The Impact of Gut Microbiome on Transplant or CAR T-cell Therapy 

Transcript of Presentation.

(00:01): [Susan Stewart]: Welcome to the workshop: The Impact of the Gut Microbiome on Transplant or CAR T-Cell Therapy. My name is Sue Stewart, and I'll be your moderator for this workshop. It's my pleasure to introduce today's speaker, Dr. Melody Smith.

(00:18): Speaker Introduction. Dr. Smith is a board-certified, fellowship-trained Hematologist-Oncologist and an Assistant Professor of Medicine in the Division of Blood and Marrow Transplantation and Cellular Therapy at Stanford University School of Medicine. In 2021, she established the Smith Lab, an independent lab investigating CAR T-cell biology to gain insights that may help to improve patient outcomes. Please join me in welcoming Dr. Smith.

(00:50): [Dr. Melody Smith]: Thank you, Sue, for the introduction and for the opportunity to present our research here at this seminar and symposium. I'll be talking today about the impact of the gut microbiome on transplant or CAR T-cell therapy.  

(01:13): Overview of Talk. Today we will discuss the role of the intestinal microbiome in outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) or chimeric antigen receptor (CAR) T-cell therapy. We will also discuss the impact of allo-HCT and CAR T-cell therapy on the intestinal microbiome, and wrap up with interventions – such as diet and lifestyle changes – that promote a healthy microbiome.

(01:41): I'd like to begin with a brief overview of cancer immunotherapy, which are any immunotherapies that harness the body's immune system in order to fight cancer.

(02:11): In this picture, there is a plane that's flying close to the surface of the ocean. Think of this as a plane that is flying below the radar. This plane represents cancer, and this plane is flying below the ‘radar detection’ of the immune system.  

(02:33): The cells within the immune system – such as T-cells – detect malignant, or cancerous cells, to eradicate and destroy them. Cancer forms when these malignant cells form and the immune system does not detect them.

(02:52): Cancer immunotherapy, is a class of immune-based therapies that harnesses and enhances the immune system's ability to detect cancer cells. These therapies have really led to novel approaches for us to be able to fight cancer.

(03:16): This slide shows the big categories that encompass cancer immunotherapy.  

(03:28): The oldest cancer immunotherapy is the allogeneic hematopoietic cell transplantation, which is a therapy that is used primarily for high-risk and relapsed blood cancers, after chemotherapy treatment.  

(03:47): Then, there are immune checkpoint blockades which inhibit specific proteins on the cancer cells, and allow the body’s T-cells to attack the cancer cells. The first immune checkpoints were anti-PD-A and anti-CTLA-4 proteins, and now there are many others being investigated. These are most commonly used for solid tumors, but they're also used in the treatment of lymphoma.

(04:04): Finally, there's adoptive cell therapy, which encompasses both chimeric antigen receptor (CAR) T-cell therapy, as well as T-cell receptor-based therapy (TCR).

(04:15): Today I'll be focusing on allo-HCTs and CAR T therapies.

(04:24): For those who are less familiar with an allogeneic hematopoietic cell transplant (allo-HCT), here is a brief overview. During this therapy, the patient’s body is conditioned – or prepared for transplant – with total body irradiation, chemotherapy, antibodies, or a combination of these. Once their body is conditioned, and the recipient's own immune cells are ablated, then receive donor hematopoietic stem cells from a genetically matched or half-matched donor.

(05:14): These donor cells are infused into the recipient. For a conventional allogeneic transplant, the recipient receives all of the cells from the donor, and the donor’s T-cells are not removed prior to infusion. The rate of graft-versus-host disease (GVHD) in this type of conventional transplant can range from as low as 40% of recipients to 60%.

(05:42): This data from the Center for International Blood and Marrow Transplant Research (CIBMTR) showing the mortality rate one-year after transplant, indicates the leading cause of death in that first year is relapse from their disease for which the patient received the transplant, followed by death due to graft-versus-host disease.

