Decoding the Immune Response to Tuberculosis

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Daniel I. Simon, MD: Thank you for listening to another episode. Today, I am happy to be joined by Dr. Stephen Carpenter.

Welcome, Stephen.

Stephen Carpenter, MD, PhD: Great to be here.

Daniel I. Simon, MD: Well, I'm so happy to be with you today. Dr. Carpenter is an infectious disease expert who trained at Mass General Brigham and Harvard Medical School and has been a leading investigator in studying vaccine-elicited memory T cell responses to mycobacterium tuberculosis.

So, we're here to talk about TB today and learn from a really rising expert in the field. So, Steven, before we begin, we like to set the ground for what we're talking about and then ask you some personal questions.

So, for our listeners, active tuberculosis affects over 10.7 million people worldwide and still kills about one point two million people annually. And a quarter of the population, almost two billion people, are infected with M. tuberculosis, although most don't have the disease. So, we know all about this, everybody knows about TB, but what we don't know is what's new in TB. And so that's why we have you here today. But before we start down that path, we always like to ask you how did you get into medicine? Tell us about some key aspects of your training and how you got to University Hospitals. What was that journey?

Stephen Carpenter, MD, PhD: Great, yes, I'd be happy too. So, I think my journey into the field of medicine started probably as an undergraduate. I was just really curious about human physiology and, and kind of how it all worked. And, you know, medical school seemed like the best path to figure that out and also to make an impact.

I really wanted to do something that could make a global impact and medicine, you know, has so many opportunities for that. So, I grew up in Massachusetts, and UMass was a really great opportunity for people in state. At the time, it was only accepting in-state students. And in medical school, I thought, you know, I had done all this research in neuroscience as an undergraduate. I thought maybe I wanted to go into neurology or neurosurgery. And in medical school I found out very quickly that I was not interested in surgery; that medicine was really interesting to me for the diagnostic abilities and all the different areas of pathophysiology you get to learn and so I found medicine very exciting.

I found infectious diseases particularly exciting because not only do you get to learn about host, but you get to learn about all these other microbes and how they interact with the human body, and I thought that was just really special. So, I applied to residencies in medicine.  I wanted to perhaps do something with infectious diseases and so one of the places that really stuck out for me was Bellevue Hospital in New York City.

So, I became a medical resident at NYU, and NYU was a place that had this nice combination of academic labs and structure, but also, you know, access to really people coming to New York City from all over the world, bringing their cultures and backgrounds and different infectious diseases to study, and that was a really cool opportunity.

Aside from my time in residency, I spent my elective time in a research lab, and the lab was focused on immunity to tuberculosis, and that is really what started my interest in TB. So, clinically, Bellevue Hospital had a TB ward where people were treated long-term for TB, including people that had multi-drug resistant or extensively drug-resistant TB.

And then you had these labs that were studying HIV and tuberculosis that together was – I found very, very fulfilling. And so, I started a research project. But, you know, in residency, you can't really, you can do a little bit, but you just don't have time. when you're doing your clinical training, but I was set-- my interests were set, and I think, that certainly piqued my interest in applying for a fellowship in infectious diseases. And so, I had the opportunity to go to Boston after that, and I was kind of looking to recapitulate that same research experience.

So, the Division of Infectious Diseases at Mass General mostly had investigators who were doing great work in bacterial pathogenesis, viral pathogenesis, but immune responses was kind of its own thing that the field of HIV had really pioneered - studying the immune system and how it responds, not in terms of autoimmunity, but in terms of responses to microbes.

There were a few labs in the division of rheumatology who focused on immunity to tuberculosis, and one of whom was Sam Behar, who became my research mentor. And I worked with Sam for a little over six years and learned all sorts of amazing immunology techniques and basic immunology in the mouse model of TB.

My desire was to translate that into studying human disease - to do more translational work. And so, thinking about doing that and starting to apply for faculty positions and my professional career, I came across an opportunity to work at a biotech company called Regeneron.

