Is stem cell therapy ready for patients? Stem Cell Therapy for Cardiac Repair. Ready for the Next Step .
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Cardiovascular therapeutic aspects of cell therapy and stem cells.
The recent advancements in stem cell biology, molecular and cell biology, and tissue engineering have paved the way to the development of a new biomedical discipline: regenerative medicine. The heart represents an attractive candidate for this emerging discipline since these emerging technologies could be used to potentially treat a variety of myocardial disorders. Here we describe our efforts in using stem cell and cell therapy strategies to restore the myocardial electromechanical properties. Specifically, our research has focused on the potential role of human embryonic stem cells (hESC) for myocardial regeneration (for the treatment of heart failure) and on using genetically engineered cell grafts to modify the myocardial electrophysiological properties (for the treatment of cardiac arrhythmias). The recently described hESC lines are unique pluripotent cell lines that can be propagated in the undifferentiated state in culture and coaxed to differentiate into cell derivatives of all three germ layers, including cardiomyocytes. The current article describes this unique cardiomyocyte differentiating system and details the molecular, ultrastructural, and functional properties of the generated hESC-derived cardiomyocytes (hESC-CMs). The ability of the hESC-CMs to integrate structurally and functionally with host cardiomyocytes in both in vitro and in vivo studies will be described as well as their ability to restore the myocardial electromechanical function in animal models of diseased hearts. We will next present detailed in vitro, in vivo, and computer simulation studies performed in our laboratory testing the hypothesis that cell grafts, engineered to express specific ion channels, can be used to modify the myocardial electrophysiological properties of cardiac tissue. The potential and drawbacks of this novel approach for the treatment of both tachyarrhythmias (using cell grafts expressing potassium channels) and bradyarrhythmias (using hESC coaxed to differentiate into pacemaking cells or conducting tissue) will be described.
Animals↗
[Cell therapy in renal cell carcinoma].
Cellular therapy in renal cell carcinoma has to be included in a strategy based on the known sensitivity to immunotherapy of renal cell carcinoma. Cellular therapy was previously initiated with Lymphokine Activated Killer cells (LAK) then Tumor Infiltrating Lymphocytes (TIL). Yet, major clinical evaluations are performed on dendritic cells and allogeneic blood stem cell transplantation.
Antigen-Presenting Cells↗
Stem cell therapy for sickle cell disease: transplantation and gene therapy.
HLA-identical sibling hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) has a strong track record of efficacy and there is growing appreciation that its benefits exceed its risks in selected individuals. In contrast, the clinical utility of replacement gene therapy for sickle cell disease remains unproven. Its challenge is to ensure viral transduction into hematopoietic stem cells (HSCs) and to generate safe, stable, erythroid-specific replacement gene expression at a level that is sufficient to have a clinical effect. The clinical necessity for fulfilling all these criteria may make this genetic disorder among the most complex to treat successfully by gene therapy. But the experience of HCT for SCD has proven that eliminating the beta(S)-globin gene is curative when the transfer is stable. Thus replacement gene therapy for sickle cell disease remains a subject of intense interest and investigation.
Anemia, Sickle Cell↗
[Cell therapy and its clinical applications. Cartilage cell therapy, present and future].
Articular cartilage has a very poor capacity for repair. In order to get a normal functional efficacy, the replaced tissue has to reproduce the structure, composition and physico-chemical properties of native cartilage tissue. The transplantation of cultured autologous chondrocytes into chondral defects is currently applicable only in the case of young sportive people with a limited lesion in an otherwise relatively normal joint. Recent experimental studies have shown that pluripotent mesenchymal cells from bone marrow could also repair experimental osteochondral defects. An advantage of this grafting procedure is that large areas of cartilage surface could be covered. Bone marrow cells are not so difficult to get, they have a high potency to divide and they can develop in vitro as chondrogenic, osteogenic or adipogenic cells. The present ways of research are: to characterize one or several growth factors capable to specifically induce the chondrogenic lineage; to determine nutrient and environmental conditions allowing the cultured chondrogenic cells to undergo a maturation process within the cell pellet; to elaborate three-dimensional synthetic, biodegradable polymeric scaffolds assessed with respect to chondrogenic cell adhesion, proliferation, maturation and cartilage matrix secretion; finally, to elaborate a mixed biomaterial composed of chondrogenic and osteogenic cells selectively distributed within polymeric scaffolds in order to get a better adherence of the implanted cells to the lesion sites.
