Projects

Our overall aim is to get novel treatment approaches to cancer patients as quickly as possible by accelerating the creation of solid and reproducible evidence. We support mechanistic, observational and interventional studies across the full spectrum of scientific and clinical research as well as other projects that may act as accelerators to our mission. There are two essential features of our endeavors: 1) each project is complementary within the framework of our nutrition/microbiome/immune system axis, 2) each institution conducting a research project nominates a Seerave “Fellow”. These “Fellows” together with their colleagues are encouraged to collaborate across disciplinary and geographic borders to increase the overall impact of the Seerave Foundation.

Preclinical mechanistic (Evidence generation)
Clinical observational (Evidence generation)
Clinical interventional (Evidence generation)
Other activities (Enabling projects)

Cancer-associated ileopathy in cancer patients

Prof. Laurence Zitvogel

show details

Impact of personalised nutrition on breast cancer patients

Prof. Eran Segal

show details

Characterising and modulating cancer-associated ileopathy to increase the efficacy of immunotherapy in cancer patients

Goals

1. Use of high dimensional technologies such as ileal single cell transcriptomics and spatial transcriptomics to understand what pathological pathways are up- or downregulated when and where during cancer-associated ileopathy.

2. In vitro modelization using enteroids to identify the stimuli that contribute to the onset of ileopathy.

3. Description of the human syndrome: collaborative work with pathologists to identify neuroendocrine and neurological pathways in tissue sections and the specificity of the pathological disorder.

4. Determine what secretory components of tumours transduce a signal from the tumour to the ileal crypts.

Partner institution
Principle investigator
Prof. Laurence Zitvogel
Seerave Fellow
Dr. Gladys Ferrere
Background

Whether gut dysbiosis is cause or consequence of tumor establishment and how it controls tumor progression remain open questions in immuno-oncology. Over the last 3 years, the Zitvogel lab has accumulated evidence showing that 50% of transplantable extra-intestinal experimental (mouse) malignancies as well as human cancers trigger a set of pathologies in the small intestine (the ileum), that were collectively named cancer-associated ileopathy. These defects include villus autophagy, apoptosis of crypt cells in the terminal ileum culminating in epithelial atrophy of the ileum, increased gut permeability, and protracted Gram+ related -dysbiosis that contribute to cancer growth and resistance to immunotherapy. This corollary syndrome of carcinogenesis coincides with neuroendocrine and Paneth cell activation and proliferation in mice and humans. Single cell transcriptomics and immunostainings revealed that stem cells and neuroendocrine cells upregulated neutrotransmitter signaling. Vancomycin (an antibiotic specific against Gram+ bacteria) and propranolol (an inhibitor of adrenaline signaling) could both transiently prevent cancer-associated ileopathy and antagonize tumor progression. The project thus aims at a) further deciphering the cellular (tumor, immune, neurological) or molecular/metabolic cues underlying cancer-associated ileopathy and b) identifying potential interceptive measures to inhibit the underlying vicious circle.

Timeline
Start
01/06/2021
Hide

Personalised Nutrition Immune Response Algorithm (PNIRA) project: personalised nutrition intervention to boost immune response and efficacy of cancer therapies.

Goals

Seerave Foundation is supporting a randomized clinical trial that assesses the effects of a personalised nutritional intervention in combination to conventional therapy in breast cancer patients.  The trial will be performed as a collaborative effort between the lab of Prof. Eran Segal at Weizmann Institute and Sheba Medical Center. The aims of the trial are 1) to develop predictive algorithms from associations between nutrition, glycemic response, gut microbiota, antibody and T cell responses, 2) with the aid of these algorithms, to validate and/or further develop personalized dietary intervention (and possibly other lifestyle) protocols which will improve clinical outcomes and minimize the use of invasive medicine, and 3) extend these algorithms and other protocols to other cancer types.

Partner institution
Principle investigator
Prof. Eran Segal
Seerave Fellows
Dr. Thomas Vogel
Michal Rein
Background

Improving the success of adjuvant treatment of breast cancer and understanding the underlying causes of interpersonal variation in the response to treatment is of utmost importance for breast cancer patients’ prognosis and survival. Multiple factors may contribute to this inter-personal variation, including baseline gut microbiome composition, diet, immune system repertoire, and interactions among all of these factors. It has previously been established that a) diet can shape the microbiome both in terms of composition and function, b) the microbiome contributes to shaping the immune system. It is thus conceivable that optimizing this axis by applying a personalised nutritional regimen based on gut microbiome profiles will boost anti-tumour immune responses and improve the efficacy of therapy in breast cancer patients.

For more information on the study, visit NCT04079270 at clinicaltrials.gov

Timeline
Start
01/07/2018
27/03/2019

IRB approval Sheba Hospital

24/07/2019

First participant recruited

26/02/2020

First participant finishing dietary intervention

Hide

Controlled dietary interventions in melanoma patients

Prof. Jennifer Leigh McQuade

Prof. Carrie Daniel-MacDougall

Prof. Jennifer Wargo

Prof. Lorenzo Cohen

show details

EPFL

Lausanne, Switzerland

AI-assisted food tracking for nutritional research

Prof. Marcel Salathé

show details

Controlled dietary interventions in melanoma patients to assess the feasibility and efficacy of enhancing immunotherapy.

Goals

Seerave Foundation is supporting a series of clinical studies to assess the effects of nutritional intervention alone or in combination with conventional immunotherapy in melanoma patients. The aims of the trials are:

1) In a Phase I study: to demonstrate the feasibility and adherence of a controlled feeding study in up to 20 disease-free melanoma patients consuming either high-fiber or ketogenic diets.

2) In a Phase 2 study: to (i) demonstrate that a high-fiber diet can modulate the gut microbiome to a pro-immunotherapy response phenotype in a cohort of 42 metastatic melanoma patients undergoing anti-PD1 immunotherapy (ii) demonstrate that a high-fiber diet can enhance systemic and anti-tumor immunity.

3) To establish novel biomarkers that are indicative of diet-induced modulation of the microbiome and immune system, which will help guide the design of future preclinical and clinical studies.

Partner institution/s
Principle investigators
Prof. Jennifer Leigh McQuade
Prof. Carrie Daniel-MacDougall
Prof. Jennifer Wargo
Prof. Lorenzo Cohen
Seerave Fellow
Dr. Ashley E Holly
Background

Pioneering work from multiple labs has shown that the gut microbiome influences response to immunotherapy. As diet is a key determinant of the gut microbiome, follow up work has focused on the relationship between diet, the microbiome, and response to immunotherapy. For example, in an observational cohort of metastatic melanoma patients, individuals who reported high dietary fiber intake and overall high dietary quality had an increased abundance of previously identified pro-response gut bacteria (consistent with role of these bacteria as fiber-fermenters) and were 5x more likely to respond to immunotherapy. Preclinical work has further shown that dietary fiber positively impacts response to anti-PD1 in mouse models (manuscript submitted, link to publication to follow). On a mechanistic level, data from pre-clinical models have shown that dietary modulation targeting systemic insulin/IGF-1 can impact tumor growth and treatment response. However, to date, dietary intervention studies targeting these two relevant targets (the gut microbiome and insulin/IGF-1) have not been conducted in patients with melanoma, or in the setting of immunotherapy in any disease which is the goal of this project. These initial studies will be performed in a highly controlled setting, so-called “controlled feeding studies” in which all food is provided for patients by the MD Anderson Bionutrition Core. Results from these studies will be essential to establish proof-of-principal for this approach prior to progressing into larger Phase III behavioral-based dietary intervention trials.

