International Society for Cell & Gene Therapy Stem Cell Engineering Committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant

Background aimsAllogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment.MethodsWe conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords “Graft-versus-Host Disease (GVHD),” “Cellular Therapies,” “Regulatory T cells (Tregs),” “Mesenchymal Stromal (Stem) Cells (MSCs),” “Natural Killer (NK) Cells,” “Myeloid-derived suppressor cells (MDSCs),” and “Regulatory B-Cells (B-regs).” All the published and available clinical studies were included.ResultsAlthough most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario.ConclusionsThere are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.     

Enhanced alleviation of aGVHD by TGF‐β1‐modified mesenchymal stem cells in mice through shifting MΦ into M2 phenotype and promoting the differentiation of Treg cells

Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is the only curative method in treating haematologic malignant diseases. Graft‐versus‐host disease (GVHD) is a common complication post–allo‐HSCT, which can be life‐threatening. Mesenchymal stem cells (MSCs) as an adult stem cell with immunoregulatory function have demonstrated efficacy in steroid resistant acute GVHD (aGVHD). However, the outcome of aGVHD treated with MSCs in clinical trials varied and its underlying mechanism is still unclear. TGF‐β1 is a potent cytokine, which plays a key role in immunoregulation. In the present study, we firstly transduced the lentivirus vector containing TGF‐β1 gene with mouse bone marrow‐derived MSCs. Then, we investigated the immunosuppressive effect of TGF‐β1 gene‐modified MSCs on lymphocytes in vitro and its preventive and therapeutical effects on murine aGVHD model in vivo. Murine MSC was successfully isolated and identified. TGF‐β1 was efficiently transduced into mouse MSCs, and high level TGF‐β1 was detected. MSC‐TGF‐β1 shared the same morphology and immunotypic features of normal MSC. In vitro, MSC‐TGF‐β1 showed enhanced immunosuppressive function on lymphocyte proliferation. In vivo, MSC‐TGF‐β1 showed enhanced amelioration on the severity of aGVHD both in prophylactic and therapeutic murine models. Finally, the macrophages (MØs) derived from MSC‐TGF‐β1–treated mice showed a remarkably increasing of anti‐inflammatory M2‐like phenotype. Furthermore, the differentiation of CD4+ CD25+ Foxp3+ Treg cells was significantly increased in MSC‐TGF‐β1–treated group. Taken together, we proved that MSC‐TGF‐β1 showed enhanced alleviation of aGVHD severity in mice by skewing macrophages into a M2 like phenotype or increasing the proportion of Treg cells, which opens a new frontier in the treatment of aGVHD.     

Therapeutic effects of hydrogen on chronic graft‐versus‐host disease

The incidence of chronic graft‐versus‐host disease (cGVHD) is rising recent years, which has been the leading cause of non‐transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti‐inflammatory, antioxidant, anti‐fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC‐incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen‐rich saline increased survival rate of cGVHD mice. Administration of hydrogen‐rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values.     

Joint regression analysis for survival data in the presence of two sets of semi‐competing risks

In many clinical trials, multiple time‐to‐event endpoints including the primary endpoint (e.g., time to death) and secondary endpoints (e.g., progression‐related endpoints) are commonly used to determine treatment efficacy. These endpoints are often biologically related. This work is motivated by a study of bone marrow transplant (BMT) for leukemia patients, who may experience the acute graft‐versus‐host disease (GVHD), relapse of leukemia, and death after an allogeneic BMT. The acute GVHD is associated with the relapse free survival, and both the acute GVHD and relapse of leukemia are intermediate nonterminal events subject to dependent censoring by the informative terminal event death, but not vice versa, giving rise to survival data that are subject to two sets of semi‐competing risks. It is important to assess the impacts of prognostic factors on these three time‐to‐event endpoints. We propose a novel statistical approach that jointly models such data via a pair of copulas to account for multiple dependence structures, while the marginal distribution of each endpoint is formulated by a Cox proportional hazards model. We develop an estimation procedure based on pseudo‐likelihood and carry out simulation studies to examine the performance of the proposed method in finite samples. The practical utility of the proposed method is further illustrated with data from the motivating example.     