I'd known a couple of people from my time in residency at NYU who had gone to Regeneron, and they were very excited about their positions. And so, I applied, and I interviewed and it, you know, really seemed like this would be a great transition step for me to do more translational work, to learn to translate some of the stuff that we're doing in mouse models for early phase clinical trials.

And I started working at Regeneron in 2017, and I-- for the first year-- I learned an amazing amount of new skills. I learned to design and run early phase clinical trials. I learned to successfully submit INDs to the FDA. I learned how I could impact and how we might take some of the molecules that the R&D groups were generating and test whether or not they block their pathways in clinical development in early phase clinical trials, but I was kind of missing something. I felt that what I really wanted to do was to use that knowledge to make basic discoveries. And that was a little bit misaligned with what my job was. They really wanted me to move these programs forward and develop these monoclonal antibodies.

And so, I started thinking about what the next phase of my career would look like and reached out to some mentors and ultimately decided to apply for academic jobs. And my former research mentor, Sam had told me, "Well, you know, Henry Bohm is actually recruiting for physician scientists in ID. You should take a look at this and talk to him." And so, I did, and we talked, and I interviewed, and it was, you know, it was the perfect fit for what I was looking for. Henry wanted somebody to work on TB and to do clinical ID work. That was exactly my background, and it was really an easy choice to come here to Cleveland. I feel like this has been a really supportive environment and I'm just very happy to be here.

Daniel I. Simon, MD: Well, that's really great. I think, you know, we've been very lucky to get two people from Regeneron, you and Matt Anderson. Matt was running neuroscience, and I think he came to the same conclusion that his contributions in autism might be better if he was back in academia. So, two Harvard guys who went to Regeneron and then come back here, so that's great.

Now, I think for the listeners, they should know that infectious disease doctors are widely considered to be the smartest physicians. When I was a cardiology fellow and junior attending at the Brigham, whenever we wanted to learn about a patient, we'd get an ID consult because they would teach us about what the patient really had. So, we were plumbers, and you guys were the smart guys.

All right, so let's go to, to, TB now. So, it's one of the world's leading infectious disease killers, but what can you tell us about the limitations in the disease? You know, is there-- are there effective drugs? Are there effective vaccines? What's the real missing thing in TB right now?

Stephen Carpenter, MD, PhD: Yeah, that's a really important question. We do have effective antibiotics against TB. The problem is—and there are new antibiotics being developed, which is great--- the problem is that if you get diagnosed with active tuberculosis, you need to be on, you know, two or more of those antibiotics for months, usually for at least six months.  And many of them, you know, have side effects and toxicities that make them hard to take. And if you miss doses or you can't afford medication, you know, and you expose the bug to a little bit of antibiotic, then you might be dealing with a resistant bug. And there's a lot of resistance, a lot of natural resistance out there anyway.

So, there are drugs, but they take a long time to work, they're toxic, and not everybody has access to them, and they don't work for all the different strains of bacteria that are out there. For vaccines, there is a vaccine. There is one vaccine that is licensed and approved called the BCG vaccine. It was first used, I think in 1921, by two French scientists, and, it was originally given as an oral formulation to infants. The data is not great, but it has been studied over and over again. And from what we know now, we think that it does help to prevent TB in infants and children under the age of five, especially disseminated forms of TB.

So, people with brand-new, naive immune system who might benefit from some, you know, antigen experience to help protect them, but, beyond age five, there's really no good evidence that it prevents tuberculosis. And we've tried a lot of-- you know, the world, has tried a lot of different ways of studying the BCG vaccine, revaccinating people, vaccinating adolescents, and adults after they have been vaccinated at birth. So far, in general, for most people, that does not seem to work to prevent TB. So, we need a better vaccine. We don't have a good preventative vaccine at least for adolescents and adults.

Daniel I. Simon, MD: So, your recent study found that the vast majority of memory CD4 positive T cells in people with latent tuberculosis can directly recognize TB infected macrophages. Why is this finding so important? What does it tell us about potential vaccine options?

