Project acronym Brain Health Toolbox
Project The Brain Health Toolbox: Facilitating personalized decision-making for effective dementia prevention
Researcher (PI) Alina Gabriela SOLOMON
Host Institution (HI) ITA-SUOMEN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Preventing dementia and Alzheimer disease (AD) is a global priority. Previous single-intervention failures stress the critical need for a new multimodal preventive approach in these complex multifactorial conditions. The Brain Health Toolbox is designed to create a seamless continuum from accurate dementia prediction to effective prevention by i) developing the missing disease models and prediction tools for multimodal prevention; ii) testing them in actual multimodal prevention trials; and iii) bridging the gap between non-pharmacological and pharmacological approaches by designing a combined multimodal prevention trial based on a new European adaptive trial platform. Disease models and prediction tools will be multi-dimensional, i.e. a broad range of risk factors and biomarker types, including novel markers. An innovative machine learning method will be used for pattern identification and risk profiling to highlight most important contributors to an individual’s overall risk level. This is crucial for early identification of individuals with high dementia risk and/or high likelihood of specific brain pathologies, quantifying an individual’s prevention potential, and longitudinal risk and disease monitoring, also beyond trial duration. Three Toolbox test scenarios are considered: use for selecting target populations, assessing heterogeneity of intervention effects, and use as trial outcome. The project is based on a unique set-up aligning several new multimodal lifestyle trials aiming to adapt and test non-pharmacological interventions to different geographic, economic and cultural settings, with two reference libraries (observational - large datasets; and interventional - four recently completed pioneering multimodal lifestyle prevention trials). The Brain Health Toolbox covers the entire continuum from general populations to patients with preclinical/prodromal disease stages, and will provide tools for personalized decision-making for dementia prevention.
Summary
Preventing dementia and Alzheimer disease (AD) is a global priority. Previous single-intervention failures stress the critical need for a new multimodal preventive approach in these complex multifactorial conditions. The Brain Health Toolbox is designed to create a seamless continuum from accurate dementia prediction to effective prevention by i) developing the missing disease models and prediction tools for multimodal prevention; ii) testing them in actual multimodal prevention trials; and iii) bridging the gap between non-pharmacological and pharmacological approaches by designing a combined multimodal prevention trial based on a new European adaptive trial platform. Disease models and prediction tools will be multi-dimensional, i.e. a broad range of risk factors and biomarker types, including novel markers. An innovative machine learning method will be used for pattern identification and risk profiling to highlight most important contributors to an individual’s overall risk level. This is crucial for early identification of individuals with high dementia risk and/or high likelihood of specific brain pathologies, quantifying an individual’s prevention potential, and longitudinal risk and disease monitoring, also beyond trial duration. Three Toolbox test scenarios are considered: use for selecting target populations, assessing heterogeneity of intervention effects, and use as trial outcome. The project is based on a unique set-up aligning several new multimodal lifestyle trials aiming to adapt and test non-pharmacological interventions to different geographic, economic and cultural settings, with two reference libraries (observational - large datasets; and interventional - four recently completed pioneering multimodal lifestyle prevention trials). The Brain Health Toolbox covers the entire continuum from general populations to patients with preclinical/prodromal disease stages, and will provide tools for personalized decision-making for dementia prevention.
Max ERC Funding
1 498 268 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym CAN-IT-BARRIERS
Project Disruption of systemic and microenvironmental barriers to immunotherapy of antigenic tumors
Researcher (PI) Douglas HANAHAN
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Advanced Grant (AdG), LS7, ERC-2018-ADG
Summary The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.
Summary
The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.