(06:02): Graft-versus-host disease (GVHD)-related mortality has dramatically decreased over the years as we've been able to develop new therapies and strategies to more effectively treat the disease and prevent GVHD. However, relapse remains an ongoing factor in terms of post-transplant morbidity and mortality. So, much of the focus within allogeneic transplant (allo-transplant) research focuses on enhancing graft-versus-leukemia activity – which is intended to help decrease relapse – and also mitigating or decreasing graft-versus-host disease.

(06:39): Let’s discuss a brief review of CAR T-cell therapy, which is a form of an adoptive cell therapy. Why is it called a ‘CAR’? Why is it called ‘chimeric’?

(06:49): In Greek mythology, the chimera was a fire-breathing, hybrid creature that consisted of the head and body of a lion, the head of a goat, and sometimes a tail ending with a snake’s head.  

(07:24): The word ‘chimera’ simply means combining different things that are not naturally together. So, it’s chimeric because a lion, a goat, and a snake aren't usually together. Similarly, B-cell receptors, which are in chimeric antigen receptors (CAR) T-cells, are not usually in a T-cell. T-cells usually have only T-cell receptors. Therefore, it's considered chimeric because introducing a chimeric antigen receptor (CAR) into the T-cell, you're making it chimeric with a B-cell receptor as well.

(07:55): This technology to introduce the CAR into the T-cell is usually a viral-based technology. And the portion of the receptor outside of the T-cell, that binds to the antigen or the marker on the tumor, is the CAR.

(08:13): Here are the five different CAR T-cell therapies that are currently approved by the FDA. These CARs are indicated for non-Hodgkin’s lymphoma B-cell acute lymphoblastic leukemia. This slide shows their names and disease indications, and they all target the CD19 antigen of the cancer cells.

(08:43): You can see the structures of these CARs. They have quite a few similarities, but some of the internal workings and designs of these CARs vary. This is important to keep in mind, because those design differences allow the different CARs to provide specific functions and benefits that are unique to that CAR.  

(09:18): CAR T-cell therapy has led to significant advances for patients with hematologic malignancies, especially those with relapsed or refractory disease. There are seven CARs that are now FDA approved; five for CD19 malignancies and two for B-cell maturation antigen (BCMA) targets for multiple myeloma – all with really encouraging data.

(09:45): This is an older photo of Emily Whitehead, who was the first pediatric B-cell acute lymphoblastic leukemia recipient of CAR in 2022. This is a photo from when she was 11 years post-therapy; she's now in college and still cancer-free. Similarly, there are reports of patients –pediatric and adult patients – who have been in remission after CAR T-cell therapy for more than a decade. So, a very promising therapy leading to better outcomes.

(10:32): However, there are still some limitations. This data is from a publication in 2021 looking at patients with non-Hodgkin's lymphoma who received CAR T-cell therapy. Up to 60% of patients with this therapy may still relapse, and most commonly relapse within the first year after CAR T-cell therapy.

(10:57): CAR-related toxicity is another limitation. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common neurotoxicities that occur following CAR T-cell therapy. They most frequently present within the first two weeks, but can occur anytime during the first 30 days after CAR T-cell therapy, and is an area that we need to continue to address and improve upon.

(11:31): Due to the various limitations that still present after an allo-HCT or CAR T-cell therapy for hematologic malignancies, we continue to investigate ways to improve patient outcomes. One approach that we're focusing on, particularly in my research, is whether endogenous factors – or factors that are within the individual – can alter patient response. One of those endogenous factors that we're investigating is the impact of the intestinal microbiome.

(12:02): The intestinal microbiome are the microorganisms that live in the human body, including bacteria, viruses, and fungi. There are 1014 microbes per person, and microbes make up about 3% of the human body mass. The majority of these microbes reside in the gastrointestinal (GI) tract from the oropharynx all the way through the gut.

(12:52): There is a growing body of literature looking at the relationship between the microbiome and cancer treatments and therapies.  

(13:20): So, in summary, cancer immunotherapies are a class of cancer treatments that enable the immune system to target cancer that may have otherwise gone undetected by the immune system. Allo-HCT and CAR-T are cancer immunotherapies that offer key therapeutic options for patients with blood cancers. And the intestinal microbiome, which consists of the bacteria, viruses, and fungi in the host, are being investigated in its role in the patient's response to these therapies.