Timeline
Start
01/06/2019
26/09/2019

AACR Paris poster presentation

01/08/2019

First patient recruited in Phase I

05/12/2019

PRIME-TR poster presentation

Hide

AI-assisted food tracking to revolutionise nutritional research

Goals

Seerave Foundation is supporting the development of the AI For Nutrition platform and its global expansion, especially into the US. The aims of the project are:

1) enhance ease of use: further development of the mobile application to provide a user-friendly experience

2) scale up internationally: establish MyFoodRepo in new countries

3) reach self-sustainability: ensure MyFoodRepo will become a non-profit service platform able to sustain itself

Principal Investigators
Prof. Marcel Salathé
Prof. Rob Knight
Seerave Fellows
Talia Salzmann
Dr. Daniel McDonald
Background

Skepticism about nutritional science is widespread both in academia and in the public. A key contributor to the problem is how food intake is measured in the first place: food-frequency questionnaires (FFQs) and diet recalls are still the standards, despite their well-known weaknesses such as imprecision, dependence on human memory, lack of associated data such as the timing of food intake, etc.

While other aspects of health and behaviour measurements have evolved and improved steadily over the past decades (genomics, metagenomics, sensors, etc.), nutrition measurement has been stuck in time: it is still done the same way it was done decades ago.

The AI For Nutrition platform provides a comprehensive, scalable, and demonstrated solution to digital diet logging specifically designed for use in research settings. The technology platform has been developed at the Digital Epidemiology Lab at the Swiss Institute of Technology in Lausanne (EPFL) and has received support by multiple foundations including the Kristian Gerhard Jebsen Foundation and Leenaards Foundation. It combines three essential parts:

MyFoodRepo
A mobile app (Android and iOS) for individuals to track food by picture taking or barcode scanning.

The Open Food Repo
A community-driven open database for barcoded food products.

MyFoodRepo image analysis
An annotation framework based on AI and human expertise for image-based food recognition.

Hide

Ketogenesis to enhance efficacy of cancer immunotherapy

Prof. Laurence Zitvogel

show details

Characterizing post-prandial inflammation in humans

Dr. Thomas Gurry

Prof. Giovanni Frisoni

show details

Ketogenic diet and its metabolite beta hydroxybutyrate to enhance efficacy of cancer immunotherapy: a phase II clinical trial in advanced renal cell cancer

Goals

Seerave Foundatio is supporting this study with the aim to investigate whether the induction of ketosis, either with a KD or with the intake of beta-Hydroxybutyrate (BHB), will overcome the primary resistance to immunotherapy. We hypothesize that the induction of ketosis might shift the gut microbiota, shaping the immune system to favor response to anticancer treatment. The translational research will focus on two main aspects

(1) Pharmacokinetics: the detection of ketosis and the bioavailability of BHB, ipilimumab and nivolumab,

(2) Pharmacodynamics: the identification of biomarkers of treatment response and the characterization of the mechanisms of action.

This will be a prospective, 4 single-arm, open-label, multicentric phase II study enrolling a total of 60 metastatic Renal Cell Carcinoma patients.

Partner institute
Principal Investigator
Prof. Laurence Zitvogel
Seerave Fellows
Dr. Gladys Ferrere
Marine Fidelle (PharmD)
Background

KETOREIN is one of the projects developed within ClinicObiome at Gustave Roussy, centered on metastatic renal cell cancer (RCC) with dismal prognosis features (intermediate or poor IMDC) amenable to first line combination of immune checkpoint inhibitors (Ipilimumab+Nivolumab). The expected response rate is <40% at 3 months with side effects in all-comers (i.e., unselected). Given the published data (Ferrere et al JCI Insight 2021, supported by Seerave), it is anticipated that preconditioning with ketogenic diet (KD) or the main resulting systemic ketone body beta hydroxybutyrate (BHB) will increase objective responses rates and decreases side effects in human cancer patients undergoing immunotherapy. Longitudinal high dimensional translational research will be performed to deconvolute which parameters (immunology, metagenomics of fecal material, plasma and fecal metabolome, peripheral inflammation; clonal hematopoiesis) will prevail in predicting the clinical benefit of the combinatorial regimen. Seerave will fully support this translational research over the next 2 years of patient enrolment and one year of follow up and analysis.

Timeline
Start
01/06/2021
Hide

High-resolution investigation of personalised post-prandial inflammation biomarkers (the HIPPIE study)

Goals

Seerave Foundation is supporting a clinical feasibility study at the Geneva University Hospitals (HUG) in aiming to:

  1. Investigate the post-prandial dynamics of plasma markers of inflammation response to different ‘extreme’ diets, with high temporal resolution.
  2. Investigate inter-individual variability in post-prandial inflammatory responses to the same meals.
  3. Investigate the post-prandial pharmacokinetics of plasma SCFAs in response to different meals, contrasted with personalised dietary fibre supplementation, to determine whether plasma SCFAs constitute a viable read-out of microbial fermentation processes in the colon.

 

Seerave Fellow
Dr. Thomas Gurry
Background

The impact of our diet on our immune system is poorly understood. As the importance of controlling inflammation becomes evermore apparent in the context of both acute and chronic diseases, there is increasing interest in the role of nutrition on these processes. As DayTwo have demonstrated using plasma glucose tracking, continuous monitoring and multi-omic technologies provide a fresh opportunity to tackle the problem of host response to dietary ingredients. Combined with a quantitative understanding of the contribution of the gut microbiome to host inflammatory processes, we can gain clinically actionable insights that can be directly applied to clinical trials targeting conditions ranging from Inflammatory Bowel Disease to cancer immunotherapy.

Using an innovative study design and scalable implementation, we propose to measure the postprandial inflammatory response of different individuals to different extreme diets, and contrast these with the response to a personalised dietary fibre supplement chosen to minimise inflammation through maximizing microbial butyrate production. To do this, we will employ an experimental framework that allows us to measure a patient’s Microbial Metabolic Phenotype’ (MMP), which we define as the microbiome’s capability of roducing the Short Chain Fatty Acids (SCFAs) acetate, propionate and butyrate from specific dietary fibres. SCFAs are the end products of bacterial fermentation of dietary fibre in the colon, and are of increasing clinical interest as imbalances in their production have been associated with a growing list of clinical indications. Moreover, it is now known that SCFAs can alter gene expression in the host, and it is therefore an open question whether these effects transcend the gut. Most importantly, SCFAs are known to have significant impact on the production of pro- and anti-inflammatory cytokines, with resulting impact on inflammatory status of the host.

Unfortunately, it is not currently possible to measure real-time SCFA production in vivo. SCFAs can be quantified in stool samples, but it remains unclear to what extent they are representative of the amounts produced and absorbed during intestinal transit. We herefore lack a good in vivo read-out that could be used to rigorously investigate whether our personalised fibre interventions do indeed lead to increased production of specific SCFAs in vivo, as expected. Such a biomarker would constitute an important step in graduating from highly general notions such as the fact that ‘high fibre intake’ is conducive to health, and moving towards a quantitative and mechanistic understanding of the role of different fibres in different individuals.

Timeline
Start
01/10/2020
Hide

ACBP/DBI in the cancer-immune dialogue

Prof. Guido Kroemer

show details

Novel diagnostic for the detection of Coronavirus antibodies

Prof. Eran Segal

show details

Characterising a novel "metabolic checkpoint protein" called ACBP/DBI in regulating autophagy and thereby the cancer-immune dialogue.

Goals

Seerave Foundation is supporting a series of studies to assess the role of a novel “metabolic checkpoint protein” called ACBP/DBI in regulating autophagy and thereby the cancer-immune dialogue.  The aims of the project are

1) Measuring the concentrations of ACBP/DBI in patient samples and correlations with clinicobiological and metabolic features,

2) performing preclinical experiments to understand the role of ACBP/DBI in the relationship between metabolism, cancer and immunity,

3) evaluate strategies for inhibiting the human ACBP/DBI system.