Max ERC Funding
2 500 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym FutureTrophicFactors
Project Elucidating therapeutic effects and mode of action of future trophic factorsin ALS and Parkinson’s disease
Researcher (PI) Merja Hannele VOUTILAINEN
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary The prevalence of neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) is growing rapidly due to an aging population and increased life expectancy. Current treatments for ALS and PD only relieve symptoms and cannot stop the progression of the disease, thus there is an urgent need for new therapies. Neurotrophic factors (NTFs) are secretary proteins that regulate the survival of neurons, neurite growth and branching. They have been explored as novel drugs for the treatment of ALS and PD but their efficacy in clinical trials is poor. CDNF is a protein with NTF properties that protects and restores the function of dopamine neurons in rodent and rhesus monkey toxin models of PD more effectively than other NTFs. CDNF is currently in phase 1/2 clinical trials on PD patients. Despite promising results with CDNF in animal models of PD, NTF and CDNF-based treatments have drawbacks. CDNF requires direct delivery to the brain through invasive surgery since, it cannot pass through the blood brain barrier (BBB). My recent discovery, however, may overcome this difficulty: I showed that a novel CDNF variant protects DA neurons in vitro and in vivo and that it efficiently enters DA neurons in culture. Furthermore, my data show the CDNF fragment can pass through the BBB as measured by 3 different methods and has a neurorestorative effect in a 6-OHDA toxin model of PD when administered subcutaneously. The ultimate goal of my research is to understand the mode of action and therapeutic effect of novel BBB penetrating CDNF-derived polypeptides in cultures of human induced pluripotent stem (iPS) cell-derived nerve cells from patients and in animal models of ALS and PD. The innovative aspect of this proposal is the new groundbreaking concept for treating neurodegenerative diseases – peripheral delivery of BBB penetrating peptides with trophic factor properties and the potential to treat non-motor and motor symptoms in ALS and PD patients.
Summary
The prevalence of neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) is growing rapidly due to an aging population and increased life expectancy. Current treatments for ALS and PD only relieve symptoms and cannot stop the progression of the disease, thus there is an urgent need for new therapies. Neurotrophic factors (NTFs) are secretary proteins that regulate the survival of neurons, neurite growth and branching. They have been explored as novel drugs for the treatment of ALS and PD but their efficacy in clinical trials is poor. CDNF is a protein with NTF properties that protects and restores the function of dopamine neurons in rodent and rhesus monkey toxin models of PD more effectively than other NTFs. CDNF is currently in phase 1/2 clinical trials on PD patients. Despite promising results with CDNF in animal models of PD, NTF and CDNF-based treatments have drawbacks. CDNF requires direct delivery to the brain through invasive surgery since, it cannot pass through the blood brain barrier (BBB). My recent discovery, however, may overcome this difficulty: I showed that a novel CDNF variant protects DA neurons in vitro and in vivo and that it efficiently enters DA neurons in culture. Furthermore, my data show the CDNF fragment can pass through the BBB as measured by 3 different methods and has a neurorestorative effect in a 6-OHDA toxin model of PD when administered subcutaneously. The ultimate goal of my research is to understand the mode of action and therapeutic effect of novel BBB penetrating CDNF-derived polypeptides in cultures of human induced pluripotent stem (iPS) cell-derived nerve cells from patients and in animal models of ALS and PD. The innovative aspect of this proposal is the new groundbreaking concept for treating neurodegenerative diseases – peripheral delivery of BBB penetrating peptides with trophic factor properties and the potential to treat non-motor and motor symptoms in ALS and PD patients.
Max ERC Funding
1 497 597 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym TALE
Project Therapeutic Allele Engineering: A novel technology for cell therapy
Researcher (PI) Lukas JEKER
Host Institution (HI) UNIVERSITAT BASEL
Call Details Consolidator Grant (CoG), LS7, ERC-2018-COG
Summary We are currently witnessing a revolution in cell therapies that are routed in decades of basic research in genetics, cell biology and immunology. A deep understanding of mammalian, and in particular immune, cells is currently being translated into highly efficient cell-based therapeutics. Technologic breakthroughs in genetic and genome engineering are further fueling the generation of customized, high precision therapies that are based on cells as “smart drugs”. For instance, reprogramming immune killer cells to recognize B cell leukemias resulted in unprecedented clinical responses in treatment-resistant and relapsed patients. However, currently only very few, highly selected patients benefit from these developments. A fundamental problem of today’s cell therapies is that transferred cells cannot be distinguished from host cells. We have developed “allele engineering”, a new technology that solves this challenge. Here, we outline how allele engineering will improve the safety and efficacy of cell therapies. We will 1) generate a non-viral, DNA-free safety/shielding switch 2) develop a radically new curative approach to acute myeloid leukemia 3) rationally design a safe allele engineering solution for human therapy and 4) use allele engineering as a curative therapy of scurfy syndrome, a lethal monogenic autoimmune disease. Allele engineering enables completely new treatment strategies and can be applied to any surface protein. Therefore, I anticipate that the results will have a major impact on the field.