Stephen Carpenter, MD, PhD: Yeah, so there's this phenomenon that we observed in trying to figure out why is it that we can't-- we haven't been able to develop a protective vaccine so far. This line of research we have discovered that in animal models of TB the majority of the T cells-- so when you talk about a protective immunity to TB, the most important subset of the immune system that seems to be the most protective are the CD4 T cells, and if you look at CD4 T cells in a mouse model of TB, if you look at mice that have been, infected via the aerosol route several studies have shown that the majority of those T cells are not actively doing what T cells should do when they see a pathogen. They're not producing interferon gamma. They may not even be recognizing the infected cell.

So why is it that only a few percent of the cells seem to be activated and producing interferon gamma in the lungs during active infection? One of the thoughts was that perhaps TB is evading the host immune system by a number of mechanisms, and people have shown this in a number of ways, and if we could elicit T cells that were greater proportion of them, we're able to recognize the infected cell, then maybe a vaccine would actually be doing something. Maybe this could be a correlate of protection. So, because in the mouse model minority of the T cells seem to be correlated with recognition of infected cells what we wanted to do was to look at human cells and ask, okay, people who have been exposed to TB have developed a memory response. We could study that. We could draw some blood, we could generate macrophages from their monocytes from the blood cells and infect them, and we could take those T cells from the blood and expose them to their own infected macrophages and ask what proportion of those T cells actually become activated. Is this similar to what we observe in mouse models during active disease? And what we found was and our hypothesis going into this was that it was going to be similar, that only a fraction of the cells would become activated. And we found exactly the opposite. About ninety percent of the CD4 T cells from healthy individuals with latent MDB infection were capable of recognizing infected cells, but not a hundred percent.

Now in retrospect, maybe this makes sense because, you know, these are individuals who successfully controlled infection and never developed active TB. So maybe that's suggestive of a robust immune response and a protective immune response. That ten percent, you know, even in a protective immune response, it's probably not the case that a hundred percent of the cells are doing what they should.

So, what we think is that ninety percent of the cells were doing the right thing and recognizing the infected cells, and about ten percent were not. And we were able to go further and sequence the T cell receptors from both groups, the T cells that recognized the infected macrophages and the ones that didn't and figured out some of the targets of those T cells, which antigens they actually target from the bug.

Last thing I'll say about this is, we found-- we were surprised to find that of the eight or nine T cell receptor sequences we were able to find antigens for they were all of the same class. They all targeted this one type of secreted protein called type seven secretion system substrates. So, these are different proteins that the bacteria secretes through this mechanism called type seven secretion system. And all these ones were targeting that particular, secreted, mechanism.

Daniel I. Simon, MD: So, does that give you insights then to design a new vaccine? Would that theoretically even be an antigen that might be good for a vaccine or is it not expressed on the cell surface? Is it only secreted?

Stephen Carpenter, MD, PhD: Yes, to all the above. So, yes, we think these would make good antigens. This really helps vaccine development in my opinion because, the SARS-CoV-2 vaccine, you know, we had one antigen that we wanted to target, the spike protein. We knew that was the one that got the virus into cells. And we knew that if we could develop neutralizing antibodies against it, we could block that entry into cells. You know, we understood the entire mechanism.

For TB, there's just so many black boxes. TB does not have, you know, a few antigens. TB has 4,000 possible antigens. So, which of those, you know, to even figure out which of those 4,000 your T cells are targeting right now is a very expensive feat of molecular acrobatics.

So, to narrow that pool of 4,000 down to maybe 400, which is now what we're doing when we talk about secreted proteins, is a really, big advance. We think that the money is going to be in those, somewhere in those 400 secreted proteins. The question is, which ones are more protective and which ones are sort of like immunogenic and could act as decoys?

We're still trying to figure that out. One bar we need to cross, though, is we need to pick antigens that the immune system actually sees and focus on those. And I think that's what we've done here.