Principal Investigator
Prof. Guido Kroemer
Seerave Fellows
Isabelle Martins
Léa Montegut
Background

Autophagy plays a fundamental role in cellular, tissue and organismal homeostasis, and is mediated by evolutionarily conserved autophagy-related (ATG) genes. Definitive etiological links exist between mutations in genes that control autophagy and human diseases, especially neurodegeneration, inflammatory disorders and cancer. Autophagy selectively targets dysfunctional organelles, intracellular microbes and pathogenic proteins, and deficiencies in these processes lead to disease. For this reason, autophagy-stimulatory compounds are being considered for the treatment of major human pathologies including aging, atherosclerosis, cancer, infection, neurodegeneration, obesity and metabolic syndrome.  Thus far, the hunt for pharmacological autophagy inducers has mostly focused on the development of drugs that act on intracellular pathways of autophagy regulation and hence disrupt the autophagy-inhibitory BCL2-BECN1 interaction, act on cytoplasmic nutrient sensors or increase the activity of pro-autophagic transcription factors.

Recently, the Kroemer lab discovered that autophagy is linked to a phylogenetically conserved (from yeast to human) non-canonical secretory pathway leading to the release of the small acyl coenzyme A binding protein (ACBP), also called diazepam binding inhibitor (DBI), from the cytoplasm. Extracellular ACBP/DBI then acts on plasma membrane receptors to inhibit autophagy in an autocrine or paracrine fashion. Hence, neutralization of ACBP/DBI with suitable (auto-)antibodies can stimulate autophagy by the interruption of this feedback loop, providing an extracellular target for autophagy induction.

ACBP/DBI plasma levels are increased in human obesity, especially in the context of hyperlipidemia, but reduced in patients with anorexia nervosa. Hence, ACBP/DBI is one of the few peripheral appetite stimulators that is actually upregulated in non-syndromic human obesity (contrasting, for example, with the appetite stimulator ghrelin that is downregulated or the appetite regulator leptin that is upregulated), suggesting that ACBP/DBI might be a useful target for therapeutic interventions on eating disorders. Of note, obesity is commonly associated with autophagy inhibition, as well as the accelerated manifestation of aging and age-related diseases including, metabolic syndrome cardiovascular disorders and neoplasia (which are all known from mouse experiments to be precipitated in conditions of suppressed autophagy). Thus, ACBP/DBI neutralization has a multipronged positive impact on obesity, by (i) reducing food intake, (ii) limiting lipo-anabolic and stimulating lipo-catabolic reactions, and (iii) reactivating deficient autophagy.

Encouraged by these findings, the Kroemer lab plans to further explore the role of ACBP/DBI in malignancy, while focusing on the dialogue between cancer and immune cells that is profoundly influenced by whole-body metabolism. For example, the Kroemer lab has previously shown that autophagy induction by fasting, ketogenic diet, and multiple pro-autophagic agents including aspirin and spermidine help immunogenic chemotherapy, alone or in combination with PD-1 blockade, to become more efficient. Given that ACBP/DBI acts as an extracellular feedback inhibitor of autophagy, one can speculate that its neutralization (which induces autophagy) will have positive effects on therapy-induced immunosurveillance as well.

Timeline
Start
01/01/2021
Hide

A novel high precision diagnostic for the detection of Coronavirus antibodies.

Goals

Seerave Foundation is supporting the development of novel diagnostics to study immune responses against Corona viruses (CoVs). This work will be performed by the lab of Prof. Eran Segal at the Weizmann Institute. Relying on next generation sequencing and samples from both infected and healthy individuals, this approach will shed light on population wide immune responses against CoVs. Thereby insights into shared immune responses and spread from asymptomatic carriers will be gained. The aims of this project are to perform 1) high resolution serotyping of CoVs, 2) epidemiological monitoring of the current outbreak, as well as 3) identifying potential novel vaccine targets. This platform could also increase preparedness for future CoV outbreaks and similar zoonotic transmissions.

Partner institution
Project leader
Prof. Eran Segal
Seerave Fellows
Dr. Thomas Vogl
Background

Current molecular diagnostics of CoV infections are either based on detecting genetic information (RNA based RT-qPCR tests) or immune responses against surface structures (antigens). Selected antigens are typically artificially produced and tested for separately with methods such as ELISAs or peptide arrays. Presently, only one out of 27 predicted proteins, that make up the 2019/2020 Corona virus, is being studied intensively. However, also the additional at least 26 other proteins may also be relevant for host response towards the virus. Given each protein contains multiple structural features (epitopes) that could be recognized by the immune system, there are potentially thousands of specific antibody responses against the current Corona virus. Identifying such novel antigens could yield improved diagnostic markers and vaccine targets.

Hide

Universitair Medisch Centrum Groningen

Groningen, The Netherlands

Predicting response to immunotherapy based on diet & microbiome

Prof. Geke Hospers

Prof. Rinse Weersma

show details

Predicting response to immunotherapy based on microbiome & metabolites

Prof. Tim Spector

Prof. Veronique Bataille

Dr. Paul Nathan

show details

Longitudinal analysis of the nutritional status and microbiome composition in melanoma patients undergoing immunotherapy

Goals

Seerave Foundation is supporting two independent centers performing complementary prospective clinical studies:

1) University Medical Center Groningen (UMCG), Netherlands, under the supervision of Prof. Geke Hospers and Prof. Rinse Weersma. The Seerave Fellows at UMCG will coordinate the efforts undertaken.

2) King’s College London (KCL), United Kingdom, under the supervision of Prof. Tim Spector and Dr. Veronique Bataille. KCL will lead a consortium of UK Melanoma Centres

Both studies aim at performing longitudinal analysis of the nutritional status and the composition and function of the gut microbiome in melanoma patients undergoing immunotherapy. The ultimate goal is to integrate the collected data into predictive “–omics signatures” including other biomarkers from blood and tumors, host genetics and immunomics as well as other clinical parameters.

Principle investigators
Prof. Geke Hospers
Prof. Rinse Weersma
Seerave Fellows
Laura Bolte
Johannes Björk
Background

More and more evidence from studies in mice but also humans suggests that the gut microbiome regulates host immunity and also modulates the efficacy and side-effects of cancer chemotherapy and immunotherapy (details in our Science section). At the same time, multiple modulators including diet are known to influence the composition and/or the metabolic output of the gut microbiome. However, it is currently unknown whether different nutritional status of cancer patients might influence the composition and/or the metabolic output of the gut microbiome, and if so, whether these parameters could indeed stratify patients responding or not-responding to cancer immunotherapy. Given that nutrition may represent the safest and easiest modulator of the gut microbiome, understanding the relationship between nutrition, the microbiome, and anti-cancer immunity could a) generate hypotheses for mechanistic work in pre-clinical models, and b) open highly interesting therapeutic avenues for cancer patients.

Hide

Predicting Response to Immunotherapy for Melanoma with gut Microbiome and metabolomics (PRIMM study)

Goals

Seerave Foundation is supporting two independent centers performing complementary prospective clinical studies:

1) University Medical Center Groningen (UMCG), Netherlands, under the supervision of Prof. Geke Hospers and Prof. Rinse Weersma. A Seerave Fellow at UMCG will coordinate the efforts undertaken.

2) King’s College London (KCL), United Kingdom, under the supervision of Prof. Tim Spector and Dr. Veronique Bataille. KCL will lead a consortium of UK Melanoma Centres

Both studies aim at performing longitudinal analysis of the nutritional status and the composition and function of the gut microbiome in melanoma patients undergoing immunotherapy. The ultimate goal is to integrate the collected data into predictive “–omics signatures” including other biomarkers from blood and tumors, host genetics and immunomics as well as other clinical parameters.

