Research depends on samples from patients and healthy volunteers. However, obtaining biospecimens from human subjects can be a challenge for researchers and patients alike. Home-based specimen collection directly connects patients to researchers, while alleviating the burden of travel to secondary sites. Using this approach, researchers efficiently collect patient samples in the comfort of their homes. This webinar, sponsored by Sanguine, will detail research experiences from researcher and patient perspectives.
Transacript:
Niki Spahich:
Hello, everyone, and welcome to today’s Lab Tools webinar. I’m Niki Spahich, scientific technical editor for The Scientist, and I’ll be moderating our discussion. Today our speakers Christine Von Raesfeld and Dr. Stephanie Culler will be discussing research experiences from researcher and patient perspectives. With that, let me introduce our first speaker, Christine Von Raesfeld. Christine is a leader in bringing a critically needed patient perspective to cutting edge medical innovation, a patient advocate committed to providing patients with chronic and rare diseases with the support they need. Christine works with patient advocacy organizations, industry representatives, and individual patients and/or families. Christine?
Christine Von Raesfeld:
Thank you for that introduction. Gosh, it makes me sound really busy. I wanted to say thank you for including me and thank you to Sanguine for giving me the opportunity to share my perspective. What we are talking about today is simplifying the patient participation in research. Before we begin, I’m going to tell you a little bit about me and a little bit about what I believe.
Christine Von Raesfeld:
Before I start, I just want to go over the difference between empathy versus sympathy, and I’ll let you know why in just a second. But empathy is feeling with or alongside someone, while sympathy is feeling sorry for them. The reason I am telling you that is because my story is a long one. It is dramatic and scary and everything else that you wouldn’t want to happen in your life. But with that story, I don’t want you to feel sorry for me. I want you to feel empathy and to feel with me. But don’t feel sorry for me, because I have an amazing life, and I’ve done some amazing things because everything that has happened.
Christine Von Raesfeld:
So, who am I? Like everyone else, I am a million things to a million different people. I’m a daughter, a sister, an aunt. But the main thing is I’m a person with my own beliefs. I have my own feelings and my own voice. I hope that by using my voice I can help to spark the change that we need in health care today. Medically, I have been diagnosed with multiple conditions. I have rare disease. I also deal with multiple autoimmune issues, including CNS Lupus. I had periods of time when I went through psychosis, and I had a psychotic break. I was hallucinating but managed to work my way back to some sort of normalcy. So, I advocate for chronic illness, rare disease, mental health. Anything that has affected me in some way in health care, I am willing to speak out about it. I use my experiences to try to evoke the change that we need here in health care.
Christine Von Raesfeld:
My health care journey, it’s a long one. It’s elaborate. You’ll see the pictures on the side of the screen which kind of show you where I’m at. In the top left corner is the brain damage I have from toxic encephalopathy which is poisoning from medication. I’ve had three joint replacements, both my knees, and a myriad of other issues. My chronic illness journey began at a very young age. I was five years old. Since then, I’ve had multiple diagnoses, several misdiagnoses, and long diagnostic time. My case management was not what it should have been. I have no real history of my disease. I was with a hospital that, when they switched over to electric medical records, just happened to lose all of mine. So, we recently found 5,000 pages, and I’m working my way back into finding out why I’ve stopped medications and basically my whole health care journey. I have diagnoses in there that I didn’t even know I had until we found those random papers.
Christine Von Raesfeld:
I also deal with mental health issues, some medication toxicity like I had explained before. I do have toxic encephalopathy, three joint replacements, and I’ve lost night vision, all due to medication used to treat the symptoms of my disease, not any of my diseases specifically. I’ve had negative experiences with industry and nonprofits which has led to some mistrust and general negative feelings sometimes in that space.
Christine Von Raesfeld:
But it has led me to some good things. I am part of some precision medicine initiatives, and I am a patient in Stanford’s Humanwide program. I’m sorry. I’m getting over a cold. I have done my pharmacogenomics where we may have lost my records, but I do now know that there are certain medications I can’t take because of that test. All of my experiences also brought me into this national advocacy where I’ve been speaking up on patients who, like me, are disabled, on Medicare, and need options.
Christine Von Raesfeld:
My own experience with research and trials started when I was young. When I was 14 years old, I was diagnosed with a rare blood disorder, thrombotic thrombocytopenic purpura. At that time, I did everything I could to find out about my disease. I would take the bus over to Stanford, and I would sit in the medical library for hours. I had this desire to get better and to improve my life. When things started happening and my diseases started to go downhill, when there was no options for some of the things that were affecting me, I decided that it was my desire to help everybody after me, including my nieces who would have been maybe showing symptoms of an autoimmune.
Christine Von Raesfeld:
So, at the time, and ever since my diagnoses, it’s been difficult. Clinical trials, I always wanted to participate. But if you’re ever been to clinicaltrials.gov, you know it’s not an easy place. It was hard to find trials that I qualified. I had no real resources or knowledge. I was with a hospital that didn’t even offer clinical trials. So, I knew basically nothing about it. The only resource I had was Stanford who had come in because I had a rare disease, and they were looking at me from that perspective.