Bone Marrow Cells↗
Cell therapy of heart failure.
Together with angiogenesis and gene therapy, cell transplantation is one of the newest treatments that have been proposed to improve the still grim outcome of patients with cardiac failure. The underlying rationale is that implantation of contractile cells into fibrous post-infarction scar can functionally 'regenerate' these areas. Primarily for practical reasons, autologous skeletal myoblasts have been the first to be tested in a clinical trial but other cell types can be considered, among which bone marrow stromal and hematopoietic stem cells are of particular interest because of their autologous origin and their purported transdifferentiation potential into cardiac and/or endothelial cells. However, several key issues still need to be addressed, including (i) the optimal type of donor cells, (ii) the mechanism by which cell engraftment improves cardiac function, actively (i.e., by increasing contractility) or passively (i.e. by limiting infarct expansion and remodelling), (iii) the optimisation of cell survival, and (iiii) the potential benefits of cell transplantation in non-ischaemic heart failure. Parallel to the numerous experimental studies designed to address these issues, initial clinical trials are underway or in preparation and, if properly designed and conducted, should allow to know whether the hopes raised by cellular therapy are met by clinically meaningful improvements in the outcomes of patients with heart failure.
Animals↗
[Plasticity of skeletal muscle differentiation generating stem cell-like phenotype: possible application to cell therapy for muscular diseases].
Drug therapy, gene therapy, and cell therapy may be effective to degenerative muscular diseases caused by genetic mutations including muscular dystrophy. Stem cells including embryonic stem (ES) cells and adult stem cells (tissue stem cells) are generally believed to be applicable to cell therapy. However, both types of cells have several problems to be solved for the cell therapy. We have shown that the expression of SV40 large T antigen in terminally differentiated mouse C2 skeletal muscle myotubes induce mitosis and dedifferentiation. This finding has exploded the concept that terminally differentiated cells never proliferate. It remains to be determined, however, whether mature myofibers in vivo are capable of dedifferentiation and proliferation. Here we present the data showing that mouse myofibers dedifferentiate and proliferate to form many mononucleated cells. Eventually, these dedifferentiated cells redifferentiate and regenerate myofibers. The isolated dedifferentiated cells show stem cell-like phenotype. These cells are expected to be applied to the cell therapy for degenerative muscular diseases.
Animals↗
[Development of universal off-the-shelf T cell therapies derived from ES/iPS cells for leukemia and COVID-19].
Cancer immunotherapy using patient-derived T cells genetically modified in vitro has been demonstrated to be effective. However, issues such as cost, time, and unstable quality must be resolved. To overcome these barriers, we developed the TCR-PS cell method, in which a specific TCR gene is introduced into pluripotent stem cells (PS cells), such as ES cells or iPS cells, and T cells are generated from those PS cells. We are currently preparing for a clinical trial in acute myeloid leukemia, targeting the WT1 antigen, with iPS cells provided by the CiRA Foundation as the starting material. In parallel, we are also investigating this approach for viral infections and preparing for clinical trials in COVID-19, with HLA-deficient ES cells as the starting material. This method should enable stockpiling of T cell therapies against known viruses such as SARS or avian influenza. Even for outbreaks caused by unknown viruses, it should be possible to produce T cell therapies within 100 days after the virus genome is defined.
Humans↗
In vitro generation of human dendritic cells and cell therapy.
