December 14, 2023
Adam Selkowitz: Welcome, everybody! We are here with another edition of “‘News From The Lab” brought to you by Lupus LA! My guest, as always, is Dr. Caroline Jeffries, who is truly one of the most spectacular lupus researchers in the country. She’s here in LA, at Cedars, and thrilled to have her as part of Lupus LA. Last time, for those of you who don’t remember, we talked about this new breakthrough in lupus treatment called CAR-T therapy. So I wanted to start today – we’re going to talk about that – but we’re also going to talk about another new therapy that looks very interesting. So why don’t we start with an update, Caroline, on car t therapy?
Dr. Caroline Jefferies, PhD: Sure. And I mean, just for people who don’t remember or are new to this session, just let me tell you what car t therapy is. So basically what researchers are doing is they are taking out your t cells, which are very important immune cells in your body and you can target these T cells. So what they’re doing is they’re introducing a piece of DNA into your t cells that basically makes the t cells target your b cells. And so for any of you who know or anything, know a little bit about lupus, you know that antibodies and autoantibodies are very important. And some of our therapies, new therapies, are targeting autoantibodies. And so the t cells are then reintroduced back into your bloodstream and they go to target the b cells in order to reduce the antibodies. And the great thing about this therapy is it doesn’t just live in your blood. It basically goes into your tissues and fights the B cells that are destructive there in place in your kidneys, in your lungs, in the tissues that are affected. So that’s why this therapy has been fairly revolutionary. And it’s amazing so many different companies, different hospitals are now looking at car T therapy for treating autoimmunity, not just lupus. They’ve started doing it in scleroderma, in myocitis. And I was just talking to a fabulous researcher from the Mayo last week and she was telling me that she went to the German university that did the initial car T therapy. And I believe they are up to twelve patients that they’ve treated so far, and they’re talking about the fact that this is curative in these patients. So using the c word for lupus is a pretty big deal. So we’re watching this space, everybody is watching it very anxiously, hoping that these studies really pan out. And the other great thing about this, what I heard is it’s not just companies, as I said, universities and hospitals are starting to do this, and that will reduce the costs considerably. So it could be something that is universally available to patients that meet the criteria for it. So these are patients that would be very sick, not responsive to other therapies, maybe have kidney disease. That sort of criteria people really haven’t worked out yet.
Adam Selkowitz: I have two questions for you. The first couple of patients, like how long now have they been in remission or cured or not showing any signs of lupus anymore?
Dr. Caroline Jefferies, PhD: I believe about two years. Okay, two and a half years. When they published this study, I think one of the patients was 18 months. So we’re a year past that. So, yeah, two and a half years.
Adam Selkowitz: Typically with a treatment like this, because I know CAR T therapy is being studied in cancer and other areas in terms of FDA approvals and safety mechanisms and all of that. Know, are we looking at many, many years out or is it moving much more quickly these days?
Dr. Caroline Jefferies, PhD: It’s definitely moving much quicker because it has been approved in, you know, the safety studies are all there. What’s different, I think, now coming through from some of the companies is that they’re modifying the DNA that they put into the t cells to make it even safer. So I know of one company here in LA that have, they are going to the start of clinical trial in lupus, I think, in the next six to twelve months. And they have a car t that’s incredibly safe. So, I think that’s the sort of thing that we’re kind of waiting for is those sort of companies to do those trials.
Adam Selkowitz: And just tell me a little bit. Like, if I were the patient going in central process of how it works.
Dr. Caroline Jefferies, PhD: So basically you’re asking me what the process is for the patient. Yeah. So from my understanding, and I’m sure there’s going to be a ton of people who’ll correct me, but basically the patient’s blood is taken at one visit and they remove your t cells from the blood and then they condition them and make them into these fighter t cells. And then while they’re doing that, that takes a couple of weeks to do that. While they’re doing that, the patient usually undergoes a form of therapy that basically removes their existing t cells. So that could be treatment with one of these antirejection drugs or something like that, and that basically cleans out anything that’s there that could get in the way of the new treatment. And then basically the patient comes back in and this is all done in house, then they’re admitted for a couple of days, and they get an infusion of their new t cells, and then they’re monitored from there. In some of the cancer studies, these t cells have generated what they call a cytokine storm. So that’s why patients are in hospital. But funnily enough, actually, the lupus patients don’t seem to get this. So I’m not quite sure.
Adam Selkowitz: And nobody really knows why we’re tough, because we’re tough.
Dr. Caroline Jefferies, PhD: Yeah, you are tough. Okay.
Adam Selkowitz: All right, let’s move on to this exciting article I just read about mitochondrial DNA and also dealing with t cells. And tell me a little bit about this study that just came out.
