Researchers in the NSU Cell Therapy Institute are dedicated to innovative translational biomedical research, focused on harnessing the healing power inherent in our own cells to treat devastating diseases. Our long-term vision is to enhance human health by advancing innovative cell-based therapies to the clinic. In this regard, three general cell types are of particular interest: immune cells, cancer cells and stem cells. Our mission is specifically focused on research in cancer immunotherapy and regenerative medicine.
Cell-based therapies are becoming a major approach to the future of personalized, precision medicine. The NSU Cell Therapy Institute is focused on laboratory research that can be translated into the clinic for safer and more effective treatment of devastating diseases. This research is part of collaborative efforts with academic institutions, government, and industry around the globe.
天天色综合,天天干影视The NSU Cell Therapy Institute represents a collaboration with leading medical research scientists Sweden’s world renowned Karolinska Institutet in Stockholm. The Life Sciences International Program (LSIP) program provides support for international educational and research experiences that contribute to global health initiatives. Together, our goal is to reduce the lag time involved in translating laboratory discoveries into the clinic.
We Focus On
Lab Head: H Thomas Temple, M.DKey Personnel: Wendy W Weston, PhD, CTBS; AnnaMaria Georgoudaki, PhD
天天色综合,天天干影视The Sarcoma Research Laboratory investigates sarcoma diagnosis, prognosis and treatment. Sarcoma is a malignancy of bone and connective tissue that affects people of all ages. The diverse sarcoma subtypes can affect bone, cartilage, connective tissue, muscle, fat, peripheral nerves, as well as fibrous and related tissues. In certain high-risk sarcomas, like chondrosarcoma and leiomyosarcoma, the overall survival is less than 15 months after metastasis. Despite many advancements in molecular diagnostics, no significant improvement has been made that enables the identification or characterization of a sarcoma early in tumor progression, before invasive treatment methods are required. We utilize valuable primary tumors and corresponding patient plasma and peripheral blood mononuclear cells to investigate molecular signatures for sarcoma and subtypes. With this, we are developing a refined catalog of information that will be expanded upon with every specimen isolation, adding resources to the clinical and research community. Our goal is to use this information to develop future diagnostics and personalized treatments for sarcomas. Three major research themes are being studied:
1) Exosomes for sarcoma diagnostics and prognostics. One of the primary biological resources we use are secreted extracellular vesicles called exosomes. Many cell types have been shown to communicate via exosomes, which deliver cargo containing bioactive factors to recipient cells, eliciting profound effects. While these are secreted by all cells, cancer cells release significantly more exosomes than normal cells, which can be found in most bodily fluids. This intercellular communication contributes to the regulatory signaling of both normal and pathological processes, including cancer. We are developing and validating an exosome isolation pipeline that allows for use with tumors, cultures and blood. Primary sarcoma cell-derived exosomes not only provide the basis for the identification of novel sarcoma biomarkers, but also provide a launching point for tracing these biomarkers in the patient blood. We expect this non invasive method for diagnostics and prognostics to ultimately direct sarcoma therapeutics. The relation of findings from tumor cell-derived exosomes to plasma-derived exosomes, as compared to healthy patient plasma exosomes, has the full potential for translation to several different cancer models.
天天色综合,天天干影视2) Sarcoma-derived exosomes in pro-tumorigenic macrophage polarization and metastasis prediction. Tumor-derived exosomes (TEX) are potent molecular messengers with the ability to sequester macrophage function in distal tissues to support tumor metastasis. We are investigating the effect of TEX on macrophage phenotype, activation and function to uncover valuable information regarding molecular pathways that are triggered upon interaction with TEX and how they drive tumor-promoting activity. This work may lead to the discovery of new candidates for targeted immunotherapy. Our comparison of the phenotype and cargo of TEX from primary versus metastatic sarcomas may give additional indications as to which molecules govern tissue-specific metastasis. Thus, detailed characterization of cell adhesion molecules, tissue-specific molecular signatures and chemokine migration axes involved in TEX-induced and macrophage assisted metastasis may serve as valuable predictors of metastatic niches.
3) Tumor-infiltrating leukocyte profiling of sarcomas for targeted antibody-mediated immunotherapy. Immunomodulatory therapies with monoclonal antibodies (mAb), such as anti-CTLA-4 (ipilimumab) and anti-PD-1 (pembrolizumab, nivolumab), targeting inhibitory pathways in T cells can generate efficient anti-tumor responses, as was recently shown for several cancers. Alternatively, immunomodulatory mAb’s can target immunosuppressive cells for re-polarization or elimination. However, for a large proportion of patients these treatments remain ineffective due to the varying composition of the tumor and tumor microenvironment (TME). Thus, we pursue detailed characterization of the patient’s individual immunosuppressive TME to select the appropriate therapeutics.
