatory T cells is the topic of this year's Nobel Prize in physiology or medicines. Regulatory T cells are a kind of white blood cell that provides a. Counterbalance to the type of inflammatory cells that you might be more familiar with in terms of white blood cells. The analogy I like to think about with the core function of regulatory T cells is that they're a kind of traffic cop. So if traffic is in response to an infection or an injury or reacting against something that the immune system is overexuberant in reacting to, so this could be autoimmunity or reacting against an organ that's been transplanted. The regulatory T cells slow that traffic. They let the traffic pass at a rate that's healthy, but they dampen inflammation so that it doesn't cause undue damage when it's not. And that's really the core function of these regulatory T cells to regulate inflammation. 

[00:05:22] Erin Spain, MS: So one of the problems with these naturally occurring tregs is they're pretty scarce, right? Our body doesn't make many of them. Can you tell me about that? 

[00:05:30] Benjamin Singer, MD: Yeah. turns out that we don't have a huge number of them in our body, but they are essential. They're absolutely required. But as people think about using these cells as a. Therapy. So taking these cells from a donor and giving them as a transfusion to help calm down inflammation in the body, you need a lot of them. And so there are protocols to expand the T cells, the regulatory T cells, from a donor, but those protocols can take awhile, they can take weeks, to get a dose. And if so, if we wanted to use them for pneumonia, we need a different way to think about them. 

[00:06:07] Erin Spain, MS: Okay. So that leads us to the paper today, you and your team decided to create induced regulatory T-cells, or I Tregs in the lab. So tell me about this experiment and how these induced. Treg cells are different from the naturally occurring tregs. 

[00:06:22] Benjamin Singer, MD: Yeah, so there are existing protocols to take conventional T-cells. So these are regular T cells. They're not regulatory T cells. Put them in a dish in the laboratory and treat them with a cocktail of molecules. These are a specific set of. Cytokines that have been worked out by other investigators to take those conventional T cells and turn them into a cell that looks somewhat like a regulatory T cell that you might find naturally occurring in the body. And our question was, could we use these cells? As a therapeutic, could we make a model of pneumonia, in this case, influenza in mice? Could we make that infection better? Could we help the lung repair faster by giving these induced regulatory T cells that we can generate very quickly, just in a few days, and model, uh, what we might one day be able to do in patients. 

[00:07:18] Erin Spain, MS: So you transplanted these iTregs into the infected mice, and you were paying close attention to a molecular key called UHR F1. What is UHR F1 and why was your team so interested in investigating this? Why does it matter for IT regs? 

[00:07:34] Benjamin Singer, MD: One of the main concerns about taking a conventional T cell and turning it into an ITT reg or an induced regulatory T cell. Is that it might not be stable, meaning that it could turn back into a conventional T-cell and paradoxically promote inflammation rather than suppressing inflammation. And so what we wanted to do in this study was try to understand the determinants of induced treg stability, meaning what helps them stay an IT reg. And we had previously identified that this molecule that you mentioned called UHR F1 is needed by natural tregs, the tregs that are found naturally in the body for them to maintain their own, uh, stability. And so we wanted to know whether it regs had the same requirement. UHR F1 is a molecule that's known as an epigenetic regulator. So epigenetics is a broad field of study where we think about how modifications to the way that DNA is packaged in the cell translates into cell identity. And what UHR F1 does is help maintain that epigenetic signature in cells that are rapidly dividing like regulatory T cells as they enter the body. 

[00:08:49] Erin Spain, MS: So you actually gave some of the mice IT regs with and some without UHR F1. What was the difference there? What did you see? 

[00:08:56] Benjamin Singer, MD: Yeah, what we found is that the Tregs that lacked UHR F1 didn't make it to the lung very well. They were unable to home to the lung. And once they made it to the lung, again, these were the lungs of mice that had been infected with influenza, with influenza pneumonia. They didn't function well. They looked a bit more like conventional T cells. They had lost that IT reg good beneficial identity. And so we think that UHR F1 is a determinant of their ability to get to the lung and function once the cells are there. 