Dr. Caroline Jefferies, PhD: Sure. So this study came from a group in Vanderbilt, and what they showed was that the t cells from patients with autoimmunity, we know that they’re overactive, right. We know that they’re basically targeting the tissues. They’re activating b cells to target tissues. They’re directly killing other cells and the tissue cells. So one of the things you want to do is basically drive them from being activated to regulatory or immunosuppressive. And there’s a ton of kind of ways that we can do that. Like, people have used stem cells to do that. They basically can reset that t cell loop. But these guys found that in lupus patients, their t cells had really, really high levels of iron. And lupus patients, by and large, are anemic. They don’t have a lot of iron in their blood. But the T cells from the lupus patients had a receptor for iron that was basically making them take up more iron into the t cell. And why that’s important is that we have organelles inside our cells called mitochondria. And mitochondria are what drives our energy. They basically respond to everything. Let me just share a slide, because I’m so excited about mitochondria right now. I’ve just written a grant on them and hopefully study them in lupus.
Okay, so you’re seeing this one over here, the one that has the two things on it, right? So the reason I’m excited about mitochondria and why there’s a lot of focus on the mitochondria is because we know that, like in lupus, they’re basically helping to drive activity of immune cells. And that’s why these researchers were super excited about this finding. And they’re basically going to try and target T cells and reduce the mitochondrial activity so that they can turn the T cells off, basically. And actually, the really cool things about mitochondria is that they’re like bacteria. They’re like bacteria inside our cells. So I don’t know if you can see my pointer, but on the left, can you see my pointer?
So this is basically an ancient cell. This cell wasn’t able to use oxygen to live. It basically was anaerobic, as they call it, so no oxygen. And then about 1.55 billion years ago, this ancient cell took up a bacteria that was able to use oxygen. And that’s kind of the endosymbiosis theory of mitochondria. So now this cell could use oxygen, and it gave it an advantage. And that’s where cells that could use oxygen, mammals that could use oxygen, it’s all down to this guy here, the mitochondria. And so the thing about the mitochondria is we used to think that they just made, used oxygen to make energy for the cells so that cells could live. But actually, they not only make energy, they regulate our immune responses by turning on or off cells. So if a mitochondria is stressed, it’s going to activate the cells. It plays a role in cell death and also regulates stem cells. And the really cool thing about the mitochondria is it senses things. It senses things in the environment, it senses stress, it senses and responds to the food that we eat and energy, food availability, and also can sense immune prompts. So if your body is inflamed, your mitochondria are going to sense it and then change things accordingly.
But why I’m really excited about this is that mitochondria can confer memory. So basically what researchers are finding now is cells can transfer mitochondria from one cell to another. And in doing that, they can either do it by forming these kind of bridges across between the donor cell and the recipient cell, or they can send the mitochondria across in little vesicles called micro vesicles, and then basically these are taken up by the recipient cell. What we’re finding is that if you’ve got a cell that is stressed and it donates its mitochondria to a recipient cell, then basically that recipient cell gets stressed. The mitochondria is delivering a memory response. And that’s what this grant that I just wrote was about, was basically to understand. Can lupus mitochondria transfer memory responses? This is a really cool concept, because if I take a cell line that’s growing in culture in the lab, I can take out mitochondria from that cell line. So you can just culture it in a different way and the mitochondria die. And then I can take platelets from lupus patients from their blood, and I can basically culture the platelets with the cell, and the platelets don’t make their mitochondria to that cell.
And then I can take the platelets off and then ask how the recipient cell is responding and do lupus mitochondria transfer memory. The reason this is so important is we have ways to modulate mitochondria to turn them off. There are drugs, honestly, there’s probably diets that we have to do all the research, but there’s probably ways that we can turn off mitochondria and deliver kind of antiviral. Sorry, not antiviral, anti inflammatory signals to cells and signals to mitochondria so that they respond differently.
Adam Selkowitz: Is this, I don’t want to say safer, but an easier way to target the T cell issues, potentially, than wiping them all out?
Dr. Caroline Jefferies, PhD: Yeah, I think so. I think these guys are basically going to develop an antibody to the iron receptor on T cells, and they’re going to tether it so that it’s only going to respond to t or basically bind to t cells. So I’m not quite sure what their strategy is here. Maybe it’s a bispecific antibody. One part targets the iron receptor and another part targets something on the surface of T cells. That’s my kind of take on that, but it’s very interesting.
Adam Selkowitz: Yeah, I think what’s interesting overall is sort of this new focus on T cells in general has sort of everybody very excited around the community. Do you still think the B cell line of thinking is also part of the equation?