Lab Head: Adil Duru, PhD天天色综合,天天干影视Key Personnel: Canan Sayitoglu, PhD; Renee Potens, MS
天天色综合,天天干影视The Targeted Immunotherapy Laboratory is focused on developing innovative Natural Killer (NK) cell-based therapie for cancer treatment. Working in close collaboration with the Sarcoma Research Laboratory, this team is using sarcomas as model solid tumors for next-generation immunotherapies. A unique biobank of sarcoma primary tumors and cell cultures has been established for identification of new therapeutic targets in sarcomas. These sarcoma tumors and cultures are being characterized in terms of tumor-associated antigens and neo-antigens, genomic alternations, and the tumor microenvironment including immune cells. This information in turn provides the basis for developing genetically modified NK cells, engineered monoclonal antibodies, and cancer vaccines that target tumor antigens specific to sarcomas. These studies also contribute to identification of new diagnostic and prognostic biomarkers for sarcomas. This research is part of NSU’s Sarcoma Research Network, a multidisciplinary research initiative with international collaborators involved in basic, translational and clinical research. The ultimate goal of this collaborative initiative is development of personalized cancer immunotherapies tailored to specific sarcoma types and patients. Four major strategies are currently being pursued:
天天色综合,天天干影视1) Generation of comprehensive sarcoma biobank. There is currently a lack of sufficient sarcoma primary tumors and cell lines to support a detailed characterization of the variety of different subtypes of this highly diverse cancer. We have developed an efficient clinic-to-bench pipeline that allows the isolation of primary sarcoma tumor cells directly from clinical samples for the generation of sarcoma cell cultures and eventually lines. Additionally, this pipeline also enables the characterization of the individual tumor microenvironment including immune cells. We aim to generate a large comprehensive sarcoma biobank comprising cellular, genomic and proteomic components from primary sarcoma tumors and tumor infiltrating leukocytes (TIL).
2) Characterization of genomic abnormalities in sarcomas. Chromosomal abnormalities in pediatric sarcomas can result in gene fusions contributing to tumorigenesis and poor prognosis through interactions with diverse signaling pathways. Several subtypes of pediatric sarcomas with genomic alterations such as single point mutations, gene fusions and chromosomal translocations have been characterized. Even though there are identified gene fusions that are crucial tools in prognosis of sarcoma subtypes, there are not enough studies that focus on the potential targeting of tumor specific fusion genes compared to other well studied cancers such as hematological malignancies. An effective therapy targeting gene fusions remains to be developed for high risk, poor prognosis and therapy-resistant pediatric sarcomas.
3) Antigen-specific personalized immunotherapy for sarcomas. We have recently established a novel technology that combines the specificity of a TCR against a tumor-associated antigen (TAA) with the potent killing capability of NK cells. With our previous experience in identifying chromosomal abnormalities involved in prognosis and treatment of hematological malignancies, we aim to identify novel gene fusions that can be targeted for immunotherapy in pediatric sarcomas. Here, we propose that chromosomal abnormalities and gene fusions observed in high-risk pediatric sarcoma patients will result in the generation of neo-antigens that can be targeted by our novel NK-TCR technology.
4) Genetically modified NK cell screening platform. To better understand NK cell-sarcoma interactions, we have developed a screening platform using genetically modified (GM) NK cells. Genetic modification of NK cells for adoptive transfer is an extremely promising new treatment for cancer patients. An in-depth understanding of NK cell-tumor interactions is necessary for tailoring the development of this treatment for patient sub-populations. The poor clinical outcomes for some sarcoma subtypes indicate that more detailed studies for each sub-population are especially critical.
Lab Head: Vladimir Beljanski, PhD天天色综合,天天干影视Key Personnel: Fiorella Rossi, PhD; Hunter Noren, MS
The goal of our research is to improve existing therapies and develop novel cell-based therapies using mesenchymal stromal cells (MSCs) for tissue repair and regeneration. Many organisms possess high regenerative capacity and can replace lost body parts or damaged tissues. In humans, mainly liver and skin demonstrate high regenerative capacity. Consequently, innovative approaches, such as treatment with therapeutic MSCs, are needed to regenerate structure and function of damaged tissues and organs in patients due to injuries and/or diseases.
天天色综合,天天干影视To devise effective new MSC therapies, we must first understand mechanistic aspects of MSC-based therapies, including molecules involved in their interactions with immune cells and the role of MSC-secreted microvesicles, such as exosomes, in tissue repair and regeneration. Unfortunately, the therapeutic efficacy of MSCs is not optimal and is substantially decreased even more with continuous cell culture and expansion, which is needed to obtain enough MSCs for injection into patients.
天天色综合,天天干影视The cellular self-digestion pathway, autophagy, is known to regulate many processes that are essential to MSC maintenance, from their overall metabolic fitness to their ability to remain quiescent. We are exploring how the therapeutic efficacy of MSCs can be improved by targeting autophagy in these cells. In particular, we are investigatiing how pharmacological or genetic modulation of autophagy affects the therapeutic properties of MSCs, with an ultimate goal of improving their therapeutic properties. Three different areas of research are currently being pursued:
1) Modulation of autophagy for improvement of MSC’s immunoregulatory properties. Therapeutic potential of MSCs and thus overall tissue regeneration can be improved by either pre-treatment of MSCs or by co-administration of adjuvant therapies and/or scaffolds. Small molecules, biologics or biomaterials can be used to target specific aspects of MSC biology and modulate interactions between cells and their environment, modulate immune responses to MSCs, and facilitate expansion, differentiation, or dedifferentiation of cells. The goal of this project is to determine how to apply pharmacologic and genetic modulation of autophagy to achieve better therapeutic outcomes by enhancing immunoregulatory properties of MSCs.