 

Partner institution
Principle investigators
Prof. Tim Spector
Dr. Veronique Bataille
Dr. Paul Nathan
Seerave Fellows
Dr. Karla Lee
Dr. Amrita Vijay
Clare Stockwell
Background

More and more evidence from studies in mice but also humans suggests that the gut microbiome regulates host immunity and also modulates the efficacy and side-effects of cancer chemotherapy and immunotherapy (details in our Science section). At the same time, multiple modulators including diet are known to influence the composition and/or the metabolic output of the gut microbiome. However, it is currently unknown whether different nutritional status of cancer patients might influence the composition and/or the metabolic output of the gut microbiome, and if so, whether these parameters could indeed stratify patients responding or not-responding to cancer immunotherapy. Given that nutrition may represent the safest and easiest modulator of the gut microbiome, understanding the relationship between nutrition, the microbiome, and anti-cancer immunity could a) generate hypotheses for mechanistic work in pre-clinical models, and b) open highly interesting therapeutic avenues for cancer patients.

For more information on the study, visit NCT03643289 at clinicaltrials.gov

Timeline
Start
01/11/2017
09/04/2018

IRB approval

29/10/2018

NIHR Portfolio approval

01/11/2018

First patient recruited

Hide

Impact of microbiome-derived metabolites on immune cells

Prof. Naama Geva-Zatorsky

show details

Yerosha Productions

New York City, USA

Documentary movie: "Missing Microbes"

Sarah Schenk

Steven Lawrence

show details

Characterizing Microbiome-Derived Metabolites That Directly impact The Immune System (CMMIIS Study)

Goals

Seerave Foundation is supporting pre-clinical research in the labs of Prof. Naama Geva-Zatorsky, aiming at identifying metabolites produced by the gut microbiota that directly impact the immune system and generate in depth mechanistic understanding about their receptors and downstream signaling. Identifying such metabolites will represent the first step in generating an in-depth mechanistic understanding of the downstream molecular pathways responsible for delivering signals from the bacterial cell to the host immune cell. This should guide the development of novel therapeutic interventions to strengthen immune responses in cancer patients including personalized and rationally designed nutrient compositions.

Principle investigator
Prof. Naama Geva-Zatorsky
Seerave Fellows
Dr. Tal-avi Gefen
Noa Mandelbaum
Background

The gut microbiome has co-evolved with the human host for millennia, creating an inextricable and dependent relationship, where the gut bacteria became a vital component of the human immune system. Both soluble metabolites secreted by the bacteria as well as cellular components such as lipopolysaccharides (LPS) found in the membrane of certain bacteria have been shown to influence the immune system. Naama Geva-Zatorsky recently identified more than 50 different bacterial strains from the gut microbiome that individually impact different systemic immune responses in mice. However, it is still unknown which metabolites secreted by these bacterial strains are the ones responsible for the modulation of immune responses, and whether the production of these metabolites depends on the availability of specific nutrients. Understanding these relationships may lead to the identification of novel, rationally-designed nutritional approaches to aid anti-cancer therapy.

Timeline
Start
01/07/2018
Hide

Documentary movie: "Missing Microbes"

Goals

The documentary “Missing Microbes” aims at explaining to a layman audience the state-of-the-art microbiome research and its potential to improve human health. Seerave is supporting this documentary since it will be produced in a rigorous and scientifically sound manner. Furthermore, Seerave is helping the team to navigate the science around the diet/microbiome/immunity/cancer axis.

Director and Producer
Sarah Schenk
Steven Lawrence
Background

Missing Microbes is a feature documentary about the critical role of microbes in human health – and how disrupting our microbes has helped trigger an unprecedented surge in chronic diseases like obesity, diabetes, cancer, allergies, and autism. As the film follows globe-trotting microbiologists Martin Blaser and Gloria Dominguez-Bello on their mission to end this crisis before it’s too late, it also tells the stories of patients in China, Israel, Europe, and the USA as they search for cures to these modern plagues.

 

Timeline
Start
01/07/2018
Hide

Helbling

Bern, Switzerland

Feasibility of continuous inflammation monitoring

Dr. Niklaus Schneeberger

show details

Preserving the diversity of human microbiota

Dr. Adrian Heuss

Dr. Dominik Steiger

show details

Technical feasibility study for the development of a biosensor to allow continuous inflammation monitoring

Goals

Seerave Foundation is performing a technical feasibility study for the development of a biosensor to allow for continuous inflammation monitoring.  The ultimate goal is to develop a portable sensor with a system architecture to measure the concentration of a single inflammatory marker (use cases similar to commercially available continuous glucose monitors). Seerave is collaborating with Helbling, an independent and world leading engineering firm with expertise in the technology and product development of medical grade, point-of-care diagnostic devices. Helbling  will contribute the technological and product engineering perspective to Seerave’s feasibility assessment of appropriate biomarkers. Specifically, the goals of the study are 1) to assess which biomarker/s may be suitable for measuring dynamic inflammatory responses to a changing environment such as diet and exercise, 2) to assess which sensor technologies could be suitable to measure such biomarkers, 3) to draft potential system architectures and their development roadmaps. A decision on how to proceed will be taken once these goals have been met.

Project leader
Dr. Niklaus Schneeberger
Background

Pioneering work from the Weizmann Institute of Science (link) has shown that different individuals respond differently to the same foods. This work has ignited a new wave of nutritional sciences and created the concept of “personalized nutrition”. A major reason that the response to diet is individual is that each person hosts a unique composition of gut bacteria, which in turn determines how food is metabolized and how the resulting metabolites are made available to the host. These findings have been made possible thanks to novel technologies which are able to capture high resolution diet-related biomarkers. These technologies include the digital tracking of food intake, metagenomics and continuous glucose monitoring. While the glucose and insulin response to diet is undoubtedly highly valuable in settings linked to insulin imbalance (diabetes, metabolic syndrome, obesity etc), there are other impacts of diet on the host that are not captured by just measuring glucose and insulin. Clinical and preclinical work suggests that the immune system and inflammatory response is key to the physiological response to diet: not only are they involved in responding to environmental toxins or bacteria contained in food, but also in regulating the metabolism of nutrients such as lipids etc. Having a system at hand that continuously monitors dynamic inflammation markers in large clinical cohorts would greatly increase our understanding of the impact of individual diets on disease, both chronic and otherwise.

Timeline
Start
27/08/2019
26/06/2020

Theoretical feasibility phase concluded

01/02/2021

Proof-of-concept phase initiated

01/06/2021

Deep Immunity Consortia formation

Hide

Feasibility study for the establishment of a "Noah’s Ark" of human microbiota

Goals

Seerave Foundation is supporting a feasibility study for the establishment of “The Microbiota Vault”. The Microbiota Vault, a non-profit US foundation, is examining the potential of setting up a global repository of human microbiota. This repository, a “Noah’s Ark for microbes” would focus on the preservation of the current global diversity of the human microbiota and on backing-up global research collections. The feasibility study is coordinated and led by experienced and independent professionals from two Swiss science evaluation agencies “advocacy” and “EvalueScience”. Specifically, the study will look to devise the technical, political and legal scenarios that would make the project feasible. It will comprise all the necessary research as well as interviews and discussion workshops. The study is co-supported by the Gerbert Rüf Foundation, Calouste Gulbenkian Foundation, Rutgers University and Kiel University (Kiel Life Science).