Dr. Caroline Jefferies, PhD: Yeah, I think it is. I think one of the things that we probably should be looking at and a lot of researchers are, is ways that we can reset T cells, and I think this is one very good way of doing it. And there’s been studies with mesenchymal stem cells as well that have been used to basically do this. So there’s a couple of ways. Your T cells, if they’re overactive, they’re going to mess everything up. But if you can reset those active T cells and differentiate them, reprogram them, actually is what is happening. And actually, the mitochondria are super important for that. So if you can reprogram them so that they’re inhibitory, then that goes a long way to turning off that side of the immune response, the adaptive side, the t cells and the b cells. We also have to worry about the innate immune response as well, our neutrophils, our monocytes, and this is a great way to do that, too.
Adam Selkowitz: Fantastic. All right, before we head off for the holidays and everybody is sitting around, what is the thing that they should be talking about with their family about the latest in lupus research? Give them something exciting.
Dr. Caroline Jefferies, PhD: Wow. I know it’s a tricky question, but I guess maybe. All right, let’s do this. Ten years ago, I think that’s a great way of looking at it. So we just published a paper, actually, and I am excited about this, and this is what’s got me so excited. We just published a paper that showed that lupus monocytes are reprogrammed to be more inflammatory through this mechanism, through, basically, activation of mitochondria. And we can turn off the mitochondria and we can turn off the effects that they have using small molecules that have already been tested in the clinic for different diseases. So, yeah, I think the more we understand what’s at play, I think the closer we’re going to get to being able to combine treatments to. We might have a t cell targeted treatment, but maybe we’ve also got to reset other cells. And so we’re going to target mitochondria a little bit more globally. It’s not going to be a specific target, but we’re just going to dampen their activity. So I think combination therapies are the way to go. We have to look at the new directions in immune targeted therapies and say car t’s or some of the antibody responses, such as the anti interference. What’s that one called? Staphnelo? Basically using that in combination with other ways of targeting the immune response, I think that’s going to be the future.
Adam Selkowitz: Fantastic. Well, I think it sounds like there’s so much attention and focus. I love hearing that the pharmaceutical companies are coming to the table in record numbers and that the scientists are excited. I mean, that’s what I think is some of the most important. That’s what wasn’t there 15-20 years ago was this real level of that. There’s a goal in mind, a tangible goal in mind that can be reached.
Dr. Caroline Jefferies, PhD: I actually think another thing people should be talking about this Christmas is the new directions that the NIH is going. The National Institute of Health, that basically funds a lot of our research. They’re really going to be focused on women’s health research and autoimmune disease. That’s going to be a huge thing. And the more we can actually talk about lupus, then. I mean, it’s important for both men and women who have lupus. But the more we can talk about the fact and understand how women are affected by lupus is great, actually, for any men on this who actually are listening to this, I have a study looking at men and women and the differences in their immune responses in lupus, and we are looking for male patients to come in and make blood to us for this.
Adam Selkowitz: We can, we can certainly spread that word. So reach out to Lupus LA, send us a Facebook message or an email, and we’ll connect you with Caroline. And, Caroline, I know you and I were both at Cedars this week or last week when first lady Dr. Jill Biden was there to talk about this new White House initiative that you’re speaking about advancing women’s medical research, and I was super excited to hear her mention autoimmune disease more than one time in her remarks. So, that was certainly an exciting day. And I think she teamed up with Maria Shriver. And you can tell that this White House is determined to shine a spotlight on women’s health, and that really means autoimmune disease.
Dr. Caroline Jefferies, PhD: Yeah. And I mean, I think Covid had played a large role in making us understand that there are differences in the immune response between men and women. And that’s really kind of focused a lot of people’s attention on female driven disease and autoimmunity. It might sound a bit paradoxical because men were affected more with then, you know, just that understanding that antiviral immune responses, autoimmunity, that these things were affecting women much more. I mean, we have a center in Cedars for women’s health research, which know we’re really trying to get it off the ground and I think that Jill Biden coming to cedars and promoting women’s health research will really help us consolidate a lot of our research in women’s health at Cedars as well as around the country.
Adam Selkowitz: Yeah, for sure. It’s an exciting time. Excellent. Well, thank you so much for joining us. This was another terrific edition of news from the lab with lupus LA and Dr. Caroline Jeffries, and have a terrific new year and holiday.
Dr. Caroline Jefferies, PhD: Best wishes to everybody for the holidays.
To learn more about Dr. Jefferies and the Jefferies Research Lab at Cedars Sinai, visit: https://www.cedars-sinai.edu/research/labs/jefferies.html