(13:49): Now, let’s talk about the impact of allo-HCT and CAR T-cell therapy on the intestinal microbiome. So again, as a broad overview, we wrote this review earlier this year that really highlights the intestinal microbiome and CAR T-cell therapy.

(14:05): Treatment with antibiotics can induce dysbiosis – or alterations in the microbiome – which can impair outcomes for transplant and CAR T. Patients with exposure to certain antibiotics prior to an allo-transplant, have increased antibiotic resistance, and increased mortality due to graft-versus-host disease of the gut. Within CAR T-cell therapy, specific antibiotics have been associated with decreased survival and increased neurotoxicity.

(14:51): We hypothesize that these antibiotic exposures lead to a loss of some of the normal constituents – what we call commensals – within the gut. They alter some of the substances that those bacteria produce into the microenvironment, and therefore decrease the diversity.

(15:18): Potential implications from these findings are that antibiotic stewardship – or really being thoughtful about the type of antibiotics that we give patients – as well as eventually giving back a specific consortia of healthy bacteria, could be beneficial. More research is needed before we begin recommending these.

(15:43): The microbiome is very diverse – there are many different types of bacteria with distinct roles – and the more diverse that bacteria is, the healthier your microbiome. A microbiome with less diversity is not a healthy microbiome.  

(16:21): We found that when we look at overall survival in allo-transplant patients, around the time of engraftment, patients with a low to intermediate-diversity microbiome, compared to those with a high-diversity microbiome had poorer outcomes. There are a lot of different things that can impact the diversity of the microbiome as well, including diet and various exposures to medications and antibiotics. Similarly, when we look at lethal graft-versus-host disease, a less diverse microbiome was associated with a higher risk of mortality compared to those patients with a higher diversity.

(17:25): Medications also have an impact on the intestinal microbiome. Antibiotics impact cellular therapy, but there is also a publication that showed exposure to other medications that patients receive, not just antibiotics, has a differential impact on the intestinal microbiome. This was an analysis from a cohort of transplant patients looking at everything from high blood pressure medications to diabetes medications and scoring the medications based on those that impacted the microbiome most. If you're really interested in delving into all the specific medications, this paper analyzes that. The main take away is that all medications impact the microbiome, but antibiotics are the most damaging because they can cause dysbiosis.

(18:23): Antibiotics, especially those aimed at obligate anaerobes – which are microorganisms that live in the gut and survive in the presence of oxygen – have a negative impact on this healthy gut bacteria that plays a crucial role in maintaining gut health.

(18:37): Obligate anaerobes are really important for the immune system, and anaerobe-targeting antibiotics have been linked to the poorer responses in transplant and CAR T-cell therapy.

(19:12):  First, these obligate anaerobe-targeting antibiotics – such as imipenem and piperacillin – are specifically designed to target obligate anaerobes. It's been found that in allo-transplant settings, exposure to these obligate anaerobe-targeting antibiotics did not impact overall survival, but was associated with a higher risk of graft-versus-host disease compared to exposure to other antibiotics or no antibiotics. So, obligate anaerobe antibiotics do have an association with increased graft-versus-host disease mortality.

(19:44): Likewise, we also analyzed similar obligate anaerobe-targeting antibiotics in the CAR T-cell therapy setting, including piperacillin/tazobactam, imipenem, and meropenem. And again, exposure to these antibiotics four weeks prior to their CAR T-cell therapy, was associated with decreased overall survival.  

(20:15): Many of these obligate anaerobe antibiotics are very important and very necessary to consider administering to patients who are neutropenic – or don't have immune cells. If patients have a fever and they’re neutropenic, you need to give them antibiotics because their immune system can't fight infections. So, that's why these obligate anaerobe antibiotics are important and often used.

(20:41): Cefepime is an antibiotic that can also be used to treat neutropenic fever. It's a great option as it fights against a large spectrum of bacteria, but does not disrupt those obligate anaerobes to the same extent.  

(20:55): When comparing exposure to cefepime to either receiving no antibiotics, or receiving anaerobic-targeting antibiotics, we discovered cefepime was not associated with decreased survival, in the same way obligate anaerobic antibiotics were.