Project leader/s
Dr. Adrian Heuss
Dr. Dominik Steiger
Background

The human microbiota (and its collective genomes, the microbiome) is made up of microbes that live in or on our bodies influencing essential host processes, including nutrition, immunity, hormone activity, gut permeability, and neurochemistry. Microbes acquired in early life play crucial roles in guiding the developing immune, metabolic and neural systems in animal models, and are assumed to be equally important in human development. The microbiome, our “other genome”, along with our human genes, is substantially passed vertically from generation to generation. The germline and somatic genomes, microbiome and external environment are all essential parameters of population variation as well as being useful for predicting host disease and health outcomes. Urbanization and modern civilization are significantly correlated with reduced diversity of the microbiota. For example, the gut diversity of South American Amerindians is about twice that of healthy people in the USA. Antibiotics, C-sections, sterile lifestyle, processed foods have all played a large part in controlling infectious diseases, but they have also impacted negatively the transmission and colonization of microbes of human microbiota. The diversity of our health-associated microbiota is becoming increasingly endangered and needs to be preserved in order to ensure the long-term health of humanity.

Timeline
Start
16/07/2019
03/08/2020

Pilot planning phase initiated

Hide

Impact of nutrients on cancer immunotherapy

Prof. Laurence Zitvogel

Prof. Guido Kroemer

show details

Fecal microbiome transfer in patients with severe depression

Dr. Laura Mählmann

Dr. André Schmidt

show details

Mechanisms of nutrient-induced immunomodulation in pre-clinical cancer models

Goals

Seerave Foundation is supporting pre-clinical research in the labs of Prof. Laurence Zitvogel and Prof. Guido Kroemer at the Institut Gustave Roussy (IGR) in Paris, France, aiming at 1) identifying the molecular mechanism of action of how nutrients can affect local and systemic cancer immunity, and 2) establishing biomarkers that will allow one to quantify the effects of nutritional interventions on the microbiome/metabolite/immunity axis. Three Seerave Fellows will coordinate the efforts undertaken.

Partner institution
Principle investigators
Prof. Laurence Zitvogel
Prof. Guido Kroemer
Seerave Fellows
Dr. Gladys Ferrere
Dr. Jonathan Pol
Dr. Maryam Tidjani Alou
Background

Even though more and more correlative data from clinics suggests that the gut microbiome regulates the efficacy and side-effects of cancer chemotherapy and immunotherapy, the exact underlying mechanisms are currently unknown. A better understanding of the molecular pathways involved in the nutrition/microbiome/metabolite/immunity axis will be needed in order to develop rational clinical interventions. Hypothesis-driven research in pre-clinical cancer models may allow one to decipher some of the involved mechanisms. One such hypothesis comes from the field of autophagy, a core process of cell metabolism responsible for the recycling of unneeded or damaged intracellular material. Evidence suggests that autophagy is essential for proper immune cell function and stimulating autophagy has been shown to enhance cancer therapies by inducing better anti-tumor immunity. Interestingly, different nutrients including Spermidine, a so-called Caloric Restriction Mimetics (CRMs), have been shown to induce autophagy, thereby altering cellular function. Another hypothesis is that the gut microbiome converts nutrients such as fibers and polyphenols to metabolites that then bind to receptors on host immune cells, thereby modulating their function.

Hide

Fecal microbiome transfer in patients with severe depression

Goals

Seerave Foundation is supporting a prospective clinical study at the University Psychiatrics Clinics Basel (UPK), Switzerland, aiming to determine for the first time if fecal microbiota transplantation (FMT) improves the effect of antidepressants in patients with severe Major Depressive Disorder (MDD).

Project leaders
Dr. André Schmidt
Dr. Laura Mählmann (former)
Background

The prevalence of psychiatric disorders such as major depression is increasing rapidly. However, only 50% of patients respond to antidepressants and often then with side effects, while about 20% don’t respond to any treatment. Recent interest has been drawn towards the importance of biochemical signaling between the gastrointestinal tract and the central nervous system also known as the “microbiome-gut-brain axis”, as for example via the vagus nerve. A new underexplored method to alter the gastrointestinal microbiota involves fecal microbiota transplantation (FMT). The goal of the procedure is to introduce or restore a stable microbial community in the gut by transferring intestinal microbiota from a healthy donor to the patient. FMT is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. At the same time, applications of FMT have shown health enhancing results in previously unexpected areas including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and oncology.

Timeline
Start
01/03/2017
22/06/2018

Ethical approval

01/10/2018

Shipment of OpenBiome FMT capsules

29/10/2018

First patient treated

01/04/2020

Finish

01/07/2020

Awaiting publication

Hide

Cancer-associated ileopathy in cancer patients

Prof. Laurence Zitvogel

show details

Characterising and modulating cancer-associated ileopathy to increase the efficacy of immunotherapy in cancer patients

Goals

1. Use of high dimensional technologies such as ileal single cell transcriptomics and spatial transcriptomics to understand what pathological pathways are up- or downregulated when and where during cancer-associated ileopathy.

2. In vitro modelization using enteroids to identify the stimuli that contribute to the onset of ileopathy.

3. Description of the human syndrome: collaborative work with pathologists to identify neuroendocrine and neurological pathways in tissue sections and the specificity of the pathological disorder.

4. Determine what secretory components of tumours transduce a signal from the tumour to the ileal crypts.

Partner institution
Principle investigator
Prof. Laurence Zitvogel
Seerave Fellow
Dr. Gladys Ferrere
Background

Whether gut dysbiosis is cause or consequence of tumor establishment and how it controls tumor progression remain open questions in immuno-oncology. Over the last 3 years, the Zitvogel lab has accumulated evidence showing that 50% of transplantable extra-intestinal experimental (mouse) malignancies as well as human cancers trigger a set of pathologies in the small intestine (the ileum), that were collectively named cancer-associated ileopathy. These defects include villus autophagy, apoptosis of crypt cells in the terminal ileum culminating in epithelial atrophy of the ileum, increased gut permeability, and protracted Gram+ related -dysbiosis that contribute to cancer growth and resistance to immunotherapy. This corollary syndrome of carcinogenesis coincides with neuroendocrine and Paneth cell activation and proliferation in mice and humans. Single cell transcriptomics and immunostainings revealed that stem cells and neuroendocrine cells upregulated neutrotransmitter signaling. Vancomycin (an antibiotic specific against Gram+ bacteria) and propranolol (an inhibitor of adrenaline signaling) could both transiently prevent cancer-associated ileopathy and antagonize tumor progression. The project thus aims at a) further deciphering the cellular (tumor, immune, neurological) or molecular/metabolic cues underlying cancer-associated ileopathy and b) identifying potential interceptive measures to inhibit the underlying vicious circle.

Timeline
Start
01/06/2021
Hide

Impact of personalised nutrition on breast cancer patients

Prof. Eran Segal

show details

Personalised Nutrition Immune Response Algorithm (PNIRA) project: personalised nutrition intervention to boost immune response and efficacy of cancer therapies.

Goals

Seerave Foundation is supporting a randomized clinical trial that assesses the effects of a personalised nutritional intervention in combination to conventional therapy in breast cancer patients.  The trial will be performed as a collaborative effort between the lab of Prof. Eran Segal at Weizmann Institute and Sheba Medical Center. The aims of the trial are 1) to develop predictive algorithms from associations between nutrition, glycemic response, gut microbiota, antibody and T cell responses, 2) with the aid of these algorithms, to validate and/or further develop personalized dietary intervention (and possibly other lifestyle) protocols which will improve clinical outcomes and minimize the use of invasive medicine, and 3) extend these algorithms and other protocols to other cancer types.