Dendritic cells (DC) are the most potent antigen-presenting cells: they, only, can prime naive T lymphocytes and even elicit generation of cytotoxic T lymphocytes to soluble antigens. Thus ex vivo antigen-pulsed DC represent a potentially powerful tool to elicit T-cell mediated responses against viral or tumor-associated antigens. Because isolation of DC as such from the blood is hampered by their scarcity, culture methods to generate them from different progenitors or precursors have been developed. Indeed, the possibility of obtaining relatively high numbers of DC from bone marrow, cord blood or adult blood CD34+ progenitors, or even blood monocytes, in cultures with different combinations of growth factors--mainly based on the use of GM-CSF, TNF-alpha and IL-4--has allowed the study of their ontogeny, the characterization of the different types of DC obtained under diverse conditions, and the assessment of whether they relate to a single pathway of differentiation. For example, the finding that monocytes and even macrophages can differentiate into DC depending on the cytokines used has to be reconciled with evidence that supports earlier branching off of the macrophage and DC lineages, and raises questions as to the identity of the latter lineage. Also, besides DC of myeloid origin, DC arise from lymphoid progenitors, and lymphoid DC display different properties than myeloid DC--at least in mice. From a practical point of view, there is a need to define the most appropriate cytokine combinations and schedules to optimize proliferation, differentiation and maturation of DC from different sources. In addition, because the capacity of DC to capture, process and present antigens varies according to their differentiation/maturation stage and origin, it appears necessary to define which type of DC to use for cell therapy in the setting of a given pathology for efficient and safe use.
Cell Differentiation↗
Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy.
Adult stem cells hold great promise for use in tissue repair and regeneration, and the delivery of autologous progenitor cells into ischemic tissue is emerging as a novel therapeutic option. We and others have recently demonstrated the potential impact of adipose tissue-derived stromal cells (ADSC) on regenerative cell therapy for ischemic diseases. The main benefit of ADSC is that they can be easily harvested from patients by a simple, minimally invasive method and also easily cultured. Cultured ADSC can be induced to differentiate into not only adipocytes, but also bone, neurons or endothelial cells in certain conditions. Interestingly, they secrete a number of angiogenesis-related cytokines, such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which might be suitable for regenerative cell therapy for ischemic diseases. In the ischemic mouse hindlimb, the angiogenic score was improved in the ADSC-treated group. Moreover, recent reports demonstrated that these ADSC can also be induced to differentiate into cardiac myocytes. These adipose tissue-derived cells have potential in angiogenic cell therapy for ischemic disease, and might be applied for regenerative cell therapy instead of bone marrow cells in the near future.
Adipose Tissue↗
[Cell therapy for renal cell carcinoma].
Renal cell carcinoma (RCC) is an immunogenic tumor that has shown some response to cytokine-therapy and other types of immune-based treatment. Since the advent of lymphocyte culture techniques in the 1980s, clinical trials of lymphokine-activatedkiller cells and tumor infiltrating lymphocytes have been conducted. Although these approaches have not shown apparent benefit compared to the standard cytokine therapy, further trials are ongoing using dendritic cell or gene-modified tumor vaccines in order to induce a tumor-specific cytotoxic T cell response in vivo. Recently, several investigators have indicated that RCC is susceptible to a graft-versus-tumor effect promoted by allogeneic stem-cell transplantation. This article reviews the clinical results of these cell therapies for metastaic RCC.
Cancer Vaccines↗
A new cell therapy using bone marrow cells to repair damaged liver.
Hepatic stem cells can transdifferentiate into hepatocytes, bile duct cells, pancreatic cells, or intestinal cells. Hepatic stem cells had been thought to be located in the canal of Hering in the liver, but recent work has demonstrated the existence of hepatic stem cells in bone marrow as well. Cell therapy using autologous bone marrow cells has few ethical problems and many applications for treating severe liver disease. Further in vitro and in vivo analysis is crucial to develop the therapy for clinical use.
Animals↗
Development of cell therapy using autologous bone marrow cells for liver cirrhosis.