Defibrotide inhibits donor leucocyte‐endothelial interactions and protects against acute graft‐versus‐host disease

Allogeneic hematopoietic stem cell transplantation (allo‐HCT) is an effective therapy for the treatment of high‐risk haematological malignant disorders and other life‐threatening haematological and genetic diseases. Acute graft‐versus‐host disease (aGvHD) remains the most frequent cause of non‐relapse mortality following allo‐HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi‐target drug successfully employed for prophylaxis and treatment of veno‐occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo‐HCT. Using a fully MHC‐mismatched murine model of allo‐HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD‐associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo‐HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte‐endothelial interactions by down‐regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo‐HCT, paving the way for new therapeutic approaches.     

Hydrogen therapy may be an effective and specific novel treatment for Acute Graft‐versus‐host disease (GVHD)

Allogeneic haematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of haematological malignant and non‐malignant haematologic diseases. However, acute graft‐versus‐host disease (aGVHD) is a kind of severe complication of HSCT limiting its application. Cytokines such as tumour necrosis factor‐α (TNF‐α), IL‐6 play an extremely important role in the formation and development of aGVHD. Besides, the oxidation phenomena and/or the formation of free radicals have been suggested to be causally related to various haematological disorders including aGVHD. Reactive oxygen species (ROS), such as hydroxyl radicals, play an important role in the formation and development of aGVHD. Hydrogen has been reported to have the ability to inhibit levels of cytokines such as TNF, IL‐6 in vivo. Our recent studies provided evidence that hydrogen inhalation can selectively reduce cytotoxic oxygen radicals and exert antioxidant effects. Therefore, we suggested that hydrogen may have therapeutic effects on aGVHD. This hypothesis entails many experimentally testable predictions. We propose the experimental study by detecting complete blood counts (CBC) and Clinic signs of aGVHD mice. We also propose to detect the levels of TNF‐α, IL‐2, IL‐1β, IL‐6 which play important roles in the pathogenesis of aGVHD. To discover potential mechanisms of the therapeutic effects of hydrogen on the aGVHD model, we will examine gene‐expression profiles. This study will open a new therapeutic avenue combining the field of therapeutic medical gases and aGVHD. This theory is original and probably of importance, because therapeutic medical gases have never been used for aGVHD previously.     

Role of cytokines in the pathophysiology of acute graft-versus-host disease (GVHD): are serum/plasma cytokines potential biomarkers for diagnosis of acute GVHD following allogeneic hematopoietic cell transplantation (Allo-HCT)?

Due to the advent of less-toxic reduced intensity conditioning regimens (RIT), allogeneic hematopoietic cell transplantation (allo-HCT) is currently widely used to treat chemotherapy-resistant hematological diseases, particularly in older patients,which are the fastest growing group of patients receiving allo-HCT. However, graft-versus-host disease (GVHD) is still the major complication after allo-HCT, causing immune deficiency, infection, organ damage, and occasionally patient death. Mortality from GVHD is in part attributed to the difficulty in making accurate diagnosis and determining the optimal timing for appropriate treatment. The diagnosis of acute GVHD is dependent on clinical features and is sometimes indistinguishable from other causes and requires invasive procedures. Therefore, non-invasive, diagnostic and predictive monitoring tools, such as plasma/serum biomarkers, are needed. Determination of the roles of cytokines in the physiopathology of acute GVHD has provided an explanation for many preclinical and clinical observations. However, measurement of a single cytokine lacks specificity for GVHD diagnosis. Therefore, comprehensive assessment of plasma/serum cytokine concentrations is required to identify a panel of biomarkers with good specificity and sensitivity for GVHD. In this review, we summarize the roles of individual cytokines in the pathophysiology of acute GVHD and discuss the possibility of cytokines as biomarkers of acute GVHD after allo-HCT.     