Christine Von Raesfeld:
The way I found help, I started connecting with my community and different organizations like Sanguine. I actually met Sanguine at a walk a few years ago and from then started a relationship with them. They had taken my information and my conditions, and anytime they had a research opportunity or a trial that pertained to me, I would get a call from their staff. I’ve been in five trials because of Sanguine and a few more with my own hospital now that I’ve learned to advocate for myself.
Christine Von Raesfeld:
Considering the patient perspective if we’re looking at simplifying the whole clinical trials process, the first thing that I’ve noticed and what we’ve talked about with several people is awareness. Most patients aren’t even aware that clinical trials are an option, and they don’t know what they actually are. People think that clinical trials are somebody mixing up medications on a side room and there’s no testing and that they can die. People think clinical trials are only for people who have no other options.
Christine Von Raesfeld:
Second, another issue that we have is access. It’s difficult for a patient to find trials, let alone go through the whole enrollment process. If you’ve ever seen clinicaltrials.gov, you know there’s a series of inclusions and exclusions. Most patients don’t know the difference between any of that.
Christine Von Raesfeld:
There is also the issue of trust and fear. There’s a general mistrust in the patient community when it comes to pharmaceutical companies and the health care industry. As you know, a lot of people don’t tell their doctors everything. There was just a hashtag recently going around of #patientsarenotfaking. So, there’s a lot of issues there that really need to be worked on.
Christine Von Raesfeld:
Also, cost of clinical trials. If an insurance company isn’t covering the clinical trial, most of the patients who use that as an option aren’t able to afford that as well. There’s also the inconvenience of trials. So, not only the time it takes. The transportation, the gas. I personally am on Social Security disability, and my budget is limited. Paying for things like gas to get to a trial isn’t going to be one of my priorities.
Christine Von Raesfeld:
So, moving on, the solution that I think is that we need to bring back empathy. So, to ask first. Patients want to be involved, and many of them are willing to participate, but they’ve never been asked, and they don’t know their options. So, we need to educate patients. They’re more willing to participate if they’re informed and they’re aware and they know what’s going on. Engage them. Become a part of the community and give patients a reason to participate. One of the main reasons why I got involved was to give myself a purpose. I had spent a year in bed hallucinating and just kind of living this weird, strange, alternate reality. The purpose and giving people something to hope for is what got me out of bed.
Christine Von Raesfeld:
So, meet patients where they are. Make the process simple. If you minimize the burden on the patients, you’re going to maximize your outcome. By empowering the individual patient, you’re empowering an entire community. Other benefits of simplifying this for the patient is better patient engagement, and it’s cost effective. Most patients get most of their information from other patients. I myself know that I receive emails from nonprofits and organizations that I work for, and I don’t really look at all of them. But I do know if I get a message from another patient who’s done something, I’m more willing to look into that. You’re also looking at improved data capture and better research.
Christine Von Raesfeld:
Last, concierge services like these offered by companies like Sanguine I think can help increase the numbers of participants in clinical trials. By making the process easy and transparent, you lessen the burden for the patients, and ultimately you build trust. And that’s what we need here. You also ensure adherence when someone else becomes accountable, and you build a community committed to finding cures. Whenever it comes to working with patients and getting involved with patients, make it easy and make it worthwhile. Make sure that your patients know that there is a purpose, and there is a reason.
Christine Von Raesfeld:
That’s all I have for you today. So, thank you for giving me the time to speak. If anyone has any questions after we’re done, I am happy to answer.
Niki Spahich:
Thank you, Christine. As a reminder to our audience, you may ask questions using the question box at any time. Our panel will have a chance to address these after our next speaker. That next speaker is Dr. Stephanie Culler. Stephanie is the co-founder and CEO of Persephone Biome, a business taking a novel approach to improving the efficacy of current cancer [inaudible 00:12:12] leveraging the systemic impact of the gut microbiome on the human immune system. Persephone’s technology platform is based on collecting and analyzing gut microbiota samples from thousands of cancer patients, then using machine learning in conjunction with systems biology tools to understand the impact of gut microbe on patient prognosis. Results are used to design novel immunotherapist and companion diagnostics for cancers of unmet need.
Niki Spahich:
Dr. Culler is a recent graduate of the prestigious Y Combinator accelerator and has spoken at TEDxSanDiego. She received her PhD in chemical engineering from the California Institute of Technology under the mentorship of Professor Christina Smolke. Dr. Culler has had over a dozen publications and patents on synthetic biology and microbial based technology. Stephanie?
Stephanie Culler:
Thank you very much. I’d like to thank The Scientist as well as Sanguine Biosciences for this opportunity for share our stories with you today. I’ll be getting into some data. But, Christine, thank you so much for your inspiring story. Like you, while I haven’t been a patient, the inspiration for starting Persephone Biome was really from the loss of both of my grandmother to cancer over two decades ago. It inspired me to become a scientist to eventually start this company and form the mission around enabling a lifetime free of cancer.
Stephanie Culler:
At Persephone Biome, we’re developing a technology platform that we call Decode Design Cure. This brings together artificial intelligence with systems biology tools to rapidly develop what we call microbial based immunotherapy to enable our vision. We are developing essentially a cocktail of bacteria that are therapeutic that can be taken in combination with cancer therapeutics.