(21:11): And I think this is a really important piece of information because it helps prove that these poorer outcomes we saw weren't just due to the fact we were looking at sicker patients receiving antibiotics who then did worse, but the antibiotics themselves and what bacteria they were targeting. This cefepime data on overall survival suggests that it's not just antibiotic exposure in general, but what the antibiotics were targeting.

(21:54): Two separate publications have also reaffirmed this data, in addition to our initial finding from 2022. A study looking at an international cohort of patients who got CAR T-cell therapy, compared outcomes after receiving no antibiotics, low-risk antibiotics, or high-risk antibiotics – many of those being obligate anaerobes targeting antibiotics. Patients exposed to the high-risk antibiotics had the lowest survival and worst outcomes than the two other groups.

(22:25): Another analysis looked at no antibiotics, cephalosporins – such as cefepime, – or anaerobic-targeting antibiotics, and again found that anaerobic-targeting antibiotic recipients did worse compared to the two other groups. So again, anaerobic antibiotic exposure before CAR T-cell infusion has been associated with decreased overall survival.

(22:52): Anaerobic antibiotic exposure before CAR T-cell infusion was also associated with increased neurotoxicity. We looked at both cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). We didn't see any association with CRS and the use of anaerobic-targeting antibiotics. However, when we looked at ICANS and neurotoxicity, we did see that patients who were exposed to these antibiotics, had worse survival compared to those patients who did not receive one of the obligate anaerobe-targeting antibiotics.

(23:35): A separate publication did a similar analysis looking at the cytokine release syndrome versus neurotoxicity, and they also concluded that exposure to the high-risk antibiotics was associated with increased neurotoxicity.

(23:50): Finally, we looked at specific bacteria, what they secrete into their environment, and the metabolic pathways that the bacteria utilize, and found that both the specific bacteria and their metabolites – these compounds that the bacteria produce – have been linked to how well patients respond to CAR T-cell therapy.

(24:15): In summary, anaerobic-targeting antibiotic exposure during allo-HCT is associated with decreased survival and increased graft-versus-host disease mortality. Exposure to anaerobic-targeting antibiotics in the weeks preceding CAR T-cell therapy is linked to decreased survival and increased neurotoxicity. This data provides potential insights regarding antibiotic stewardship for clinicians caring for CAR T-cell and allo-HCT patients.

(24:46): One important point I want to highlight is when patients have a fever and they're neutropenic, they need antibiotics; that's not a question.  

(24:55): What this data suggests, is that we may be able to select antibiotics that are less damaging to the gut, and associated with less harmful outcomes during treatment. Antibiotics are lifesaving and critical when patients don't have immune cells to fight an infection. Ongoing studies are investigating the mechanisms behind these antibiotic associations, and we're currently doing some of this work in my lab – trying to understand the mechanics behind what the bacteria and their metabolites are doing the CAR T-cells, and how they are modulating the immune system.

(25:33): There are interventions, including diet and lifestyle changes, that patients can do to help promote a healthy microbiome.

(25:45): A common question I get is, "What can I do to enhance my microbiome? What about probiotics?”

(26:02): I want to show you some data from a study that was performed at MD Anderson Cancer Center by Dr. Jen Wargo. This specifically looked at a cohort of patients who received immune checkpoint blockade therapies, giving a probiotic supplement to half the group, and nothing to the other.  

(26:38): Patients who were taking probiotics had poorer outcomes and decreased survival probability. These findings were not statistically significant, because the P value is 0.29, but there was a clear trend.

(27:03): These findings highlight the fact that many of the probiotics are just a different consortia of bacteria, but not necessarily the bacteria that the microbiome may need, or are most important for the improvement of outcomes. And so just a word of caution. Probiotic supplementation has not been studied in the setting of CAR T or allo-HCT, so we can only extrapolate what we know from this setting.

(27:41): A study looking at fiber intake found that patients who had a sufficient fiber intake, compared to those who didn’t, had improved survival. I can't remember what the exact threshold was, but promoting a high-fiber diet, and having a serving of fiber at each meal was considered sufficient versus insufficient.