Daniel I. Simon, MD: You know, it's really amazing. I think one of the things that a lot of us, you know, who aren't infectious disease experts don't exactly understand is we've all almost all of us have had childhood chickenpox, and yet only some of us get shingles. And so, this activation from latent to active, you know, there are two billion people in the world who've been exposed to TB, but only a small percentage get active TB.

So, I guess your approach is to say it would be far more effective for us to vaccinate and prevent people from ever being exposed and becoming, you know, having a chronic latent infection. But is there any new information in why people reactivate other than that they're transiently immunosuppressed? What have we learned about TB's latency to active phase?

Stephen Carpenter, MD, PhD: We don't know why most people reactivate. We know that there are certain things that are associated with reactivation. You know, if you receive certain medications like anti-TNF agents, we know that in some cases, not all, but in some cases, people who receive a PD-1 inhibitor for cancer immunotherapy develop tuberculosis even after a single infusion.

We know that if you acquire HIV that you have a higher risk of developing active TB even before your CD4 count drops. So, there's effects on... I think there's inflammatory effects, there's CD4 T cell depletion that all play into this, diabetes, aside from HIV, diabetes is one of the major risk factors for developing active tuberculosis, and we don't really understand why that is yet either.

In terms of vaccination, you know, there's, there's a couple different schools of thought out there. One is the type of vaccination that you mentioned, which is to prevent infection. That has been studied with BCG, and so far, it hasn't worked, but maybe it would work with another vaccine.

The other type of vaccination that we focus on in TB is prevention of disease. So regardless of whether or not you've been exposed - infected, you get a vaccine so that your immune system can enforce latency and you are less likely to develop active TB. In my opinion, I think that that could be a really promising approach, because active disease is a thing that is continuing to fuel the TB pandemic. And if we could just decrease the rate of active TB, we could hopefully decreas the pandemic.

Daniel I. Simon, MD: Okay, so best case scenario for all of our listeners who want to know when they're going to potentially get their TB vaccine. So, your type 7 secretion system substrates become, let's say, the lead. You know, these are some of the antigens for this, how long does it take to go from, you know, phase one clinical trial to definitive trial in the population of people who have been exposed? What's that time course? Is it five years? Is it 10 years?

Stephen Carpenter, MD, PhD:  Typically, I think to go from the drug or the vaccine being delivered to a healthy volunteer to approval from a phase three clinical study is often as much as 10 years. But I think, you know, the pandemic, the COVID-19 pandemic has shown us that, I think there's a lot we can do to try to accelerate those timelines, especially for diseases with really high unmet need.

One of the kind of promising vaccines that's being studied right in a phase three clinical trial that is funded by the Gates Foundation, this, M72 vaccine. It showed some efficacy in a phase two study. And this phase 2B study it had about 50% efficacy. Now, there weren't a lot of patients in that study. The event rate was low, and I think that's one of the things people are watching really closely for... there were only 20 or 22 cases of active TB in the placebo group and about 10 cases in the vaccinated group. So, we're talking about low event number, but because that really is the only vaccine that's shown some promise in a phase two study, the Gates Foundation has invested in it and is conducting that phase three study now. And they finished enrolling, I think, last year. 

Daniel I. Simon, MD: Yeah, 50% of people with chronic TB is a huge impact on mankind.

Stephen Carpenter, MD, PhD: It would make a big impact.

Daniel I. Simon, MD: Yeah, well, listen, this has been really fascinating for me. I think that, obviously everything in medicine now is circling back to immunology, cancer, autoimmune disease, many mucosal, autoimmune diseases in GI spaces, certainly in the CNS. So, it's so great to have infectious disease experts, right, who are working with the rheumatologist, who's now taking things back to ID.

Thank you so much for joining me today, Stephen.

And to learn more about research at University Hospitals, please visit UHhospitals.org/UHResearch.

Thank you so much for joining me.

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