Stephanie Culler:
The following slide is essentially what we’re focused on. In the field of cancer, there’s been really a breakthrough with the discovery of immunotherapy drugs, specifically checkpoint inhibitors. As many of you know, these are a type of immunotherapy that essentially awaken the immune system and allow it to recognize, attack, and kill cancer quite effectively. It has been approved to treat over 40% of cancers, which is a very significant patient population in the United States alone, and as we know they can result in complete cures. We have cures for cancer.
Stephanie Culler:
The main problem is that 70% of cancers … Excuse me. 70% of cancer patients fail to respond to these therapies. For patients, similar to what was just discussed earlier, these therapies are very expensive, over $150,000 per year. Failures not only lead to lost lives but for pharma in particular this is a lot of money that’s being left on the table and lost in potential revenue. In addition, what’s been found through back-to-back science papers early last year that cancer patients who failed therapy, the 70 to 80% of cancer patients, are missing crucial bacteria in their microbiome.
Stephanie Culler:
We at Persephone Biome essentially have two solutions. One is to put back those missing microbes. So, we’re developing what we called microbial based immunotherapy that full enable the curative power of checkpoint inhibitors. Second, in order to really maximize the efficacy of our therapeutics, we’re developing what we call microbial diagnostics, essentially a simple, noninvasive diagnostic based on a stool sample from these patients to enhance the efficacy for everyone.
Stephanie Culler:
The gut microbiome, just as a quick refresher for all of you … The microbiome is the collection of all the microbes that live within our GI tract. What’s important here to recognize is that truly a healthy gut microbiome prevents and fights cancer. That’s the role of the microbiome, including many other disease. But now we’ve come … Through thousands of papers and publications in the literature, we now know that damaged microbiomes and what we call dysbiotic microbiomes are associated with disease, including cancer, diabetes, and Parkinson’s. And every day, there seems to be another connection to a notable disease.
Stephanie Culler:
On this slide, we have a schematic here that represents the key findings in the field of cancer immunotherapy and microbiome research. So, I mentioned that there were three seminal science papers that came out last year. These papers together demonstrated that gut microbes very much impact patient response to checkpoint inhibitor. What was found and shown on the left-hand side is that for the majority of cancer patients, those that are nonresponders and 70 to 80% of cancer patients, who failed therapy, they are missing crucial gut microbes. As a consequence, they have a severely impaired immune system, and it doesn’t allow them to respond to these checkpoint inhibitors.
Stephanie Culler:
This is in contrast to the 20 to 30% of cancer patients that do respond to checkpoint inhibitors. They essentially have a full functional microbiome, quite diverse. So, lots of different kinds of gut microbes, diverse in function. And their immune system is on. It can respond to the checkpoint inhibitor.
Stephanie Culler:
Our goal at Persephone Biome is to convert these immunotherapy nonresponders into becoming responders with what we call microbiome medicines or, as the FDA has termed our product, a live biotherapeutic, which restores these missing gut microbes to turn on the immune system. We want to go from 20 to 30% potential cure to 50% or higher. That’s the mission at Persephone Biome.
Stephanie Culler:
In order to do that, we’ve built an artificial intelligence driven drug discovery platform that very much leverages patient data, patient specimens, that we collect through efforts with Sanguine Biosciences as well as other partners. But patient specimens is really what drives our research. Without it, we wouldn’t be able to develop the therapeutics that we’re looking to. This is really a first step in precision medicine for our field, and being able to access a wide variety of patients for our research is really critical.
Stephanie Culler:
So, how we use artificial intelligence … We mainly use it right now to discover the missing gut microbes in these cancer immunotherapy nonresponders. At a very high level, to walk you through this schematic in our technology platform that really allows us to go rapidly from patient data to first generation therapeutics. Hopefully in the clinic in the next year and a half, we begin the journey with patients. We begin the journey with their specimens, mainly stool, which is a reflection of what’s happening in the gut microbiome, as well as blood samples to understand what’s happening in their immune system and how they’re responding to the immunotherapy. We also collect the same samples longitudinally from healthy individuals so that we can compare the results from cancer patients to those that do not have cancer.
Stephanie Culler:
We then perform something that’s called decoding, and this is where systems biology tools come in, mainly omic techniques like genomics, DNA sequencing, transcriptomics, RNA sequencing, proteomics, essentially protein sequencing, and metabolomics, looking at all the metabolites. We perform these analyses on both the stool and the blood, and what that allows us to do is essentially unlock what we call the metabolic relationship between the microbiome, the human microbiome, and the immune system. We identify the bacteria, their function, the metabolites, and how that impacts immune response.
Stephanie Culler:
All of these complex data sets, or omics data sets, are then fed into machine learning. The machine learning then rapidly looks for essentially patterns that are unique in these cancer patients that are nonresponders. With this, we are able to then discover what are the missing gut microbes and their function, or how does that impact a patient’s response to immunotherapy. We then further use computational models to define and essentially refine the therapeutic, and then go into the lab and build our consortia, either rational mixtures of gut bacteria that have been isolated from healthy individuals.
Stephanie Culler:
Through these efforts, we’ve collected and discovered over 1,000 strains of gut bacteria that we can use as the input to our therapeutic. We iterate this approach going through and then validating our therapeutics both in vitro and in vivo, in mouse models of cancer, until we have a very robust therapeutic.