Partner institution
Principle investigator
Prof. Eran Segal
Seerave Fellows
Dr. Thomas Vogel
Michal Rein
Background

Improving the success of adjuvant treatment of breast cancer and understanding the underlying causes of interpersonal variation in the response to treatment is of utmost importance for breast cancer patients’ prognosis and survival. Multiple factors may contribute to this inter-personal variation, including baseline gut microbiome composition, diet, immune system repertoire, and interactions among all of these factors. It has previously been established that a) diet can shape the microbiome both in terms of composition and function, b) the microbiome contributes to shaping the immune system. It is thus conceivable that optimizing this axis by applying a personalised nutritional regimen based on gut microbiome profiles will boost anti-tumour immune responses and improve the efficacy of therapy in breast cancer patients.

For more information on the study, visit NCT04079270 at clinicaltrials.gov

Timeline
Start
01/07/2018
27/03/2019

IRB approval Sheba Hospital

24/07/2019

First participant recruited

26/02/2020

First participant finishing dietary intervention

Hide

Controlled dietary interventions in melanoma patients

Prof. Jennifer Leigh McQuade

Prof. Carrie Daniel-MacDougall

Prof. Jennifer Wargo

Prof. Lorenzo Cohen

show details

Controlled dietary interventions in melanoma patients to assess the feasibility and efficacy of enhancing immunotherapy.

Goals

Seerave Foundation is supporting a series of clinical studies to assess the effects of nutritional intervention alone or in combination with conventional immunotherapy in melanoma patients. The aims of the trials are:

1) In a Phase I study: to demonstrate the feasibility and adherence of a controlled feeding study in up to 20 disease-free melanoma patients consuming either high-fiber or ketogenic diets.

2) In a Phase 2 study: to (i) demonstrate that a high-fiber diet can modulate the gut microbiome to a pro-immunotherapy response phenotype in a cohort of 42 metastatic melanoma patients undergoing anti-PD1 immunotherapy (ii) demonstrate that a high-fiber diet can enhance systemic and anti-tumor immunity.

3) To establish novel biomarkers that are indicative of diet-induced modulation of the microbiome and immune system, which will help guide the design of future preclinical and clinical studies.

Partner institution/s
Principle investigators
Prof. Jennifer Leigh McQuade
Prof. Carrie Daniel-MacDougall
Prof. Jennifer Wargo
Prof. Lorenzo Cohen
Seerave Fellow
Dr. Ashley E Holly
Background

Pioneering work from multiple labs has shown that the gut microbiome influences response to immunotherapy. As diet is a key determinant of the gut microbiome, follow up work has focused on the relationship between diet, the microbiome, and response to immunotherapy. For example, in an observational cohort of metastatic melanoma patients, individuals who reported high dietary fiber intake and overall high dietary quality had an increased abundance of previously identified pro-response gut bacteria (consistent with role of these bacteria as fiber-fermenters) and were 5x more likely to respond to immunotherapy. Preclinical work has further shown that dietary fiber positively impacts response to anti-PD1 in mouse models (manuscript submitted, link to publication to follow). On a mechanistic level, data from pre-clinical models have shown that dietary modulation targeting systemic insulin/IGF-1 can impact tumor growth and treatment response. However, to date, dietary intervention studies targeting these two relevant targets (the gut microbiome and insulin/IGF-1) have not been conducted in patients with melanoma, or in the setting of immunotherapy in any disease which is the goal of this project. These initial studies will be performed in a highly controlled setting, so-called “controlled feeding studies” in which all food is provided for patients by the MD Anderson Bionutrition Core. Results from these studies will be essential to establish proof-of-principal for this approach prior to progressing into larger Phase III behavioral-based dietary intervention trials.

Timeline
Start
01/06/2019
26/09/2019

AACR Paris poster presentation

01/08/2019

First patient recruited in Phase I

05/12/2019

PRIME-TR poster presentation

Hide

EPFL

Lausanne, Switzerland

AI-assisted food tracking for nutritional research

Prof. Marcel Salathé

show details

AI-assisted food tracking to revolutionise nutritional research

Goals

Seerave Foundation is supporting the development of the AI For Nutrition platform and its global expansion, especially into the US. The aims of the project are:

1) enhance ease of use: further development of the mobile application to provide a user-friendly experience

2) scale up internationally: establish MyFoodRepo in new countries

3) reach self-sustainability: ensure MyFoodRepo will become a non-profit service platform able to sustain itself

Principal Investigators
Prof. Marcel Salathé
Prof. Rob Knight
Seerave Fellows
Talia Salzmann
Dr. Daniel McDonald
Background

Skepticism about nutritional science is widespread both in academia and in the public. A key contributor to the problem is how food intake is measured in the first place: food-frequency questionnaires (FFQs) and diet recalls are still the standards, despite their well-known weaknesses such as imprecision, dependence on human memory, lack of associated data such as the timing of food intake, etc.

While other aspects of health and behaviour measurements have evolved and improved steadily over the past decades (genomics, metagenomics, sensors, etc.), nutrition measurement has been stuck in time: it is still done the same way it was done decades ago.

The AI For Nutrition platform provides a comprehensive, scalable, and demonstrated solution to digital diet logging specifically designed for use in research settings. The technology platform has been developed at the Digital Epidemiology Lab at the Swiss Institute of Technology in Lausanne (EPFL) and has received support by multiple foundations including the Kristian Gerhard Jebsen Foundation and Leenaards Foundation. It combines three essential parts:

MyFoodRepo
A mobile app (Android and iOS) for individuals to track food by picture taking or barcode scanning.

The Open Food Repo
A community-driven open database for barcoded food products.

MyFoodRepo image analysis
An annotation framework based on AI and human expertise for image-based food recognition.

Hide

Ketogenesis to enhance efficacy of cancer immunotherapy

Prof. Laurence Zitvogel

show details

Ketogenic diet and its metabolite beta hydroxybutyrate to enhance efficacy of cancer immunotherapy: a phase II clinical trial in advanced renal cell cancer

Goals

Seerave Foundatio is supporting this study with the aim to investigate whether the induction of ketosis, either with a KD or with the intake of beta-Hydroxybutyrate (BHB), will overcome the primary resistance to immunotherapy. We hypothesize that the induction of ketosis might shift the gut microbiota, shaping the immune system to favor response to anticancer treatment. The translational research will focus on two main aspects

(1) Pharmacokinetics: the detection of ketosis and the bioavailability of BHB, ipilimumab and nivolumab,

(2) Pharmacodynamics: the identification of biomarkers of treatment response and the characterization of the mechanisms of action.

This will be a prospective, 4 single-arm, open-label, multicentric phase II study enrolling a total of 60 metastatic Renal Cell Carcinoma patients.

Partner institute
Principal Investigator
Prof. Laurence Zitvogel
Seerave Fellows
Dr. Gladys Ferrere
Marine Fidelle (PharmD)
Background

KETOREIN is one of the projects developed within ClinicObiome at Gustave Roussy, centered on metastatic renal cell cancer (RCC) with dismal prognosis features (intermediate or poor IMDC) amenable to first line combination of immune checkpoint inhibitors (Ipilimumab+Nivolumab). The expected response rate is <40% at 3 months with side effects in all-comers (i.e., unselected). Given the published data (Ferrere et al JCI Insight 2021, supported by Seerave), it is anticipated that preconditioning with ketogenic diet (KD) or the main resulting systemic ketone body beta hydroxybutyrate (BHB) will increase objective responses rates and decreases side effects in human cancer patients undergoing immunotherapy. Longitudinal high dimensional translational research will be performed to deconvolute which parameters (immunology, metagenomics of fecal material, plasma and fecal metabolome, peripheral inflammation; clonal hematopoiesis) will prevail in predicting the clinical benefit of the combinatorial regimen. Seerave will fully support this translational research over the next 2 years of patient enrolment and one year of follow up and analysis.