(28:22): So, prioritize fiber, as opposed to a probiotic. Fiber is a prebiotic because bacteria feeds on this fiber, and it helps to promote a healthy microbiome. Fiber basically gives the bacteria the sustenance it needs to help to promote a healthier consortia of bacteria.

(28:54): A group of my colleagues here at Stanford also really wanted to understand the impact or potential benefit of fiber versus fermented foods. They did a 10-week diet randomization study for 36 healthy adults, who were randomly assigned to a high in fiber diet versus a high in fermented food diet.

(29:23): On this slide you can see the apple versus kimchi, but the food could be anything. With high-fiber foods, we think of fruit, vegetables, whole grains, things like that. Fermented foods would be like kimchi, sauerkraut, yogurt, kefir, kombucha, those types of things. Within the study, they controlled to make sure that those who were on the high-fiber diet were not eating a lot of kimchi and vice versa, to ensure they’d get a clean assessment.

(30:04): What they found was that the high-fiber diet certainly did have some benefits; it increased some microbiome function, short-chain fatty acids, and changes in inflammation over time. But the high-fermented-food diet increased the diversity of the microbiome and decreased inflammatory signals and activity. So it was more anti-inflammatory for the gut.  

(30:37): While both diets did show some functional benefits, they found that the high-fermented-food diet had some increased immune benefits compared to the high-fiber diet that they thought were significant.

(30:55): There's still limited data on dietary interventions and cancer immunotherapy, and much has to be extrapolated from other studies. But the data does suggest that both a diet high in fermented and high-fiber foods promotes a healthy microbiome. I think a diet really enriched in both would help to promote a healthy microbiome.

(31:17): And there's really no evidence to support the use of probiotics to improve the microbiome or clinical outcomes in this setting. The data that we have shows that probiotics for cancer immunotherapy – although not statistically significant – did show a trend for worse outcomes in those patients taking probiotics.

(31:38): With that, I'd like to conclude and thank our patients and fecal microbiome donors who helped to contribute to our research, my microbiome colleagues both at Stanford, UNC, and Duke, my lab, and funding sources. With that, I would love to take any questions in our remaining time. Thank you.

Question and Answer.

(32:06): [Susan Stewart]: Thank you very much, Dr. Smith. That was a very interesting and thought-provoking presentation. Let's get to some questions.  

(32:25): "Do you recommend a butyrate supplement for CAR T-cell therapy patients?"

(32:43): [Dr. Melody Smith]: So, butyrate, just for those who are not as familiar, is a short-chain fatty acid that's produced by various bacteria within the gut, and has been shown to have various immune cell functions, such as enhancing regulatory T-cells. Regulatory T-cells are like an anti-inflammatory type of T-cell. Butyrate has been shown to be beneficial there and in other contexts as well.

(33:23): I am not familiar with any butyrate supplements. I think, again, as opposed to taking metabolite supplements or probiotics, the thing that you can do to specifically help to enhance bacteria of all different types is by having a healthy diet. A diet that's high in fiber and high in fermented foods is going to help the bacteria that are butyrate producers to be enriched, as opposed to stimulating them specifically with a butyrate supplement. That would be my thought on that.

(34:01) [Susan Stewart]: “How does continued use of immunomodulatory drugs like lenalidomide impact the gut microbiome after stem cell transplant?"

(34:15): [Dr Melody Smith]: I didn't touch on that here in the talk, but there is research performed by Dr. Matt Pianko, who evaluated the microbiome in patients who had multiple myeloma and specifically those receiving lenalidomide. The microbiome does change in that context, so, I would recommend looking into that literature.

(34:56): The other person who comes to mind is Dr. Alexander Lesokhin. He is another investigator that's specifically been focusing on the microbiome and multiple myeloma, not just lenalidomide, but also other myeloma-targeting therapies and the microbiome's impact.

(35:21): [Susan Stewart]: "How does one know if they have a low-diversity microbiome?"

(35:28): [Dr. Melody Smith]: So, you wouldn't know unless you directly sampled the microbiome. There are commercial tests out there, but I don't necessarily recommend those. The only way that you would know about the diversity of your microbiome is by 16S or metagenomic shotgun sequencing. That is sequencing that we routinely do, to analyze the bacteria within the gut and analyze the metabolites that they produce. That is the way to directly assess the diversity.  