Stephanie Culler:
Now, on the following slide is an overview of our campaign called Poop for the Cure. This is a nationwide collection of whole stool samples for our research. And the reason why we initiated this campaign was because of the difficulty in accessing stool samples. There are no bio banks for stool samples that exist today. There are no standardized techniques. This is not something that’s implemented as a standard sample that’s received from patients on clinical trials. There just does not exist an infrastructure.
Stephanie Culler:
As we started this effort of collecting stool samples from cancer patients as well as healthy individuals, we quickly realized that the kit we were previously using was not sufficient. It was difficult to use. We had a lot of complaints. And really thinking with the patient in mind, we wanted to take the stigma out of providing a stool sample. We wanted to make it easy to use, and we wanted to make it fun and also educational. We want people to understand that there is a tremendous wealth of information in a stool sample, and we’re just beginning to unlock what that data means. But in order to do so and eventually develop therapeutics and diagnostics and other potentially down the road consumer applications, we need to be able to get these samples.
Stephanie Culler:
So, that’s how we came up for Poop for the Cure and redesigned our kit, as you can see, to look like a luxury handbag. We have an online questionnaire that examines a person’s medical history and allows us to bring in thousands of stool samples to really enable our machine learning platform. We are looking with Poop for the Cure for stool samples from anybody with cancer, those patients that are in remission from cancer, as well as healthy individuals. In return for a stool sample, we provide the donor a $50 gift card as well as very cool Poop for the Cure T-shirt. We implement this kit on our observational clinical trials, which I’ll describe shortly.
Stephanie Culler:
So, on this page is a dashboard of the efforts that we’ve conducted to date. Again, we need thousands of patients’ samples in order to really perform and develop precision medicine. As you can see, we’ve had very good success with Poop for the Cure to date, over 1,500 patients involved. It’s growing daily. We have coverage from the entire United States, which is really critical when we’re talking about designing therapeutics for diverse patient populations and making sure that our therapeutic will work for both men and women and individuals with different ethnicities.
Stephanie Culler:
We have collaborators. As I mentioned, Sanguine Biosciences has been very critical in really enabling our science, going from an idea in a project proposal to initiating getting patient samples within a very short amount of time. Other efforts take months to potentially more than a year to get the infrastructure in place to collect samples from patients on clinical trials as well as at home. So, we’re very thankful for that relationship.
Stephanie Culler:
We also have ongoing observational studies with UC San Diego Moores Cancer Center as well as City of Hope. These studies are slightly different than Poop for the Cure in the sense that they’re longitudinal. So, these are studies that go on for months if not years where we collect every few months a stool and a blood sample from a patient. And that’s really critical when we go to talk about designing our therapeutics and what’s needed there.
Stephanie Culler:
Also on this dashboard I have a little bit of a sample of the types of metadata. We have samples from a diverse set of cancer types, so pretty much all the top cancers as well as those that are rare, and a good subset of patients who have been receiving the FDA-approved checkpoint inhibitors. This is all critical, because, if we go to design therapeutics for a number of different types of cancers, we have a large database which we can mine to start the development.
Stephanie Culler:
The finally going back to patient advocacy, the patients are the ones who really support our research. Much of the growth in terms of donations have come from our patient support group nationwide. We can’t thank them enough for their help.
Stephanie Culler:
Then this is an overview of just the types of longitudinal studies. I would say 70% of our efforts at Persephone Biome are from collections that we’ve received through longitudinal manners. Longitudinal collection is very, very critical, because it allows us to understand the changes in the immune system as well as the microbiome of these patients over time, and that helps us better understand two things: one, designing our therapeutic, we want to understand the needs of the patient throughout the course of treatment as well as their cancer; and two, to develop robust therapeutics. We want to be able to take a stool sample before they receive immunotherapy to better predict if they will respond to that drug, but also, how can we find the right patient who will be most likely to respond to our therapeutic? That’s really the goal there, to maximize efficacy.
Stephanie Culler:
Getting into the technology, I want to describe a little bit more about our decoding, and I’ll present some data shortly. As I mentioned earlier, the real focus here is to decode the difference between nonresponding cancer patients on the left and those that are responders on the right. We really want to understand the metabolic relationship between the microbiome and the immune system that enables response. So, what do the microbes … What do they produce? What are the metabolites they produce, and how does that impact the immune system and in this case cancer patients’ response to immunotherapy?
Stephanie Culler:
So, essentially on the right-hand side, if you look at the schematic, we are trying to use these techniques to map out the mechanism. We’re mapping out through genomics or deep whole genome sequencing. We’re validating and discovering what are the microbes in the stool samples of these patients, the metabolomics. We find the metabolites through immune profiling or immunophenotyping. We then understand the immune response. Then through either patient provided data or physician provided data, we understand their response to the immunotherapy drug.
Stephanie Culler:
The very first step in our process on trying to discover what’s truly critical in the microbiomes of these cancer patients is to perform whole genome sequencing, essentially DNA sequencing, on the stool samples that we collect. From these patients, essentially the stool sample has a collection of gut microbes that reflects the environment that exists within their colon. We then provide DNA sequencing, perform DNA sequencing. And from that, we then have a DNA sequence that we can mine to see what’s different between cancer patients that are nonresponders than those that are responders.