Timeline
Start
01/06/2021
Hide

Characterizing post-prandial inflammation in humans

Dr. Thomas Gurry

Prof. Giovanni Frisoni

show details

High-resolution investigation of personalised post-prandial inflammation biomarkers (the HIPPIE study)

Goals

Seerave Foundation is supporting a clinical feasibility study at the Geneva University Hospitals (HUG) in aiming to:

  1. Investigate the post-prandial dynamics of plasma markers of inflammation response to different ‘extreme’ diets, with high temporal resolution.
  2. Investigate inter-individual variability in post-prandial inflammatory responses to the same meals.
  3. Investigate the post-prandial pharmacokinetics of plasma SCFAs in response to different meals, contrasted with personalised dietary fibre supplementation, to determine whether plasma SCFAs constitute a viable read-out of microbial fermentation processes in the colon.

 

Seerave Fellow
Dr. Thomas Gurry
Background

The impact of our diet on our immune system is poorly understood. As the importance of controlling inflammation becomes evermore apparent in the context of both acute and chronic diseases, there is increasing interest in the role of nutrition on these processes. As DayTwo have demonstrated using plasma glucose tracking, continuous monitoring and multi-omic technologies provide a fresh opportunity to tackle the problem of host response to dietary ingredients. Combined with a quantitative understanding of the contribution of the gut microbiome to host inflammatory processes, we can gain clinically actionable insights that can be directly applied to clinical trials targeting conditions ranging from Inflammatory Bowel Disease to cancer immunotherapy.

Using an innovative study design and scalable implementation, we propose to measure the postprandial inflammatory response of different individuals to different extreme diets, and contrast these with the response to a personalised dietary fibre supplement chosen to minimise inflammation through maximizing microbial butyrate production. To do this, we will employ an experimental framework that allows us to measure a patient’s Microbial Metabolic Phenotype’ (MMP), which we define as the microbiome’s capability of roducing the Short Chain Fatty Acids (SCFAs) acetate, propionate and butyrate from specific dietary fibres. SCFAs are the end products of bacterial fermentation of dietary fibre in the colon, and are of increasing clinical interest as imbalances in their production have been associated with a growing list of clinical indications. Moreover, it is now known that SCFAs can alter gene expression in the host, and it is therefore an open question whether these effects transcend the gut. Most importantly, SCFAs are known to have significant impact on the production of pro- and anti-inflammatory cytokines, with resulting impact on inflammatory status of the host.

Unfortunately, it is not currently possible to measure real-time SCFA production in vivo. SCFAs can be quantified in stool samples, but it remains unclear to what extent they are representative of the amounts produced and absorbed during intestinal transit. We herefore lack a good in vivo read-out that could be used to rigorously investigate whether our personalised fibre interventions do indeed lead to increased production of specific SCFAs in vivo, as expected. Such a biomarker would constitute an important step in graduating from highly general notions such as the fact that ‘high fibre intake’ is conducive to health, and moving towards a quantitative and mechanistic understanding of the role of different fibres in different individuals.

Timeline
Start
01/10/2020
Hide

ACBP/DBI in the cancer-immune dialogue

Prof. Guido Kroemer

show details

Characterising a novel "metabolic checkpoint protein" called ACBP/DBI in regulating autophagy and thereby the cancer-immune dialogue.

Goals

Seerave Foundation is supporting a series of studies to assess the role of a novel “metabolic checkpoint protein” called ACBP/DBI in regulating autophagy and thereby the cancer-immune dialogue.  The aims of the project are

1) Measuring the concentrations of ACBP/DBI in patient samples and correlations with clinicobiological and metabolic features,

2) performing preclinical experiments to understand the role of ACBP/DBI in the relationship between metabolism, cancer and immunity,

3) evaluate strategies for inhibiting the human ACBP/DBI system.

Principal Investigator
Prof. Guido Kroemer
Seerave Fellows
Isabelle Martins
Léa Montegut
Background

Autophagy plays a fundamental role in cellular, tissue and organismal homeostasis, and is mediated by evolutionarily conserved autophagy-related (ATG) genes. Definitive etiological links exist between mutations in genes that control autophagy and human diseases, especially neurodegeneration, inflammatory disorders and cancer. Autophagy selectively targets dysfunctional organelles, intracellular microbes and pathogenic proteins, and deficiencies in these processes lead to disease. For this reason, autophagy-stimulatory compounds are being considered for the treatment of major human pathologies including aging, atherosclerosis, cancer, infection, neurodegeneration, obesity and metabolic syndrome.  Thus far, the hunt for pharmacological autophagy inducers has mostly focused on the development of drugs that act on intracellular pathways of autophagy regulation and hence disrupt the autophagy-inhibitory BCL2-BECN1 interaction, act on cytoplasmic nutrient sensors or increase the activity of pro-autophagic transcription factors.

Recently, the Kroemer lab discovered that autophagy is linked to a phylogenetically conserved (from yeast to human) non-canonical secretory pathway leading to the release of the small acyl coenzyme A binding protein (ACBP), also called diazepam binding inhibitor (DBI), from the cytoplasm. Extracellular ACBP/DBI then acts on plasma membrane receptors to inhibit autophagy in an autocrine or paracrine fashion. Hence, neutralization of ACBP/DBI with suitable (auto-)antibodies can stimulate autophagy by the interruption of this feedback loop, providing an extracellular target for autophagy induction.

ACBP/DBI plasma levels are increased in human obesity, especially in the context of hyperlipidemia, but reduced in patients with anorexia nervosa. Hence, ACBP/DBI is one of the few peripheral appetite stimulators that is actually upregulated in non-syndromic human obesity (contrasting, for example, with the appetite stimulator ghrelin that is downregulated or the appetite regulator leptin that is upregulated), suggesting that ACBP/DBI might be a useful target for therapeutic interventions on eating disorders. Of note, obesity is commonly associated with autophagy inhibition, as well as the accelerated manifestation of aging and age-related diseases including, metabolic syndrome cardiovascular disorders and neoplasia (which are all known from mouse experiments to be precipitated in conditions of suppressed autophagy). Thus, ACBP/DBI neutralization has a multipronged positive impact on obesity, by (i) reducing food intake, (ii) limiting lipo-anabolic and stimulating lipo-catabolic reactions, and (iii) reactivating deficient autophagy.

Encouraged by these findings, the Kroemer lab plans to further explore the role of ACBP/DBI in malignancy, while focusing on the dialogue between cancer and immune cells that is profoundly influenced by whole-body metabolism. For example, the Kroemer lab has previously shown that autophagy induction by fasting, ketogenic diet, and multiple pro-autophagic agents including aspirin and spermidine help immunogenic chemotherapy, alone or in combination with PD-1 blockade, to become more efficient. Given that ACBP/DBI acts as an extracellular feedback inhibitor of autophagy, one can speculate that its neutralization (which induces autophagy) will have positive effects on therapy-induced immunosurveillance as well.

Timeline
Start
01/01/2021
Hide

Novel diagnostic for the detection of Coronavirus antibodies

Prof. Eran Segal

show details

A novel high precision diagnostic for the detection of Coronavirus antibodies.

Goals

Seerave Foundation is supporting the development of novel diagnostics to study immune responses against Corona viruses (CoVs). This work will be performed by the lab of Prof. Eran Segal at the Weizmann Institute. Relying on next generation sequencing and samples from both infected and healthy individuals, this approach will shed light on population wide immune responses against CoVs. Thereby insights into shared immune responses and spread from asymptomatic carriers will be gained. The aims of this project are to perform 1) high resolution serotyping of CoVs, 2) epidemiological monitoring of the current outbreak, as well as 3) identifying potential novel vaccine targets. This platform could also increase preparedness for future CoV outbreaks and similar zoonotic transmissions.