CD4^＋CD25^＋Foxp3^＋调节性T细胞的体外扩增及其在移植物抗宿主病中的应用

同种异基因造血干细胞移植是急、慢性白血病及其他恶性血液病重要的治疗方法,但急慢性移植物抗宿主病（graft—versus-host disease,GVHD）作为异基因造血干细胞移植的主要并发症严重影响移植患者的存活率,阻碍移植的临床推广。很多研究发现,高表达Foxp3的CD4^＋CD25^＋调节性T细胞（regulatory T cells,Treg）不仅能控制急慢性GVHD的发生,而且不影响移植物抗白血病效应（graft-versusleukemia,GVL）,在急慢性GVHD发生发展及治疗方面有重要的作用。但Treg细胞在体内的数量很少,不能满足临床应用需求。目前应用外源的IL-2联合TCR、CD28信号通路共同刺激以及运用树突状细胞（dendritic cell,DC）刺激均能达到体外有效扩增Treg细胞的目的。这些扩增的Treg细胞在控制造血干细胞移植过程中急慢性GVHD的发生及防治自身免疫性疾病和移植排斥等方面具有明显作用,在疾病控制和临床应用中具有广阔前景。     

Systematic profiling of ACE2 expression in diverse physiological and pathological conditions for COVID‐19/SARS‐CoV‐2

Recent retrospective studies of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) disease (COVID‐19) revealed that the patients with common comorbidities of cancers and chronic diseases face significantly poorer clinical outcomes than those without. Since the expression profile of ACE2, a crucial cell entry receptor for SARS‐CoV‐2, could indicate the susceptibility to SARS‐CoV‐2 infection, here we systematically dissected ACE2 expression using large‐scale multi‐omics data from 30 organs/tissues, 33 cancer types and some common chronic diseases involving >28 000 samples. It was found that sex and age could be correlated with the susceptibility of SARS‐CoV‐2 infection for certain tissues. Strikingly, ACE2 was up‐regulated in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, oesophageal carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma and uterine corpus endometrial carcinoma compared to controls. Furthermore, the patients with common chronic diseases regarding angiocardiopathy, type 2 diabetes, liver, pneumonia and hypertension were also with higher ACE2 expression compared to related controls, which were validated using independent data sets. Collectively, our study may reveal a novel important mechanism that the patients with certain cancers and chronic diseases may express higher ACE2 expression compared to the individuals without diseases, which could lead to their higher susceptibility to multi‐organ injury of SARS‐CoV‐2 infection.     

Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease

Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or ‑mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios.Abbreviations: BMT, bone marrow transplantation; GVHD, graft-versus-host disease; GVL, graft-versus-leukemia; HCT, hematopoietic cell transplantation; TBI, total-body irradiation     

Pathway mapping and development of disease‐specific biomarkers: protein‐based network biomarkers

It is known that a disease is rarely a consequence of an abnormality of a single gene, but reflects the interactions of various processes in a complex network. Annotated molecular networks offer new opportunities to understand diseases within a systems biology framework and provide an excellent substrate for network‐based identification of biomarkers. The network biomarkers and dynamic network biomarkers (DNBs) represent new types of biomarkers with protein–protein or gene–gene interactions that can be monitored and evaluated at different stages and time‐points during development of disease. Clinical bioinformatics as a new way to combine clinical measurements and signs with human tissue‐generated bioinformatics is crucial to translate biomarkers into clinical application, validate the disease specificity, and understand the role of biomarkers in clinical settings. In this article, the recent advances and developments on network biomarkers and DNBs are comprehensively reviewed. How network biomarkers help a better understanding of molecular mechanism of diseases, the advantages and constraints of network biomarkers for clinical application, clinical bioinformatics as a bridge to the development of diseases‐specific, stage‐specific, severity‐specific and therapy predictive biomarkers, and the potentials of network biomarkers are also discussed.     