(36:06): However, I would say patients who have recently been exposed to antibiotics or had some notable changes in their diet, there likely has been an impact on your diversity, and it's probably lower than the baseline for you.

(36:31); To enhance that would be to enrich your diet with fiber and fermented food that will promote a healthy microbiome. As I was showing on one of the final slides, think of fermented foods as a dietary probiotic. Fermented foods have live bacteria, so they're going to help repopulate your microbiome. If you are concerned that you had a recent intervention that could have lowered your diversity, a fermented diet, or also a high-fiber diet, would be something to consider focusing on a little bit more to promote better microbiome health.

(37:17): [Susan Stewart]: "Can you give some examples beyond kimchi of fermented foods?"

(37:26): [Dr. Melody Smith]:  I did during the talk, but a few to keep in mind would be kimchi, sauerkraut, kefir-type yogurts, and kombucha for those who like the taste. Those are all things that are fermented and have live bacterial cultures within them, and that's why they help to promote microbiome health.

(38:08): [Susan Stewart]: "When you refer to antibiotics taken before CAR-T infusion, does it matter when those antibiotics were taken, like three months before versus 3 years or 20 years?"

(38:23): [Dr. Melody Smith]: All of the studies thus far looking at antibiotic exposure as it relates to CAR T-cell therapy have either looked at three weeks before or four weeks before; they've not gone any further out. This is because many patients who are referred to receive CAR T-cell therapy, are referred to tertiary centers, not their primary oncologists. So even being able to have the data to look much further than that, needless to say years beyond that, would not really be feasible because the data would be limited.

(39:38): Because patients also are exposed to antibiotics after CAR T-cell therapy, that's another period of time that could be evaluated. But to date, the published data is all in the three- to four- week time period before CAR-T.

(39:55): [Susan Stewart]: "How long does it typically take for the body to recover from antibiotics and the microbiome to return to normal?"

(40:05): [Dr. Melody Smith]: We've done a longitudinal analysis looking at how the microbiome changes over time and when it starts to recover back to its baseline. At least in our early studies, we start to see that the microbiome starts to return to baseline or approach the baseline phenotype by as early as six to eight weeks after CAR T-cell therapy.

(40:58): [Susan Stewart]:  "For someone who is preparing for a transplant, does chemo have similar effects on the gut microbiome as different kinds of antibiotics?"

(41:11): [Dr. Melody Smith]: It doesn't have the exact same effect, but chemo definitely impacts the microbiome as well. Some of the allotransplant literature looked at that, and we do see that the microbiome is decreased after chemotherapy exposure.

(41:31): That is independent of any antibiotic effect. We've also looked into CAR T-cell therapy, because the chemotherapy given for allo-transplant is much more intensive when compared to what's given for CAR T-cell therapy. Chemo administered prior to CAR-T did impact the microbiome, but certainly not as significant compared to chemotherapy prior to an allo-transplant.

(42:09): [Susan Stewart]: "What are your thoughts on the use of azithromycin in FAM treatment for lung GVHD? Do you think that the use of fiber and fermented foods still plays a similar role in spite of the continued use of azithromycin?"

(42:26): [Dr. Melody Smith}: So, azithromycin is not considered an anaerobic-targeting antibiotic. Its impact on the microbiome is present, but it's not as notable, and not one of those antibiotics that is as much of a concern. Again, while on antibiotics; fiber and fermented foods will help offset any changes that might be caused by FAM treatment. But azithromycin is not as damaging to the gut as some of the ones I was mentioning, like piperacillin, meropenem, or imipenem.

(43:06): [Susan Stewart]:  "Does CAR T-cell therapy cause a change in taste buds and impact appetite?"

(43:15): [Dr. Melody Smith]: Not generally. I have not really heard patients report a change in taste buds from CAR T-cell therapy. Certainly, the chemotherapy that's given to prepare the body for CAR T-cell therapy – like cyclophosphamide and fludarabine – can have some GI side effects, including nausea, and maybe a modest impact on taste buds. But it's not generally a common complaint that I hear patients report.