天天色综合,天天干影视2) Autophagy and the therapeutic properties of MSC-secreted exosomes. Recent discoveries suggest that many of the therapeutic benefits of MSCs can be attributed to the secretion of various biomolecules that can be delivered via exosomes. Exosomes contain proteins, DNA, mRNA, and microRNA, all of which have a role in cell-cell communication. Importantly, exosome formation and release are impacted by the autophagy pathway, a homeostatic quality control mechanism that recycles proteins and organelles via recognition, sequestration, and lysosomal degradation. The goal of this project is to increase our understanding of the role autophagy plays in regulating exosomal RNA content. This study should also reveal whether targeting autophagy could be used to modify exosomal RNA content, their immunomodulatory properties and thus potentially increase their therapeutic efficacy.
3) Systems biology approaches to examining consequences of therapeutic cell engraftment. We are applying exploratory approaches to determine the key genes and pathways that respond to cellular engraftment, in order to understand how these impact on engraftment efficacy of MSCs. Genomics approaches that utilize RNA-sequencing and/or DNA methylation are utilized to determine optimal cell types for tissue repair and understand how such cells respond to changes in their microenvironment. Results of these studies will help lay the foundation for improved cell therapies building on basic research in this area.
Lab Head: Geeta Ravindran, PhD天天色综合,天天干影视Key Personnel: Benjamin Josey, PhD
Stem cells are pluripotent cells that possess the ability to differentiate into many specialized cell types including neurons, muscle cells, and immune cells. Stem cells have critical roles in normal development and tissue repair. The stem cells that exist in the very early phase of embryonic development are known as embryonic stem cells (ESCs), and these cells have the ability to become virtually any cell type found in the body. As the body develops, ESCs disappear, although stem cell populations of more restricted pluripotency continue to exist in the adult, such as hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Additionally, technologies have been developed where differentiated adult cells can be “reprogrammed” back to an ESC-like state. These cells are called induced pluripotent stem cells (iPSCs). This unique ability to take an easy to access cell, such as a skin fibroblast or a blood cell, from patients with incurable diseases and create iPSCs that can then be directed to differentiate into other cell types found in the body, allows for re-creation of patient-specific model systems in the laboratory. These “disease-in-a-dish” model systems hold great promise for studying the underlying mechanisms of degeneration and healing with a level of detail that was never before possible. Despite significant progress and exciting scientific discoveries being made on a regular basis, a detailed understanding of the fundamental principles governing pluripotency and differentiation of stem cells is still lacking. The goal of our research is to identify stem cells that can be used for the study and development of new treatments for degenerative diseases, regenerative medicine and cancer. Three complementary areas of research are currently being pursued:
1) Using stem cells to understand the mechanisms underlying neurodegenerative disease. Neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s Disease (PD) are characterized by a progressive loss of neurons and the functions they perform. PD is a chronic and progressive movement disorder, mainly caused by the death of dopaminergic neurons in the brain. ALS is a progressive neurodegenerative disease caused by the selective loss of both spinal and upper motor neurons. One of the goals of our lab is to use patient-derived iPSCs to recapitulate the cellular environment surrounding the types of neurons affected in degenerative diseases. We use these model systems to identify novel treatments and diagnostic biomarkers in the laboratory.
2) Using stem cells to develop therapies for regenerative medicine. The ultimate purpose of studying degeneration is to develop methods to either slow it down or reverse it. One promising therapeutic approach for PD is cell-replacement therapy, in which dopaminergic neurons or precursors are grafted in the brain. Adult iPSCs are considered to be a promising source for derivation of specialized dopaminergic neurons for the future cell therapy of PD. In the case of ALS, one strategy is to use iPSC derived motor neurons to replace lost spinal motor neurons. However, transplanted stem cell-derived motor neurons may not survive when exposed to the microenvironment in the spinal cord. The main aim of cell therapy for ALS will be not only to regenerate motor neurons but also provide a favorable cellular microenvironment.
3) Identifying stem cell populations in rare and treatment resistant cancers. Much in the way that normal stem cells support the development and maintenance of normal tissues, several cancer types have been shown to harbor “cancer stem cell” (CSC) populations. These small hidden populations of CSCs can be responsible for the recurrence and metastases of tumors, and they are often resistant to typical cancer treatments and evade immune system detection. Of particular interest in our research are common mesenchymal stem cell progenitors among normal cells and sarcomas, as well as genomic alterations common to sarcomas and certain neurodegenerative diseases, including ALS and PD. Our lab collaborates with cancer researchers to use stem cells to better understand the tumor microenvironment and develop more effective immunotherapies for treatment-resistant cancers like sarcomas.