Allogeneic peripheral blood stem cell transplantation

Granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) are now widely used instead of bone marrow for autologous transplantation due to earlier hematopoietic recovery after transplant. The low toxicity of G-CSF has prompted phase I and II studies to evaluate PBSC for allogeneic transplantation; these studies have demonstrated that engraftment of neutrophils, red blood cells and platelets is faster with peripheral blood cells compared to marrow. In randomized studies comparing mobilized PBSC and marrow for allogeneic transplantation, most trials have confirmed significantly earlier engraftment with PBSC and similar risks of acute graft-vs.-host disease (GVHD). In some trials, an increase of 10-15% in grade II-IV GVHD has been noted with PBSC. All studies showed a trend towards more chronic GVHD with PBSC. Some randomized studies have shown improved survival and disease-free survival with the use of PBSC due to lowered transplant-related mortality and fewer relapses in recipients of PBSC as a result of improved immune reconstitution and a graft-vs.-leukemia (GVL) effect. This survival benefit is most apparent in patients with more advanced hematologic malignancies, but further studies are needed to define the relative benefits of PBSC for patients with less advanced disease. The GVL effect of PBSC is currently being exploited with the use of non-ablative allografts.     

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.     

移植物抗宿主病和移植物抗白血病相关细胞因子的研究进展

异基因造血干细胞移植（allogeneic hemotoic stem cell transplantation,allo-HSCT）是治疗血液系统恶性肿瘤的有效方法,治疗效果主要依赖于移植物抗白血病效应（graft-versus-leukemia,GVL）,可以清除残存肿瘤细胞,达到完全治愈恶性血液病的目的。然而,GVL与allo-HSCT的并发症移植物抗宿主病（graft-versus-host disease,GVHD）紧密相连。通过合理调节一些细胞因子的作用可以达到降低GVHD、保留GVL的目的。该文就GVHD与GVL发生机制中相关细胞因子作用的研究进展做一综述。     

A five‐step risk management process for geriatric dental practice during SARS‐CoV‐2 pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is an RNA virus that causes coronavirus infection (COVID‐19). COVID‐19 is a highly contagious disease transmitted through respiratory droplets, saliva and other contact routes. Within 10 months of its outbreak, SARS‐CoV‐2 has infected more than 23 million people around the world. Evidence suggests that older adults are the most vulnerable to infection and have an increased risk of mortality. Reduced immunity and underlying medical conditions make them risk‐prone and vulnerable to critical care. Older adults affected with the SARS‐CoV‐2 virus present with distinct clinical manifestations necessitating specific treatment needs and management protocols. While it is crucial to prevent the spread of novel coronavirus (2019‐nCoV), the role of oral healthcare workers in addressing the specific needs of ageing adult patients by adopting specific guidelines and appropriate infection control protocols is timely. This paper aims to develop specific guidelines and protocols for the dental management of geriatric patients during the COVID‐19 pandemic.     

B‐cell acute lymphoblastic leukaemia: towards understanding its cellular origin

B‐cell acute lymphoblastic leukaemia (B‐ALL) is a clonal malignant disease originated in a single cell and characterized by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B‐cell differentiation. B‐ALL origin has been a subject of continuing discussion, given the fact that human disease is diagnosed at late stages and cannot be monitored during its natural evolution from its cell of origin, although most B‐ALLs probably start off with chromosomal changes in haematopoietic stem cells. However, the cells responsible for maintaining the disease appear to differ between the different types of B‐ALLs and this remains an intriguing and exciting topic of research, since these cells have been posited to be responsible for resistance to conventional therapies, recurrence and dissemination. During the last years this problem has been addressed primarily by transplantation of purified subpopulations of human B‐ALL cells into immunodeficient mice. The results from these different reconstitution experiments and their interpretations are compared in this review in the context of normal B‐cell developmental plasticity. While the results from different research groups might appear mutually exclusive, we discuss how they could be reconciled with the biology of normal B‐cells and propose research avenues for addressing these issues in the future.     