(43:59): [Susan Stewart]: "What can prebiotics contribute by specialists with concern that supplements might encourage bacterial infections? I was taking prebiotics without issue until advised to stop. Do you agree that they can cause bacterial infections?"

(44:19): [Dr. Melody Smith]: I think I'm just going to clarify; I think that question might've meant to ask about probiotics. Prebiotics would be fermented food or a high fiber diet. Probiotics are capsules that contain different bacterial consortia.

(44:40): And so, yes, even at my center, we don't generally have patients taking probiotics during their therapy. I think they vary from vendor to vendor, and are not very well regulated. I don't really see any potential clinical benefits when you can offset microbiome changes with your diet as opposed to taking bacteria in a capsule form.

(45:12): [Susan Stewart]: "Are yogurt and cheese considered fermented food?"

(45:19): [Dr. Melody Smith]: Some types of yogurts, like the kefir, but not cheese.

(45:23): [Susan Stewart]: "How can one prophylactically prepare the microbiome for treatment in advance?"

(45:33): [Dr. Melody Smith]: Again, I would say that one of the best things you can do is through the diet. The diet plays a critical role in the health of the microbiome. And so, knowing that you're going into a therapy where treatments may impact the microbiome, one of the best things you can do is just make sure you're going into it with as healthy a microbiome as possible. And that would be with diet. I think that's the most lasting impact that you can have and the most consistent impact you can have.

(46:09): And then, also knowing that the CAR T-cell therapies and allo-transplant, may impact dietary intake, the taste buds, and appetite for a period of time. Once you can, incorporate those things that are healthy for the microbiome back into your diet.

(46:34): [Susan Stewart]: This person wants to confirm her understanding. She said, "I think I've shied away from fermented foods because I was worried about the risk of GI infection. So, what I'm taking away from your presentation is that fermented foods are not associated with GI infection as long as I'm not neutropenic. Is that correct?"

(46:55): [Dr. Melody Smith]: Correct. As long as you're not neutropenic, I would say you are okay to consume fermented foods. We aren’t actually telling neutropenic patients, at least at my center, to shy away from fermented foods, but certainly fermented foods have live bacteria, and when you're neutropenic, the gut barrier is not as strong. So, bacteria can go from the GI tract into the bloodstream. But, even if you're neutropenic, you can still eat things like yogurt. I think that as long as you are complying with a neutropenic diet, which at least at our center, doesn't exclude yogurt, you should be fine.

(47:42): [Susan Stewart]: "My stomach always hurts. If it's not diarrhea, it's constipation. Miralax sometimes works. What else can I do?"

(47:55): [Dr. Melody Smith]: That can be a complex thing. It could be that there are medications that you're taking that could be contributing to constipation. Reviewing your medications with your healthcare team to see if any have a side effect of constipation is the first step.

(48:20): Another thing to consider is your diet. We've already talked about quite a few things in our diet, but I think one thing that's often forgotten or missed is the important role that fluid intake – water particularly – has on maintaining regular bowel movements. So just evaluate if you are hydrating as much as you need to, and as much as your body needs because that could also be an important feature.

(48:54): Additionally, I would like to mention that there are definitely changes to the gut after an allo-transplant. It takes some time for the bowels to recover after undergoing an allogeneic transplant. Patients may have loose stool for some time; that's not uncommon. That might be something that could improve over time if you are still pretty recent post your therapy.

(49:26): [Susan Stewart]: "Can fecal transplants help restore the diversity in the gut biome?”

(49:37): [Dr. Melody Smith]: Yes. Fecal microbiota transplants have been investigated in clinical trials to restore the diversity of the intestinal microbiome. There are ongoing studies that are actively interrogating that.

(49:49): I think one thing to keep in mind is that if you are considering or interested in this, I would ask whether there is a clinical trial in your area that you would be eligible for. I do not recommend attempting this on your own because there are risks associated with fecal microbiota transplants.

(50:11): I mention this because there have been some instances where folks have attempted to do fecal microbiota transplants from a loved one or something, and they're immunocompromised, and that's just not advised. And the reason one might do a fecal microbiota transplant is because it gives a transplant of the fecal microbiome from a healthy individual, or from patients who've responded to, for example, immune checkpoint blockade. There was a clinical trial where fecal microbiota transplant from responders was given to those who didn't respond, and those non-responders ultimately had a response.