Stephanie Culler:
From that, we’ve been able to, through analysis of several hundred patient samples, identify about a half a dozen to 16 or so gut bacteria that are either clearly missing or a very low abundance in these cancer patients. We believe that these are the microbes that are responsible for patient response, and these are the microbes that essentially make up our therapeutic.
Stephanie Culler:
On the following slide is results from whole genome sequencing of stool samples from three particular patients. Each pie chart that is shown here is the result of whole genome sequencing, so DNA sequencing, of these stool samples. The pie represents the entire microbiome composition from somebody, as well as each slice of the pie represents a different gut microbe.
Stephanie Culler:
What you can see with the cancer patient who’s a nonresponder on the left-hand side, a few things. One, they have very low diversity, so limited kinds of bacteria. But what’s been striking that we’ve observed consistently throughout our dataset with cancer patients who are nonresponders is that one or two microbial species essentially dominate their microbiome. This is concerning, because these species can be highly inflammatory in nature, that can cause cancer, those that have been actually connected to carcinogenesis, and finally many of them are pathogens. We see this pretty consistent with the advanced cancer patients who are nonresponders.
Stephanie Culler:
What’s striking to us is that this information today is not provided to patients. Again, as I mentioned, there’s not infrastructure for being able to review this type of data with a physician and have an actionable insight. That’s really the goal of our efforts at Persephone Biome. It’s not just to develop therapeutics or diagnostics but to have some type of actionable insight from this type of data.
Stephanie Culler:
Next to the patient who’s a nonresponder you have a microbiome sample from a cancer patient who has responded very well to immunotherapy. In fact, they are currently in remission. As you can see, it’s a very diverse microbiome, I would say very similar in nature to that of a healthy person.
Stephanie Culler:
As we go to this next slide, what we have discovered … As I mentioned earlier, we have discovered that these cancer patients are missing crucial gut microbes. What I have shown here is just a display of essentially the abundance of these microbes in all of the stool samples or a portion of the stool samples we’ve collected and analyzed to date using whole genome sequencing.
Stephanie Culler:
So, on the Y axis you have microbes A through J. These are all microbes that we have identified to be statistically different between cancer patients, which are dots in dark blue, and healthy controls, which are dots in light blue. Again, each of these dots represents a whole microbiome sample from that sample, and then the amount of that microbe is shown essentially on the X axis.
Stephanie Culler:
We consider anything that has an abundance less than 10 to the -4th to be essentially undetectable. So, as you can see here for the majority of these microbes, the cancer patients seem to have either low abundance or are essentially missing these microbes. Again, these are the microbes that we’ve identified that we believe are the ones that we need to push forward for therapeutic purposes. Cancer patients in general are not just missing one or two microbes. It’s a set of about 12 to 16. So, all of the microbes I’m showing here are essentially missing, or those that are really, we think, important for immune response to checkpoint inhibitor therapy.
Stephanie Culler:
On this slide is a different pictorial view of the data I just showed you, but it looks over our entire dataset that we have collected today. Again, this is from whole genome sequencing, and this is what we call a volcano plot. On the right-hand side are bacteria that we have found to be enriched in cancer patients. So, not only does our technology platform identify the bacteria that are probably good for you as well as important for response to immunotherapy, we can quickly identify the bad guys or the pathogens.
Stephanie Culler:
What is shown here on the right-hand side and highlighted are a few types of bacteria that have been known to either cause disease or are highly inflammatory. I’ve highlighted Clostridium difficile, a very infectious microorganism, as well as B. fragilis which produces an endotoxin that causes inflammation.
Stephanie Culler:
On the left-hand side is bacteria that are enriched in healthy individuals, and what I’ve highlighted as some of the missing microbes. The Y axis here shows the statistical significance, and what I have put into the boxes are essentially those that we find to be very important between healthy individuals and in cancer patients.
Stephanie Culler:
So, then how do we use artificial intelligence to then look at our data and drive the development of our therapeutic? Essentially, we use artificial intelligence to predict our therapeutic composition. As I mentioned earlier, we’ve discovered missing gut microbes that we think are very important for patient response to immunotherapy. Well, there’s quite a few of these bacteria, and that’s a very large sequence base.
Stephanie Culler:
We use essentially artificial intelligence to look at combinations of gut bacteria that, when added in silico, so computationally added back to a stool sample that is a nonresponder, what are some combinations of gut bacteria that can convert that nonresponding stool sample into becoming a responder? So, what are the therapeutic combinations of gut bacteria that convert somebody from becoming a nonresponder to a responder? Essentially that’s what the AI algorithm puts out to us. The output of the algorithm is a set of therapeutic candidates that has mixtures of gut bacteria that shows computationally can do that conversion.
Stephanie Culler:
So, to reduce the number of combinations that come out from artificial intelligence and reduce it to a size that we can experimentally validate, both in vitro and in vivo in mouse models of cancer, we look at the gut bacteria that are selected most often by the machine learning. That then becomes essentially our top gut microbe that we then validate as our therapeutic. We typically validate therapeutic compositions on the order of four to six gut microbes. We don’t like to go higher than that. Simply from a manufacturing standpoint, it becomes technically very challenging to do that and can cause issues when you’re trying to scale for clinical trials.