A cure‐rate model for Q‐learning: Estimating an adaptive immunosuppressant treatment strategy for allogeneic hematopoietic cell transplant patients

Cancers treated by transplantation are often curative, but immunosuppressive drugs are required to prevent and (if needed) to treat graft‐versus‐host disease. Estimation of an optimal adaptive treatment strategy when treatment at either one of two stages of treatment may lead to a cure has not yet been considered. Using a sample of 9563 patients treated for blood and bone cancers by allogeneic hematopoietic cell transplantation drawn from the Center for Blood and Marrow Transplant Research database, we provide a case study of a novel approach to Q‐learning for survival data in the presence of a potentially curative treatment, and demonstrate the results differ substantially from an implementation of Q‐learning that fails to account for the cure‐rate.     

CXCR4‐SF1 bifunctional adipose‐derived stem cells benefit for the treatment of Leydig cell dysfunction‐related diseases

Stem cell transplantation is a candidate method for the treatment of Leydig cell dysfunction‐related diseases. However, there are still many problems that limit its clinical application. Here, we report the establishment of CXCR4‐SF1 bifunctional adipose‐derived stem cells (CXCR4‐SF1‐ADSCs) and their reparative effect on Leydig cell dysfunction. CD29⁺ CD44⁺ CD34^? CD45^? ADSCs were isolated from adipose tissue and purified by fluorescence‐activated cell sorting (FACS). Infection with lentiviruses carrying the CXCR4 and SF1 genes was applied to construct CXCR4‐SF1‐ADSCs. The CXCR4‐SF1‐ADSCs exhibited enhanced migration and had the ability to differentiate into Leydig‐like cells in vitro. Furthermore, the bifunctional ADSCs were injected into BPA‐mediated Leydig cell damage model mice via the tail vein. We found that the CXCR4‐SF1‐ADSCs were capable of homing to the injured testes, differentiating into Leydig‐like cells and repairing the deficiency in reproductive function caused by Leydig cell dysfunction. Moreover, we investigated the mechanism underlying SF1‐mediated differentiation and testosterone synthesis in Leydig cells, and the B‐box and SPRY Domain Containing Protein (BSPRY) gene was proposed to be involved in this process. This study provides insight into the treatment of Leydig cell dysfunction‐related diseases.     

Human expression patterns: qualitative and quantitative analysis of thrombospondin‐1 under physiological and pathological conditions

Thrombospondin‐1 (TSP‐1), a matricellular protein and one of the first endogenous anti‐angiogenic molecules identified, has long been considered a potent modulator of human diseases. While the therapeutic effect of TSP‐1 to suppress cancer was investigated in both research and clinical settings, the mechanisms of how TSP‐1 is regulated in cancer remain elusive, and the scientific answers to the question of whether TSP‐1 expressions can be utilized as diagnostic or prognostic marker for patients with cancer are largely inconsistent. Moreover, TSP‐1 plays crucial functions in angiogenesis, inflammation and tissue remodelling, which are essential biological processes in the progression of many cardiovascular diseases, and therefore, its dysregulated expressions in such conditions may have therapeutic significance. Herein, we critically analysed the literature pertaining to TSP‐1 expression in circulating blood and pathological tissues in various types of cancer as well as cardiovascular and inflammation‐related diseases in humans. We compare the secretion rates of TSP‐1 by different cancer and non‐cancer cells and discuss the potential connection between the expression changes of TSP‐1 and vascular endothelial growth factor (VEGF) observed in patients with cancer. Moreover, the pattern and emerging significance of TSP‐1 profiles in cardiovascular disease, such as peripheral arterial disease, diabetes and other related non‐cancer disorders, are highlighted. The analysis of published TSP‐1 data presented in this review may have implications for the future exploration of novel TSP‐1‐based treatment strategies for cancer and cardiovascular‐related diseases.