(50:55): So, there are definitely benefits of fecal microbiota transplant, but the challenge or the risk is that those samples, when they're given, have to be screened for the bacteria that is in them. Our gut can sometimes have pathogenic bacteria – bacteria that could cause an infection. If you transmit that or give that to someone who is immunocompromised, that could cause a blood infection. There have been instances where patients have died, unfortunately, because of fecal microbiota transplants that transmitted a pathogenic bacteria.

(51:32): All that to say, yes, there is promise there in helping diversity and helping to improve clinical response. And that has been published in various clinical settings, but it's just not without its risks. It should be done under the supervision of a medical provider on a clinical trial at this stage.

(51:52): [Susan Stewart]: "Can stem cell transplant cause small bowel intestinal overgrowth?"

(52:05): [Dr. Melody Smith]: I am not familiar with any data in that space in terms of small bowel intestinal overgrowth.

(52:11): [Susan Stewart]: "Do patients routinely receive antibiotics prior to CAR-T or allotransplant as part of their therapy?"

(52:22): [Dr. Melody Smith]: It depends on the center and their treatment protocol, but many centers do give antibiotics and other antimicrobials like antifungals and antivirals to patients during the CAR-T or allo-HCT setting. Especially when they have low counts. So yes, it's pretty common to receive some prophylactic antibiotics.

(52:54): [Susan Stewart]: "Could teclistamab affect one's microbiome?"

(53:00): [Dr. Melody Smith]: There is no data right now on teclistamab in the microbiome, but I do know there are active studies looking at teclistamab and other bispecifics – including teclistamab and talquetamab – on the microbiome.

(53:22): In patients who are getting those therapies, their fecal samples are being banked by various investigators, and that data is forthcoming. Because of the data that we already have on immune checkpoint blockade and CAR T-cell therapy, I would hypothesize that the microbiome is implicated in bispecifics such as teclistamab, but that data is still being generated right now. I know there are a few investigators that I'm familiar with, who are looking at that specific question.

(54:05): [Susan Stewart]: "If you get the antibiotic injected into your blood, will it have the same effect as if you swallow a pill?"

(54:13): [Dr. Melody Smith]: Yes, it's not so much about the route of administration; it's the scope of the antibiotics' activity. So intravenous versus oral antibiotic administration is not more or less damaging to the microbiome. It's the scope of the activity of those antibiotics.

(54:34): [Susan Stewart]: "I'm on chronic medications; like meds for acid reflux, metformin, and antibiotics. What does that do to my microbiome, and how can I help improve it?"

(54:44): [Dr. Melody Smith]: The paper that I alluded to was really insightful. The one that looked at a cohort of patients who received an allo-transplant and looked at all the medications, not just antibiotics, they were exposed to. We already knew that antibiotics – some more than others – altered the microbiome. That paper did a score ranking of all different types of medications. I know that there is for sure some data on metformin in the microbiome.

(55:37): I think the one that has been more so investigated and reported on are proton pump inhibitors because those proton pump inhibitors decrease acid secretion, therefore they do also have a direct impact on the microbiome.

(55:54): If those are medications you need, definitely take them. I think the way to offset some of those impacts that those medications have on a consistent basis to your microbiome would, again, be dietary interventions to round out the things that your microbiome might not be producing as much.

(56:21): [Susan Stewart]: "I have chronic GVHD. Would a high-fiber or plant-based diet help reduce the inflammation?"

(56:33): [Dr. Melody Smith]: Referring to that dietary randomization study that looked at fermented versus high fiber – if I remember correctly – high fiber lowered inflammation more. So I think a high-fiber diet--it doesn't have to be plant-based, but definitely a diet rich in fiber--would help with decreasing the inflammation promoted by the microbiome.

(57:16): [Susan Stewart]: Closing. With that, we will wrap up this session. I want to thank Dr. Smith for a very interesting presentation and great responses to the questions. And, I want to thank the audience for asking some excellent questions. Please contact BMT Infonet if we can help you in any way. And I hope that you enjoy the rest of the symposium. Thank you.