Stephanie Culler:
The following slide, we wanted to show a few things, one, that there is a causal relationship between the biome and response to checkpoint inhibitors. We also wanted to show efficacy of our therapeutic in converting a nonresponding microbiome into becoming a responder. In order to show causation, we performed a fecal transplantation from a cancer patient who’s a nonresponder to immunotherapy and transplanted that into a cancer mouse model. We in conjunction administered a checkpoint inhibitor, and we looked for the response in the mice.
Stephanie Culler:
As you can see on the left-hand side in red, the mice essentially who were fed this fecal transplant from a nonresponder became a nonresponder. They had a very low response to the checkpoint inhibitor, as you can see. Large tumor volume signals low response to the checkpoint inhibitor. Then we wanted to see if co-administration of our therapeutic, PB-327, a consortia of six gut microbes fed orally to the mice, those that were fed the nonresponding fecal material. Could we rescue the response? Could we convert this human nonresponding microbiome into become a responder? And indeed, you can see the case.
Stephanie Culler:
So, this was a very important study for us, because it proved the translational proof of concept that we’d like to achieve in the clinic, that we can treat a human nonresponding microbiome into becoming a responder. This is actually how we validate our therapeutics, again, being very patient-focused. The design of our therapeutic is based on patient data, real world patient data. How we validate our therapeutic is in the background of a human nonresponding fecal sample. That’s what we think is important for derisking and improving how we translate our therapeutics to human patients.
Stephanie Culler:
In summary, our technology platform, the decoding has allowed us to rapidly discover the key missing microbes from cancer patients who are nonresponders. We’ve been able to use our design technology to create a therapeutic that contains those missing microbes required for response. And finally, in terms of the cure aspect, we have been able to show … Again, this is in mine. We’ve been able to convert a human nonresponding microbiome into becoming a responder. We look forward to hopefully being in the clinic in mid 2021, so in about a year and a half. We’re focused on optimizing our therapeutic and achieving our IND sometime next year.
Stephanie Culler:
So, thank you for your time. Just in closing, the vision of our company right now is to treat, eventually cure, and we want to see diseases prevented. Cancer of course is our first focus, but we believe that we’re developing a technology platform that can be applied to virtually any disease really. Again, it’s all based on patient samples, the medical history of these patients, to really inform the design of our therapy. In closing, the patients are waiting, and we are focused on trying to deliver therapies in a meaningful and a timely manner to them. Thank you.
Niki Spahich:
Thank you, Stephanie. The audience has submitted several questions, so let’s get to them. Christine, can you briefly walk us through working with a concierge service like Sanguine? How do patients sign up and what happens next?
Christine Von Raesfeld:
I met Sanguine actually out at a community event. I was doing a walk for a local lupus foundation, and they had a booth. The women that they had working the booth were very friendly. They knew the disease, and they were very easy to talk to. They were offering an incentive, a cash or a gift card incentive, I think it was, if you signed up and you qualified for a new type of lupus study. So, of course I was looking into that, clinical trials, and they came in right at the right time. So, of course I signed up, because anything I can do as a patient to help with research, I’m going to do.
Christine Von Raesfeld:
I signed up. They contacted me the first time, and I went through with everything. What they did do, which was amazing to me, is I didn’t have to do anything. They called me on the phone. They had somebody walk me through the process. They told me what they were doing. They said what they were looking to do. They asked my permission. They told me what to expect along the way. And then openly asked for any questions. Completely guided me through the process.
Christine Von Raesfeld:
Instead of me having to go get my medical records and try to sort out everything myself, they sent me a DocuSign document. They had me sign it, and they got all of my medical records for me. On most of the ones that I’ve done for them, they’ve sent a phlebotomist out to my home for the first time and collected samples from my home, which was amazing to me, especially at times where I wasn’t driving or didn’t have reliable transportation. So, that helped a lot there.
Christine Von Raesfeld:
The girls that had called me and that I was in contact with knew everything about these studies. I could call at any time with any questions, and I knew exactly what to expect. Every time they have something that I qualify for, they contact me, which is nice, because I don’t have to go out looking for myself.
Christine Von Raesfeld:
So, I have done five. I was on my fifth one back when I spoke with Sanguine last year. I’m just waiting for other opportunities. I’m happy to give any samples. The fact that they make it easy and come out to my home, and they schedule it around me, it just makes it so much simpler. I don’t have a headache of worrying about anything. They’re very gracious. They call. They make sure everything went well after the whole procedure and make sure that I’m happy. And they’ve been in our community. So, it’s nice to see a company that actually gets into the community.
Christine Von Raesfeld:
When I hear about something, I tell my friends. Like I said before, I can get a million emails from a million different organizations, but if a friend or a patient tells me that they did this and they like this and these are the reasons why, I’m going to go with them.
Niki Spahich:
Great. Thank you. Stephanie, do we know what causes the microbiome dysbiosis in cancer patients? Is it the cancer itself, or is there a predisposition that then leads to the cancer?
Stephanie Culler:
That’s a very good question and a question that I think a lot of individuals and researchers are contemplating and looking into right now. For us, we don’t look too much into what’s causing this dysbiosis. We’re focused on treating advanced staged cancer patients. Most of the patients we treat have failed prior therapy, mainly immunotherapy, and some have failed chemotherapy and other types of therapies that are applied.