[00:09:32] Erin Spain, MS: So now, does this research offer some new pathways for you to improve iTregs and make them more effective going forward? 

[00:09:39] Benjamin Singer, MD: We think so. So there have been experimental protocols to administer natural tregs to patients with a variety of diseases, including to promote tolerance to organ transplants too. Suppress inflammation in patients with autoimmune diseases or, uh, graft versus host disease. And the idea is that we might be able to use it regs for similar types of indications. Here we're interested in, in using them for, treatment of severe lung injury due to pneumonia. Some of these molecular features that we've identified, like their epigenetic state, the Urf one mediated epigenetic state, we think does offer a target to promote the stability and ideally the function of these cells so that once we administer them to a patient, perhaps one day we could have a little bit more ability to, uh, enhance their ability to heal. 

[00:10:35] Erin Spain, MS: This was a proof of concept paper, like you mentioned. Yeah, this was in a mouse model, but people are always very interested in this next step. How do we get it to patients? So what do you see as the path forward in the next five to 10 years? 

[00:10:46] Benjamin Singer, MD: I think the next steps are learning a bit more about the basic biology of these cells, and that will come through techniques in the laboratory. And then I think building up the groundwork. To think about what it would take to start a clinical trial, so what it would take to design a clinical trial of giving these cells to patients. There have already been small clinical trials of administering natural regulatory T cells, uh, to patients with severe viral pneumonia. So this isn't too much of a reach. I think one, uh, important detail as we were talking about the patients on the ventilator who have this persistent damage to their lung after pneumonia, and we don't have a therapy that can promote the recovery of the lung by rebuilding the lung through a process of repair. One of the important things that we found in this paper is that administering these IT regs, these induced regulatory T cells to mice did promote repair. The lungs were regenerating faster when they received the induced regulatory T cells, uh, compared with mice that received either nothing or another kind of T cell that didn't have the induced regulatory T cell properties. 

[00:11:57] Erin Spain, MS: Can you just talk about the reaction in the lab of your team when you see something like that happen? I mean, that's pretty incredible. 

[00:12:04] Benjamin Singer, MD: Yeah. It's so exciting because you, you know, pretty quickly when the mice are doing better, uh, and then you try to figure out why we, we were trying to answer was, is it the traffic cop function that I started out talking about? Or is it something more interesting I think, which is the ability of these cells to coordinate repair. Another analogy I like to think about for a damaged lung is an orchestra that has just gone off into disarray with the oboes playing one part on their own and the violins playing another part. And what you need is an orchestra conductor, and that's the regulatory T cell to stand up front. And Reorchestrate or Reguide, everyone playing in harmony again as the organ rebuilds itself to play in harmony and restore a state of normal function. 

[00:12:52] Erin Spain, MS: Talking about the team that you have around you and the resources that you have around you and the experts we have here in Northwestern and epigenetics and other areas, can you just talk about how all these things come together at Northwestern Medicine to make research like this happen? 

[00:13:06] Benjamin Singer, MD: Northwestern Medicine is one of the few, if not only places where studies like this can really shine. We have incredible colleagues and resources here in the division of Pulmonary and Critical Care Medicine and the Simpson Query Lung Institute for Translational Sciences. And then the Epigenetics angle is enormously benefited by the Department of Biochemistry, molecular Genetics, and the Simpson Query Institute for epigenetics. Where we can bring together expertise from incredible scientists in the lung, incredible scientists in the world of epigenetics, and then also immunology supported by the Center for Human Immunobiology, uh, here on the Chicago campus. Uh, it's just an incredible environment to do this type of work and make these types of discoveries. I do want to acknowledge the incredible work of the first author on the paper. Dr. Anthony Judy, who is an instructor of medicine. Uh, he has a clinical interest In lung transplantation. He's an incredible physician, an incredible scientist, and all of the kudos for the work in this paper really belong to him. 

[00:14:10] Erin Spain, MS: Taking a look back five years ago, we were in the midst of a major COVID-19 pandemic, and here we are today. You're doing research like this and we've learned so many things. Do you mind just taking a look back at me at how far we've come in the past five years, specifically looking at this type of research of the lungs? 

