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Cancer is a worldwide health problem. Nevertheless, new technologies in the immunotherapy field have emerged. Chimeric antigen receptor (CAR) technology is a novel biological form to treat cancer; CAR-T cell genetic engineering has positively revolutionized cancer immunotherapy. In this paper, we review the latest developments in CAR-T in cancer treatment. We present the structure of the different generations and variants of CAR-T cells including TRUCK (T cells redirected for universal cytokine killing. We explain the approaches of the CAR-T cells manufactured ex vivo and in vivo. Moreover, we describe the limitations and areas of opportunity for this immunotherapy and the current challenges of treating hematological and solid cancer using CAR-T technology as well as its constraints and engineering approaches. We summarize other immune cells that have been using CAR technology, such as natural killer (NK), macrophages (M), and dendritic cells (DC). We conclude that CAR-T cells have the potential to treat not only cancer but other chronic diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell therapy approaches, including adoptive cell therapy with engineered T cells remains challenging in the clinical setting of solid tumors. Clinical results have not been encouraging so far, with a general lack of significant therapeutic response and presence of on-target off-tumor toxicity. For this reason, novel cell therapy programs are currently exploring (i) advanced therapy medicinal products capable of increasing T cell affinity or avidity; and (ii) cell therapy in combination with other therapeutic agents. Our review will focus on the current clinical research in this setting, which will likely play a role in improving cancer treatment outcomes in the near future. In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most prevalent cerebral cancer in adults without proven therapy. Chimeric antigen receptor T cell treatment has demonstrated good clinical success in hematologic cancers. The application of chimeric antigen receptor T cell therapy to solid tumors, such as glioblastoma, is currently the subject of scientific investigation. The creation of chimeric antigen receptor T cells and its iterations are briefly described in this article. Specifically, this study addresses the obstacles and hurdles faced and glioblastoma targets studied in recent years. This review provides the reader with a comprehensive understanding of the current state of chimeric antigen receptor T cell therapy for glioblastoma and a clear understanding of each therapeutic target. Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood–brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer has remained the leading cause of death among gynecologic malignancies. The current standard of treatment, in most cases, is a combination of surgery and chemotherapy, based on platinum agents and taxanes. Despite the increasing usage of newer drug groups, such as bevacizumab and PARP inhibitors, and the expansion of patient groups for these drugs, ovarian cancer is characterized by recurrences, particularly in the form of peritoneal implants. This review focuses on immunotherapy for ovarian cancer. It considers the current state of knowledge in areas such as cancer vaccines, adoptive cell therapy, CAR-T therapy, and anti-CTLA-4 monotherapy. The paper specifically considers PD-1/PDL-1 as drug targets. Anti-PD-1/PD-L1 monotherapy, and anti-PD-1/PD-L1 immunotherapy in combination with other agents, are analyzed. Ovarian cancer is one of the most fatal cancers in women worldwide. Cytoreductive surgery combined with platinum-based chemotherapy has been the current first-line treatment standard. Nevertheless, ovarian cancer appears to have a high recurrence rate and mortality. Immunological processes play a significant role in tumorigenesis. The production of ligands for checkpoint receptors can be a very effective, and undesirable, immunosuppressive mechanism for cancers. The CTLA-4 protein, as well as the PD-1 receptor and its PD-L1 ligand, are among the better-known components of the control points. The aim of this paper was to review current research on immunotherapy in the treatment of ovarian cancer. The authors specifically considered immune checkpoints molecules such as PD-1/PDL-1 as targets for immunotherapy. We found that immune checkpoint-inhibitor therapy does not have an improved prognosis in ovarian cancer; although early trials showed that a combination of anti-PD-1/PD-L1 therapy with targeted therapy might have the potential to improve responses and outcomes in selected patients. However, we must wait for the final results of the trials. It seems important to identify a group of patients who could benefit significantly from treatment with immune checkpoints inhibitors. However, despite numerous trials, ICIs have not become part of routine clinical practice for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cell carcinoma (RCC) is common, affecting over 400,000 patients globally each year. In limited stage disease and where surgery is a feasible therapeutic option, event free survival rates are high. In contrast, locally advanced disease is associated with frequent relapse, and up to 30% of patients present with metastatic disease. Standard of care treatments for metastatic disease include tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), but clinical responses are variable and generally not durable. Novel cell-based immunotherapy approaches such as Chimeric Antigen Receptor T-cells (CAR-T) and T-cell receptor engineered T-cells (TCR-T) have shown efficacy in some blood cancers and are currently under evaluation in solid tumours including RCC. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies and outline how advanced engineering solutions may further enhance this therapeutic approach. Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer stands as the predominant form of cancer identified in women, underscoring the urgent demand for innovative targeted therapies. Engineered adoptive cell therapies represent a groundbreaking approach, empowering the immune cells of patients to precisely target their tumors through cancer-specific receptors. Encouragingly, preclinical studies have illuminated the immense promise of this strategy. Nonetheless, the translation of this technique into clinical practice hinges on the accumulation of additional robust clinical data. Within this review, we offer a comprehensive examination of the current landscape surrounding engineered cell therapies for breast cancer, delving into both their limitations and the compelling prospects for enhancement. Breast cancer remains a significant health challenge, and novel treatment approaches are critically needed. This review presents an in-depth analysis of engineered adoptive T-cell therapies (E-ACTs), an innovative frontier in cancer immunotherapy, focusing on their application in breast cancer. We explore the evolving landscape of chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies, highlighting their potential and challenges in targeting breast cancer. The review addresses key obstacles such as target antigen selection, the complex breast cancer tumor microenvironment, and the persistence of engineered T-cells. We discuss the advances in overcoming these barriers, including strategies to enhance T-cell efficacy. Finally, our comprehensive analysis of the current clinical trials in this area provides insights into the future possibilities and directions of E-ACTs in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The specific mechanisms by which tumors acquire resistance to chimeric antigen receptor (CAR) T cell therapy are not completely understood. The aim of this study was to elucidate the complex interactions between tumor cells and CAR T cells targeting epithelial cell adhesion molecule (EpCAM) in a xenograft model of gastric cancer. Using whole-body CAR T cell imaging and single-cell multiomic analyses, we noticed that within resistant tumors, CAR T cells exhibited a tendency to proliferate, but they were largely dysfunctional, losing their ability to fight cancer effectively. Specifically, most CD8 T cells became exhausted within tumors, while CD4 T cells transformed into regulatory T cells that can dampen the immune response. Additionally, the resistant tumor cells had specific gene changes that could promote cancer growth and make the disease more challenging to cure. This research provides valuable information for understanding how tumors resist CAR T cell therapy and may guide future developments in cancer treatment. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioma is the most common and aggressive brain tumor worldwide, and most patients suffer from a recurrence. Additionally, recurrent glioma is often resistant to chemotherapies and radiotherapy. Hence, immunotherapy has come into people's sights. The most-used immunotherapy is immune checkpoint blockade (ICB), which has shown encouraging efficacy when combined with other immune strategies, especially with antiangiogenetic antibodies. Other promising immune regimes include multiple immunotherapies which function through different mechanisms, such as oncolytic viruses, chimeric antigen receptor T cell therapies and vaccination strategies. In this review, we discuss current immune therapies applied to recurrent glioma, based on the literature of preclinical animal models, and current ongoing clinical trials published in the last 5 years. These immunotherapies have been proved to be safe and tolerant, while some combinational regimes have provided satisfying efficacy on a subgroup of patients with specific gene mutation backgrounds. Though great progress has been made, further exploration of different combination strategies is needed. Glioma is the most aggressive malignant tumor of the central nervous system, and most patients suffer from a recurrence. Unfortunately, recurrent glioma often becomes resistant to established chemotherapy and radiotherapy treatments. Immunotherapy, a rapidly developing anti-tumor therapy, has shown a potential value in treating recurrent glioma. Multiple immune