Stephanie Culler:
But what we see, and there’s a lot of data in the literature, is that we’re seeing damage that is caused by years of various therapeutics, antibiotic use, aspects of diet and lifestyle. All of these are different factors that play a role into causing dysbiosis. It’s difficult to parse out the impact of cancer or vice versa, just because of the complexity of cancer, and everybody’s cancer is different. We can somewhat parse that out in animal models, but still it’s very, very difficult.
Stephanie Culler:
So, I would say that really the focus has been trying to understand more so not necessarily how the microbiome causes this dysbiosis or vice versa. It’s really how to understand what’s happening with dysbiosis, how to prevent dysbiosis. I think those are more of the factors that I think researchers are focused on today.
Niki Spahich:
Great. Thanks. Christine, do you think it’s more important to educate doctors on clinical trials or go directly to the patients for education?
Christine Von Raesfeld:
I actually think that doctors should know about them. I don’t think it should be a doctor’s duty. I think that it should be patients telling other patients. Personally with my doctors, they don’t have enough time. I have enough issues, and, when I go in, it’s to discuss my medical issues, to discuss my symptoms. I know they have limited time. They have limited staff. I’d like them to focus strictly on my health when they’re working on that.
Christine Von Raesfeld:
As far as clinical trials and things like that, most of that I’ve heard from other patients. I get them now. I’m at a teaching hospital, so it’s a lot easier. I have my doctors over at Stanford throw me in whatever I qualify for with them. But most people don’t have that … I don’t know if you’d say that’s a luxury, but for me it is. Most people don’t have that access. And I think the patients are the ones that need to know. They’re the ones making the decisions, and they’re going to listen more to patients. I think that the conversation in the patient community … I get more out of the patient community than I do in my doctor’s office. A lot of times I come to my doctor’s office with things that he can confirm because of things that I have said.
Christine Von Raesfeld:
So, it’s an interesting mix, but I do think the doctors have other things on their plates. I think it’s nice for them to know that there are clinical trials running for certain things, but I don’t think it’s their responsibility. I think patients telling other patients is going to get the word out there, and it’s a reliable source when you’re going through other patients who have been through it and who … They’re the ones that are giving their blood, sweat, and tears for these studies. I think it’s just that patient-to-patient community that we need to build.
Niki Spahich:
Thanks. Stephanie, is the response to your therapeutic short term or long term in the [inaudible 00:47:08]
Stephanie Culler:
Right now, a therapeutic is always invalidated in the context of preclinical mouse studies. For the most part, the response is we only validate the response during the cancer treatment. Our focus is to having complete regression in the mouse models which we hope will translate to regression in cancer patients. Our therapeutic would be taken daily, similar to how you take probiotics, for example, or a vitamin. We believe that the actually of our therapeutic, mainly the bacteria, are temporal. These are bacteria essentially that do not engraft. So, from a permanent standpoint, we don’t believe that our therapeutic will have essentially a permanent effect. We’re really trying to focus on enhancing the efficacy of the therapy that we’re combined with.
Stephanie Culler:
Now, that being said, this opens up the door to having a different therapy, a different version of our therapy post that of the combination. So, once somebody is in remission, we may want to develop a different type of therapeutic that can be taken chronically to really create a homeostasis. This would likely have a lot more different diversity in the bacteria that’s there as well as those that engraft.
Stephanie Culler:
One other reason why we don’t necessarily for this therapeutic purpose want our bacteria to engraft … This is a point of discussion in the microbiome space today. We want our modality to be very similar to traditional drug therapeutics that don’t have a permanent effect on the patient. We want them to essentially wash through somebody’s system in case we wanted to provide a different type of microbial therapeutic. That’s really the focus and how our therapeutic works today.
Niki Spahich:
As a follow-up to that, have you looked at all at the mouse gut microbiome after the therapy has kind of gone through? Are there differences before and after that are maybe lasting?
Stephanie Culler:
Yes, and that’s what I mentioned. We analyze stool samples collected from mice throughout the study as well as once dosing stops for over a month, for example, to look at the engraftment of our bacteria. I would say a small fraction of the bacteria that we have included in our composition engraft, and those are the ones that are essentially associated with the gut mucosa that in terms of physiology have been associated to engraft and be a part and kind of stick to the GI tract. Those are the ones that engraft. But I would say by and large, our bacteria are transient in nature, and they wash out of the system within hours of the dose.
Niki Spahich:
Thank you. Christine, based on your own experience, could you please explain further the importance of showing empathy as a patient advocate in the health field?
Christine Von Raesfeld:
Do you mean showing empathy as me being a patient advocate, or as somebody in industry looking at a patient advocate?
Niki Spahich:
I believe someone looking at the patient.
Christine Von Raesfeld:
At the patient. I have a really quick story about that. I had gone to a rare disease drug development seminar, and I sat in a room with a bunch of executives. They were talking about getting together and collaborating and getting a rare drugs market. In the room, the woman that was speaking had said, “How many in this room would be willing to collaborate and work together?” While we sat there, nobody raised their hand.