[00:14:30] Benjamin Singer, MD: as an ICU doc. When I meet with the families of patients who are on a mechanical ventilator and aren't recovering, uh, I will often say to them, I wish we had better medicines. I wish we had better ways to treat patients that could get them better faster. And we learned a lot during the pandemic through studying what happened to patients and through running clinical trials. That we hope of therapies that would benefit patients. And we have come a long way in learning about what doesn't work in, uh, the context of viral pneumonia and some promising things about what may work. And I think beginning to think outside the box about some of these cell-based therapies like regulatory T-cells and how we can use them as a therapeutic is a bit of a sea change in the way that we think about treating patients beyond supporting their bodies, which is, as we said in the introduction, the standard of care that we have now. 

[00:15:25] Erin Spain, MS: I wanna talk a little bit about some of your other work. At Northwestern Medicine, you lead a project called the Socrates Project, also known as the difficult to diagnose team. This is a pretty unique concept. Can you tell me about this project and where it stands today? 

[00:15:40] Benjamin Singer, MD: Yeah, so this is a group. Of physicians, mostly general internists, uh, that. Have an interest in patients that despite a thorough evaluation in an incredible health system like Northwestern Medicine, still don't have a firm diagnosis or they have a diagnosis, but it just doesn't explain all of the features of their symptoms and signs, or the diagnosis is not responding to a treatment the way that would be expected and what we like to think of ourselves as is a group that can come alongside physicians caring for those patients and help them to think a bit outside of the box in a way. We now, through the resources supported by the health system, have the ability to see patients in clinic. And we see patients in the hospital if they're hospitalized at Northwestern Memorial Hospital. And again, we try to be helpful in thinking outside the box, doing a deep literature review, and bringing the resources of a group of really talented physicians together, to try to think about ways that we can come up with alternative diagnostic possibilities, for these patients. 

[00:16:50] Erin Spain, MS: Have there been some really tough cases where you were able to find a diagnosis and maybe even a possible treatment for a patient? 

[00:16:57] Benjamin Singer, MD: We come at this clinical activity from a standpoint of humility. We recognize that this is an incredible health system and patients who are cared for in this health system have seen the top physicians in the field. And so patients who are left without a diagnosis, we know that it's unlikely. That we are going to be able to find that one thing that is transformative, but that doesn't mean that we don't try. And we have over the years managed to find an unusual diagnosis that. Does lead to a different treatment paradigm for patients. That's not the usual type of thing. It's not like a 60 minute TV show, uh, where we have a nice tidy bow at the end. Uh, but that's what we're always striving for. 

[00:17:42] Erin Spain, MS: We are about to walk into cold and flu season right now, and as we wrap up today, thinking about this research that you've just published and everything that lies ahead, is there a message that you'd like to leave listeners with about the future of care for folks with severe viral pneumonia. I, 

[00:18:02] Benjamin Singer, MD: I think the headline message going into cold and flu season is that prevention is far and away the most important part of this. By the time that a patient becomes ill with a virus makes it into the ICU. There's so many things that have happened and yes, as an ICU physician, I am dedicated to trying to find ways to help patients with the severe form of pneumonia do better. But it all starts with not coming to the ICU at all. And the best way to do that is through vaccination, being up on the local guidelines for influenza vaccination, COVID, 19 vaccination, RSV vaccination. These vaccines save lives and I. Encourage everybody to talk with their physicians about the opportunities they have to get vaccinated and prevent severe pneumonia in the first place. 

[00:18:52] Erin Spain, MS: Well, that is a perfect note to end this episode on Dr. Singer. Thank you again for coming back to the show and we appreciate you sharing all your knowledge today. 

[00:19:01] Benjamin Singer, MD: My pleasure.  

[00:19:02] Erin Spain, MS: You can listen to shows from the Northwestern Medicine Podcast Network. To hear more about the latest developments and medical research, healthcare and medical education, leaders from across specialties speak to topics ranging from basic science to global health to simulation education. Learn more at feinberg.northwestern.edu/podcast. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Benjamin Singer, MD, has stock options, excluding diversified mutual funds in Zoe Biosciences. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.