The plasticity of bone marrow has been confirmed by the autopsy of a female recipient of bone marrow cell transplantation from a male donor. To establish new clinical cell therapies using autologous bone marrow cells for patients with liver failure, we developed a new in vivo model named the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model. Using the GFP/CCl4 model, we found that transplanted Liv8-negative cells efficiently repopulated into cirrhotic liver tissue and differentiated into albumin-producing hepatocytes under persistent liver damage induced by carbon tetrachloride. Moreover, bone marrow cell transplantation into mice with liver cirrhosis improved liver function and liver fibrosis with the strong expression of matrix metalloproteinases (MMPs), especially MMP-9 activity, resulting in an improved survival rate. Results from the GFP/CCl4 model showed that cell therapy using autologous bone marrow cells has the potential to become an effective treatment for patients with liver failure. A summary of findings from the GFP/CCl4 model is described.
Animals↗
Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy.
Th1 and Th2 cells obtained from OVA-specific T cell receptor transgenic mice completely eradicated the tumor mass when transferred into mice bearing A20-OVA tumor cells expressing OVA as a model tumor antigen. To elucidate the role of Tc1 or Tc2 cells during tumor eradication by Th1- or Th2-cell therapy, spleen cells obtained from mice cured of tumor by the therapy were re-stimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1-cell therapy produced high levels of IFN-gamma, while spleen cells from mice cured by Th2-cell therapy produced high levels of IL-4. Intracellular staining analysis demonstrated that a high frequency of IFN-gamma-producing Tc1 cells was induced in mice given Th1-cell therapy. In contrast, IL-4-producing Tc2 cells were mainly induced in mice after Th2-cell therapy. Moreover, Tc1, but not Tc2, exhibited a tumor-specific cytotoxicity against A20-OVA but not against CMS-7 fibrosarcoma. Thus, immunological memory essential for CTL generation was induced by the Th1/Tc1 circuit, but not by the Th2/Tc2 circuit. We also demonstrated that Th1-cell therapy is greatly augmented by combination therapy with cyclophosphamide treatment. This finding indicated that adoptive chemoimmunotherapy using Th1 cells should be applicable as a novel tool to enhance the Th1/Tc1 circuit, which is beneficial for inducing tumor eradication in vivo.
Animals↗
Cell therapy with preimmunized effector cells mismatched for minor histocompatible antigens in the treatment of a murine mammary carcinoma.
Cell therapy with allogeneic donor cells mismatched for minor histocompatible (MiHC) antigens was applied to a murine mammary carcinoma (4T1) model to test the feasibility of graft versus tumor (GVT) effect against metastatic epithelial tumor cells. BALB/c mice bearing a 4T1 tumor of BALB/c origin were given syngeneic or MiHC-mismatched splenocytes. GVT effects were determined in secondary recipients of adoptively transferred lung cells derived from primary hosts who had previously been inoculated intravenously with 4T1 cells, and injected with one of the following: 1) naive BALB/c splenocytes, 2) naive DBA/2 splenocytes, 3) 4T1-immune DBA/2 splenocytes, or 4) DBA/2 splenocytes immunized with host-derived BABL/c spleen cells. Naive DBA/2 splenocytes inhibited tumor growth only slightly and only slightly prolonged the survival of secondary recipients, in comparison with fully matched tumor/host BALB/c spleen cells. An efficient GVT reaction was demonstrated in vitro and in vivo with MiHC-mismatched DBA/2 splenocytes from mice presensitized by multiple injections of irradiated tumor or BALB/c-derived spleen cells. All 30 mice adoptively inoculated with lung cells from primary hosts that had previously been treated with these presensitized effector cells were tumor free for >250 days. Secondary recipients inoculated with lung cells from mice given naive BALB/c or DBA/2 spleen cells died of metastatic tumors within 33 to 46 days. These results suggest that preimmunized donor cells represent an effective tool against metastatic disease; hence, the next goal should be to control graft-versus-host disease while exploiting the GVT potential.
Animals↗
Cell Therapy With Preimmunized Effector Cells Mismatched for Minor Histocompatible Antigens in the Treatment of a Murine Mammary Carcinoma.