Christine Von Raesfeld:
So, after the session closes, as you all know at conferences they open it up to questions. At the end of the session, I stood up, and I said, “I’m not one of you, and I’m a patient. To sit in the room and to know that you are one of my only hopes in getting a cure for these diseases, and to know that you’re going to go home to your family and your children and plan your vacation, and I’m going to go home and figure out what I need to eat or what I’m giving up to pay for meds, it really is disappointing to know that that would happen.”
Christine Von Raesfeld:
I think people don’t think of patients and what they’re working for as patients. They don’t look at us as people until illness hits somebody in their family, and then they think … It puts a different spin or a different perspective. So, I think you have to realize that people that are next to you, and that they look normal, they’re also people that could be dealing with illness. I think that’s a big, huge part that people lose focus. It becomes about other things, and it’s not about the patient. I think just having that empathy and knowing that this person is giving everything to you. They’re literally giving you their blood and their sweat and their tears and their poop. Just to look at them as somebody makes a difference.
Christine Von Raesfeld:
So, I think everybody in the world does things for a reason or to get something out of it for themselves, and so just look at it as, I guess, they’re people. We’re not numbers, and we’re not samples. It puts a different perspective and a different spin on everything, and I think that empathy could really make a difference in building communities and even just engaging people in clinical trials, just building that trust and building these communities where you get in there, and you’re helping these people. If you help them get in these communities, they will do everything to help you. I think that just needs to be brought back.
Niki Spahich:
As maybe a little bit of a follow-up, how can really any patient better advocate for themselves in the doctor’s office and beyond?
Christine Von Raesfeld:
I think just being prepared, knowing what you’re going into, a lot of times taking someone with you. I like to email my doctors beforehand with my concerns so that they know ahead of time, because you do have limited time with your doctor. I think just focusing on telling your story and knowing that, whatever you are feeling is right, and that nobody else can tell you how you feel.
Christine Von Raesfeld:
For a long time when I was having the brain issues, I was going in, and my blood test was fine. I kept saying I felt off, and I didn’t feel right, and the doctor said, “Everything looks great. You look amazing. Go see a psychiatrist.” So, I did. For two years, I saw the psychiatrist who said, “It’s not my issue, and you need to get checked out again.” By the time I did, I had ended up with toxic encephalopathy.
Christine Von Raesfeld:
I think you know your body best. You know what you need and to focus on what you need. If somebody doesn’t hear you, to go to someone else. So, I think that’s just the most important thing. I know a lot of people who didn’t advocate for themselves and who aren’t here anymore. Just to keep in mind that nobody else knows you, and you’re not crazy for what you’re feeling.
Niki Spahich:
Thank you. Stephanie, could you supplement the missing metabolites rather than the microbes as therapy?
Stephanie Culler:
That’s a really good question. The number of metabolites and metabolic pathways that we discovered that we believe are part of this is immense. From a FDA perspective and a small molecule approach, it would be very, very challenging to do so. The response and the role of the microbes seems to be pleiotropic, so multiple mechanisms that are inducing an immune response that’s beneficial to these cancer patients. That is something that we looked into initially, but the results are just so complex that it’s almost infeasible that it’s a single metabolite or just a few. It seems like there’s many metabolites that are involved at different levels and would become very challenging from a drug perspective to pursue that route.
Niki Spahich:
Okay. Stephanie, this next question’s for you. Do gut microbes impact treatments to other diseases other than cancer in the same manner by interacting with the immune system? Does anyone know anything about that?
Stephanie Culler:
Yes. In fact, there’s been many, many reviews as well as some clear studies looking at that. One of the reasons … I’m a chemical engineer and fascinated by the, I call it, catalytic capacity of the microbiome. Most people don’t know that there are about 100- to 300-fold more genes in the microbiome than there are in our own cells, so immense opportunity in terms of chemistry. This chemistry actually impacts how many drugs work. Some cases, favorably. Some cases, inactivating the drugs. And in other cases, that chemistry is what’s involved in how the immune system response to that therapy happens.
Stephanie Culler:
So, what we’ve seen in the literature is that there are at least 50 or so FDA approved drugs that are impacted by the microbiome through those mechanisms, some catalytic and some in ways that the immune system counteracts or affects in ways we don’t know yet. But we know that this is the case for not just cancer therapies, including checkpoint inhibitors or chemotherapy, but this has happened with therapeutics that are used for Alzheimer’s. This has happened with therapeutics that are used for cardiovascular disease or actually cardiac arrest, places where you really don’t want to have almost a black box impacting efficacy.
Stephanie Culler:
So, yes, what we determine in terms of these rules of the microbiome and the impact on just in the case of cancer can be equivalently applied to kind of unlocking how the microbiome impacts the immune response or some type of chemistry that’s involved with other types of therapeutics and for a variety of diseases. Absolutely.
Niki Spahich:
Unfortunately, that’s all the time we have for today. If you have any further questions, please consider reaching out to the speakers directly. Their email addresses are shown on the screen. As a reminder, the webinar will be archived on The Scientist website. I’d like to thank everyone who took the time to join us today and particularly those of you who shared your questions and comments. On behalf of The Scientist, I’d also like to thank our speakers, Christine Von Raesfeld and Dr. Stephanie Culler, as well as our webinar sponsor, Sanguine. Thanks, everyone, and goodbye.