Summary
We are currently witnessing a revolution in cell therapies that are routed in decades of basic research in genetics, cell biology and immunology. A deep understanding of mammalian, and in particular immune, cells is currently being translated into highly efficient cell-based therapeutics. Technologic breakthroughs in genetic and genome engineering are further fueling the generation of customized, high precision therapies that are based on cells as “smart drugs”. For instance, reprogramming immune killer cells to recognize B cell leukemias resulted in unprecedented clinical responses in treatment-resistant and relapsed patients. However, currently only very few, highly selected patients benefit from these developments. A fundamental problem of today’s cell therapies is that transferred cells cannot be distinguished from host cells. We have developed “allele engineering”, a new technology that solves this challenge. Here, we outline how allele engineering will improve the safety and efficacy of cell therapies. We will 1) generate a non-viral, DNA-free safety/shielding switch 2) develop a radically new curative approach to acute myeloid leukemia 3) rationally design a safe allele engineering solution for human therapy and 4) use allele engineering as a curative therapy of scurfy syndrome, a lethal monogenic autoimmune disease. Allele engineering enables completely new treatment strategies and can be applied to any surface protein. Therefore, I anticipate that the results will have a major impact on the field.
Max ERC Funding
2 397 082 €
Duration
Start date: 2019-06-01, End date: 2024-05-31
Project acronym TIL-FIT
Project Increasing the fitness of tumor-infiltrating T cells for cellular immunotherapy
Researcher (PI) Roger GEIGER
Host Institution (HI) FONDAZIONE PER L ISTITUTO DI RICERCA IN BIOMEDICINA
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary Adoptive T cell therapies (ACTs) are emerging as a promising strategy to treat cancer. Tumor-infiltrating lymphocytes (TILs) are expanded ex vivo, selected for recognition of neoantigens, further expanded and then infused back into patients. This procedure requires extensive culturing and expansion of TILs during which many T cell clonotypes are lost. As tumor-reactive TILs are often exhausted and tend to be overgrown by functional, non-specific T cells in culture, the chance to identify potent tumor-reactive T cells dramatically decreases. Moreover, extensive expansion of T cells diminishes their anti-tumor activity and persistence in the body after adoptive transfers. Thus, improving the fitness of T cells is crucial to increase the success rate of ACTs and make this therapy accessible to a broad spectrum of cancer patients. Our first aim is to increase the fitness of T cells by designing metabolic and pharmacological interventions based on proteomic profiles of TILs from patients with liver cancer. Second, we will use machine-learning algorithms for the extraction of signatures to predict whether TILs grow well in culture, require and respond to metabolic interventions, or cannot be revitalized and do not grow at all. To deal with non-growing T cells, we aim at establishing a microfluidics-based workflow to graft the entire T cell receptor (TCR) repertoire from thousands of non-growing TILs onto fast growing Jurkat cells. After selecting Jurkat cells that recognize neoantigens, their TCRs will be expressed on naïve T cells obtained from the patient’s blood that are fit and suitable for ACT. This project will contribute to a better understanding of the T cell response to liver cancer and help increasing the success of personalized ACTs for solid tumors.
Summary
Adoptive T cell therapies (ACTs) are emerging as a promising strategy to treat cancer. Tumor-infiltrating lymphocytes (TILs) are expanded ex vivo, selected for recognition of neoantigens, further expanded and then infused back into patients. This procedure requires extensive culturing and expansion of TILs during which many T cell clonotypes are lost. As tumor-reactive TILs are often exhausted and tend to be overgrown by functional, non-specific T cells in culture, the chance to identify potent tumor-reactive T cells dramatically decreases. Moreover, extensive expansion of T cells diminishes their anti-tumor activity and persistence in the body after adoptive transfers. Thus, improving the fitness of T cells is crucial to increase the success rate of ACTs and make this therapy accessible to a broad spectrum of cancer patients. Our first aim is to increase the fitness of T cells by designing metabolic and pharmacological interventions based on proteomic profiles of TILs from patients with liver cancer. Second, we will use machine-learning algorithms for the extraction of signatures to predict whether TILs grow well in culture, require and respond to metabolic interventions, or cannot be revitalized and do not grow at all. To deal with non-growing T cells, we aim at establishing a microfluidics-based workflow to graft the entire T cell receptor (TCR) repertoire from thousands of non-growing TILs onto fast growing Jurkat cells. After selecting Jurkat cells that recognize neoantigens, their TCRs will be expressed on naïve T cells obtained from the patient’s blood that are fit and suitable for ACT. This project will contribute to a better understanding of the T cell response to liver cancer and help increasing the success of personalized ACTs for solid tumors.
Max ERC Funding
1 406 250 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