SUMMARY: Cell therapy with allogeneic donor cells mismatched for minor histocompatible (MiHC) antigens was applied to a murine mammary carcinoma (4T1) model to test the feasibility of graft versus tumor (GVT) effect against metastatic epithelial tumor cells. BALB/c mice bearing a 4T1 tumor of BALB/c origin were given syngeneic or MiHC-mismatched splenocytes. GVT effects were determined in secondary recipients of adoptively transferred lung cells derived from primary hosts who had previously been inoculated intravenously with 4T1 cells, and injected with one of the following: 1) naive BALB/c splenocytes, 2) naive DBA/2 splenocytes, 3) 4T1-immune DBA/2 splenocytes, or 4) DBA/2 splenocytes immunized with host-derived BABL/c spleen cells. Naive DBA/2 splenocytes inhibited tumor growth only slightly and only slightly prolonged the survival of secondary recipients, in comparison with fully matched tumor/host BALB/c spleen cells. An efficient GVT reaction was demonstrated in vitro and in vivo with MiHC-mismatched DBA/2 splenocytes from mice presensitized by multiple injections of irradiated tumor or BALB/c-derived spleen cells. All 30 mice adoptively inoculated with lung cells from primary hosts that had previously been treated with these presensitized effector cells were tumor free for >250 days. Secondary recipients inoculated with lung cells from mice given naive BALB/c or DBA/2 spleen cells died of metastatic tumors within 33 to 46 days. These results suggest that preimmunized donor cells represent an effective tool against metastatic disease; hence, the next goal should be to control graft-versus-host disease while exploiting the GVT potential.
Journal Article↗
[Combined cell therapy by using dendritic cells, T-cells and NK cells to human polymorphic cancer].
Although an expression of MHC molecules and tumor associated antigens of the cancer are not uniform, we consider that the cancer immunotherapy for some specific tumor antigens cannot correspond to molecular biological varieties of the cancer. Consequently, we tried to develop a method to separate dendritic cells (DC), T-cells and natural killer (NK) cells from peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers. PBMC were separated by centrifugation on Ficoll-Hypaque gradients from peripheral blood obtained from healthy volunteers. After separating these cells, the cells were put into a plastic flask, and we isolated monocyte fraction (dendritic cells), NK cell fraction and T-cell fraction one after another by the difference in its ability to adhere to a plastic flask. We analyzed surface markers and activation states of these groups. We could induce dendritic cells from the monocyte fraction, CD3-activated T-cells (CAT) from the T-cell fraction, and adherent lymphokine activated-killer cells (A-LAK) from the NK cell fraction. Therefore, we indicate the possibility of the combined cell therapy with three immune cell fractions in which we can induce from the same blood at once.
Antigens, Surface↗
Phase Ib trial of pentoxifylline and ciprofloxacin in patients treated with interleukin-2 and lymphokine-activated killer cell therapy for metastatic renal cell carcinoma.
The dose of interleukin 2 (IL-2) which can be administered to cancer patients is limited largely by a capillary leak syndrome. Pentoxifylline (PTX) is a methylxanthine which reduces IL-2 toxicity in animals. Ciprofloxacin (Cipro) modifies the metabolism of methylxanthines and, when coadministered with PTX, increases levels of PTX and certain of its metabolites. We conducted a phase Ib trial in patients receiving IL-2 and lymphokine-activated killer cell (LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX which could be coadministered with Cipro in this setting. Eighteen patients received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m2/day on days 1-5 and underwent leukapheresis on days 7-9. LAK cells were infused on days 12-14. IL-2 was administered at 2 x 10(6) units/m2/day on days 10-20. Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v. infusion every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o. every 12 h) on days 1-5 and 10-20. Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical regimen of IL-2/LAK without PTX/Cipro. PTX at 2.5-3.9 mg/kg and Cipro were well tolerated. The maximum tolerated dose of PTX was 3.9 mg/kg. Dose-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible. Two complete, one partial and one minor, responses were observed. Patients treated with 3.9 mg/kg PTX received 95.0% of the planned dose of IL-2 as compared to 72.8% in the control patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients. The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK without apparent loss of therapeutic efficacy. Moreover, PTX/Cipro recipients exhibited less toxicity than historical controls. Therefore, treatment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.
Adult↗