Partner institution
Project leader
Prof. Eran Segal
Seerave Fellows
Dr. Thomas Vogl
Background

Current molecular diagnostics of CoV infections are either based on detecting genetic information (RNA based RT-qPCR tests) or immune responses against surface structures (antigens). Selected antigens are typically artificially produced and tested for separately with methods such as ELISAs or peptide arrays. Presently, only one out of 27 predicted proteins, that make up the 2019/2020 Corona virus, is being studied intensively. However, also the additional at least 26 other proteins may also be relevant for host response towards the virus. Given each protein contains multiple structural features (epitopes) that could be recognized by the immune system, there are potentially thousands of specific antibody responses against the current Corona virus. Identifying such novel antigens could yield improved diagnostic markers and vaccine targets.

Hide

Universitair Medisch Centrum Groningen

Groningen, The Netherlands

Predicting response to immunotherapy based on diet & microbiome

Prof. Geke Hospers

Prof. Rinse Weersma

show details

Longitudinal analysis of the nutritional status and microbiome composition in melanoma patients undergoing immunotherapy

Goals

Seerave Foundation is supporting two independent centers performing complementary prospective clinical studies:

1) University Medical Center Groningen (UMCG), Netherlands, under the supervision of Prof. Geke Hospers and Prof. Rinse Weersma. The Seerave Fellows at UMCG will coordinate the efforts undertaken.

2) King’s College London (KCL), United Kingdom, under the supervision of Prof. Tim Spector and Dr. Veronique Bataille. KCL will lead a consortium of UK Melanoma Centres

Both studies aim at performing longitudinal analysis of the nutritional status and the composition and function of the gut microbiome in melanoma patients undergoing immunotherapy. The ultimate goal is to integrate the collected data into predictive “–omics signatures” including other biomarkers from blood and tumors, host genetics and immunomics as well as other clinical parameters.

Principle investigators
Prof. Geke Hospers
Prof. Rinse Weersma
Seerave Fellows
Laura Bolte
Johannes Björk
Background

More and more evidence from studies in mice but also humans suggests that the gut microbiome regulates host immunity and also modulates the efficacy and side-effects of cancer chemotherapy and immunotherapy (details in our Science section). At the same time, multiple modulators including diet are known to influence the composition and/or the metabolic output of the gut microbiome. However, it is currently unknown whether different nutritional status of cancer patients might influence the composition and/or the metabolic output of the gut microbiome, and if so, whether these parameters could indeed stratify patients responding or not-responding to cancer immunotherapy. Given that nutrition may represent the safest and easiest modulator of the gut microbiome, understanding the relationship between nutrition, the microbiome, and anti-cancer immunity could a) generate hypotheses for mechanistic work in pre-clinical models, and b) open highly interesting therapeutic avenues for cancer patients.

Hide

Predicting response to immunotherapy based on microbiome & metabolites

Prof. Tim Spector

Prof. Veronique Bataille

Dr. Paul Nathan

show details

Predicting Response to Immunotherapy for Melanoma with gut Microbiome and metabolomics (PRIMM study)

Goals

Seerave Foundation is supporting two independent centers performing complementary prospective clinical studies:

1) University Medical Center Groningen (UMCG), Netherlands, under the supervision of Prof. Geke Hospers and Prof. Rinse Weersma. A Seerave Fellow at UMCG will coordinate the efforts undertaken.

2) King’s College London (KCL), United Kingdom, under the supervision of Prof. Tim Spector and Dr. Veronique Bataille. KCL will lead a consortium of UK Melanoma Centres

Both studies aim at performing longitudinal analysis of the nutritional status and the composition and function of the gut microbiome in melanoma patients undergoing immunotherapy. The ultimate goal is to integrate the collected data into predictive “–omics signatures” including other biomarkers from blood and tumors, host genetics and immunomics as well as other clinical parameters.

 

Partner institution
Principle investigators
Prof. Tim Spector
Dr. Veronique Bataille
Dr. Paul Nathan
Seerave Fellows
Dr. Karla Lee
Dr. Amrita Vijay
Clare Stockwell
Background

More and more evidence from studies in mice but also humans suggests that the gut microbiome regulates host immunity and also modulates the efficacy and side-effects of cancer chemotherapy and immunotherapy (details in our Science section). At the same time, multiple modulators including diet are known to influence the composition and/or the metabolic output of the gut microbiome. However, it is currently unknown whether different nutritional status of cancer patients might influence the composition and/or the metabolic output of the gut microbiome, and if so, whether these parameters could indeed stratify patients responding or not-responding to cancer immunotherapy. Given that nutrition may represent the safest and easiest modulator of the gut microbiome, understanding the relationship between nutrition, the microbiome, and anti-cancer immunity could a) generate hypotheses for mechanistic work in pre-clinical models, and b) open highly interesting therapeutic avenues for cancer patients.

For more information on the study, visit NCT03643289 at clinicaltrials.gov

Timeline
Start
01/11/2017
09/04/2018

IRB approval

29/10/2018

NIHR Portfolio approval

01/11/2018

First patient recruited

Hide

Impact of microbiome-derived metabolites on immune cells

Prof. Naama Geva-Zatorsky

show details

Characterizing Microbiome-Derived Metabolites That Directly impact The Immune System (CMMIIS Study)

Goals

Seerave Foundation is supporting pre-clinical research in the labs of Prof. Naama Geva-Zatorsky, aiming at identifying metabolites produced by the gut microbiota that directly impact the immune system and generate in depth mechanistic understanding about their receptors and downstream signaling. Identifying such metabolites will represent the first step in generating an in-depth mechanistic understanding of the downstream molecular pathways responsible for delivering signals from the bacterial cell to the host immune cell. This should guide the development of novel therapeutic interventions to strengthen immune responses in cancer patients including personalized and rationally designed nutrient compositions.

Principle investigator
Prof. Naama Geva-Zatorsky
Seerave Fellows
Dr. Tal-avi Gefen
Noa Mandelbaum
Background

The gut microbiome has co-evolved with the human host for millennia, creating an inextricable and dependent relationship, where the gut bacteria became a vital component of the human immune system. Both soluble metabolites secreted by the bacteria as well as cellular components such as lipopolysaccharides (LPS) found in the membrane of certain bacteria have been shown to influence the immune system. Naama Geva-Zatorsky recently identified more than 50 different bacterial strains from the gut microbiome that individually impact different systemic immune responses in mice. However, it is still unknown which metabolites secreted by these bacterial strains are the ones responsible for the modulation of immune responses, and whether the production of these metabolites depends on the availability of specific nutrients. Understanding these relationships may lead to the identification of novel, rationally-designed nutritional approaches to aid anti-cancer therapy.

Timeline
Start
01/07/2018
Hide

Yerosha Productions

New York City, USA

Documentary movie: "Missing Microbes"

Sarah Schenk

Steven Lawrence

show details

Documentary movie: "Missing Microbes"

Goals

The documentary “Missing Microbes” aims at explaining to a layman audience the state-of-the-art microbiome research and its potential to improve human health. Seerave is supporting this documentary since it will be produced in a rigorous and scientifically sound manner. Furthermore, Seerave is helping the team to navigate the science around the diet/microbiome/immunity/cancer axis.

Director and Producer
Sarah Schenk
Steven Lawrence
Background

Missing Microbes is a feature documentary about the critical role of microbes in human health – and how disrupting our microbes has helped trigger an unprecedented surge in chronic diseases like obesity, diabetes, cancer, allergies, and autism. As the film follows globe-trotting microbiologists Martin Blaser and Gloria Dominguez-Bello on their mission to end this crisis before it’s too late, it also tells the stories of patients in China, Israel, Europe, and the USA as they search for cures to these modern plagues.

 

Timeline
Start
01/07/2018
Hide