strategies have been explored. The most-used ones are immune checkpoint blockade (ICB) antibodies, which are barely effective in monotherapy. However, when combined with other immunotherapy, especially with anti-angiogenesis antibodies, ICB has shown encouraging efficacy and enhanced anti-tumor immune response. Oncolytic viruses and CAR-T therapies have shown promising results in recurrent glioma through multiple mechanisms. Vaccination strategies and immune-cell-based immunotherapies are promising in some subgroups of patients, and multiple new tumor antigenic targets have been discovered. In this review, we discuss current applicable immunotherapies and related mechanisms for recurrent glioma, focusing on multiple preclinical models and clinical trials in the last 5 years. Through reviewing the current combination of immune strategies, we would like to provide substantive thoughts for further novel therapeutic regimes treating recurrent glioma. [ABSTRACT FROM AUTHOR]

Simple Summary: The receptor tyrosine kinase Axl is upregulated in up to 40% of hepatocellular carcinoma (HCC) cases correlating with an unfavorable prognosis. It is an open issue how Axl and its ligand Gas6 drive disease development at a molecular level. The aim of this study was to identify target genes of Gas6/Axl and to assess their contribution to HCC progression. One of the targets is the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which is currently exploited for its capacity in T cell-based immunotherapy. We show that PRAME induces hepatic dedifferentiation, epithelial-to-mesenchymal transition and invasiveness in liver cancer cells. Together, these data provide evidence that PRAME is induced by the Gas6/Axl/Mek/Erk1/2 signaling axis and exerts pro-oncogenic functions in HCC. (1) Background: Activation of the receptor tyrosine kinase Axl by Gas6 fosters oncogenic effects in hepatocellular carcinoma (HCC), associating with increased mortality of patients. The impact of Gas6/Axl signaling on the induction of individual target genes in HCC and its consequences is an open issue. (2) Methods: RNA-seq analysis of Gas6-stimulated Axl-proficient or Axl-deficient HCC cells was used to identify Gas6/Axl targets. Gain- and loss-of-function studies as well as proteomics were employed to characterize the role of PRAME (preferentially expressed antigen in melanoma). Expression of Axl/PRAME was assessed in publicly available HCC patient datasets and in 133 HCC cases. (3) Results: Exploitation of well-characterized HCC models expressing Axl or devoid of Axl allowed the identification of target genes including PRAME. Intervention with Axl signaling or MAPK/ERK1/2 resulted in reduced PRAME expression. PRAME levels were associated with a mesenchymal-like phenotype augmenting 2D cell migration and 3D cell invasion. Interactions with pro-oncogenic proteins such as CCAR1 suggested further tumor-promoting functions of PRAME in HCC. Moreover, PRAME showed elevated expression in Axl-stratified HCC patients, which correlates with vascular invasion and lowered patient survival. (4) Conclusions: PRAME is a bona fide target of Gas6/Axl/ERK signaling linked to EMT and cancer cell invasion in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has become the standard frontline treatment for patients with advanced hepatocellular carcinoma (HCC). However, drug resistance is a major limitation and novel strategies are needed for better clinical outcomes. In this review, we discuss adoptive cell therapy (ACT) as an emerging cancer therapy in the treatment of HCC and provide a summary of ongoing clinical trials. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Immune checkpoint inhibitors (ICIs) have become the new reference standard in first-line HCC treatment, replacing tyrosine kinase inhibitors (TKIs) such as sorafenib. Many clinical trials with different combinations are already in development to validate novel immunotherapies for the treatment of patients with HCC. Adoptive cell therapy (ACT), also known as cellular immunotherapy, with chimeric antigen receptors (CAR) or gene-modified T cells expressing novel T cell receptors (TCR) may represent a promising alternative approach to modify the immune system to recognize tumor cells with better clinical outcomes. In this review, we briefly discuss the overview of ACT as a promising treatment modality in HCC, along with recent updates of ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Certain immune cells, namely T cells, of cancer patients can be genetically manipulated to express so-called chimeric antigen receptors (CARs), which enables these cells to kill the tumor cells after recognition by the receptor. This therapy is very successful in the treatment of hematologic tumors such as lymphoma or leukemia. However, tumors growing as a solid mass are less susceptible to this kind of treatment. This review summarizes known data of all clinical trials using this therapy against solid tumors that are registered at clinicaltrials.gov. CAR-T cells showed great potential in the treatment of patients with hematologic tumors. However, the clinical efficacy of CAR-T cells against solid tumors lags behind. To obtain a comprehensive overview of the landscape of CAR-T cell clinical trials against this type of cancer, this review summarizes all the 196 studies registered at clinicaltrials.gov. Special focus is on: (1) geographical distribution; (2) targeted organs, tumor entities, and antigens; (3) CAR transfer methods, CAR formats, and extra features introduced into the T cells; and (4) patient pretreatments, injection sites, and safety measurements. Finally, the few data on clinical outcome are reported. The last assessment of clinicaltrials.gov for the data summarized in this paper was on 4 August 2020. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor T cells (CAR T-cells) are engineered T cells that target tumor-associated antigens. CAR T-cell therapy is a novel developed immunotherapy initially for destroying hematological malignancies. Its great success in clinical practice of hematological malignancies encourages oncologists and scientists to use CAR T-cells for the treatment of solid cancers. However, the efficacy of CAR T-cells in solid tumors is not as good as expected in hematological malignancies. In this review, we summarized the efficacy, safety, and challenges of CAR T-cell therapy in the clinical management of solid tumors. We also discussed the potential strategies currently applied to improve the efficacy and safety of CAR T-cell therapy in solid tumors, and finally prospected the future study direction for CAR T-cell therapy. Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored. [ABSTRACT FROM AUTHOR]

Simple Summary: Induced pluripotent stem cells (iPSCs) that can be genetically engineered and differentiated into different types of immune cells, providing an unlimited resource for developing off-the-shelf cell therapies. Here, we present a comprehensive review that describes the current stages of iPSC-based cell therapies, including iPSC-derived T, nature killer (NK), invariant natural killer T (iNKT), gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such as high cost, challenging large-scale manufacturing, and inaccessibility to the therapy for lymphopenia patients. Therefore, it is in great demand to generate the universal off-the-shelf cell products with significant scalability. Human induced pluripotent stem cells (iPSCs) provide an "unlimited supply" for cell therapy because of their unique self-renewal properties and the capacity to be genetically engineered. iPSCs can be differentiated into different immune cells, such as T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). In this review, we describe iPSC-based allogeneic cell therapy, the different culture methods of generating iPSC-derived immune cells (e.g., iPSC-T, iPSC-NK, iPSC-iNKT, iPSC-γδT, iPSC-MAIT and iPSC-Mφ), as well as the recent advances in iPSC-T and iPSC-NK cell therapies, particularly in combinations with CAR-engineering. We also discuss the current challenges and the future perspectives in this field towards the foreseeable applications of iPSC-based immune therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute lymphoblastic leukemia is the most common blood cancer in pediatric patients. Despite the enormous progress in ALL treatment, which is reflected by a high 5-year overall survival rate that reaches up to 96% in the most recent studies, there are still patients that cannot be saved. Treatment of ALL is based on conventional methods, including chemotherapy and radiotherapy. These methods carry with them the risk of very high toxicities. Severe complications related to conventional therapies decrease their effectiveness and can sometimes lead to death. Therefore, currently, numerous studies are being carried out on novel forms of treatment. In this work, classical methods of treatment have been summarized. Furthermore, novel treatment methods and the possibility of combining them with chemotherapy have been incorporated into the present work. Targeted treatment, CAR-T-cell therapy, and immunotherapy for ALL have been described. Treatment options for the relapse/chemoresistance ALL have been presented. Acute lymphoblastic leukemia is the most common blood cancer in pediatric patients. There has been enormous progress in ALL treatment in recent years, which is reflected by the increase in the 5-year OS from 57% in the 1970s to up to 96% in the most recent studies. ALL treatment is based primarily on conventional methods, which include chemotherapy and radiotherapy. Their main weakness is severe toxicity, which prompts dose reduction, decreases the effectiveness of the treatment, and, in some cases, can lead to death. Currently, numerous modifications in treatment regimens are applied in order to limit toxicities emerging from conventional approaches and improve outcomes. Hematological treatment of pediatric patients is reaching for more novel treatment options, such as targeted treatment, CAR-T-cells therapy, and immunotherapy. These methods are currently used in conjunction with chemotherapy. Nevertheless, the swift progress in their development and increasing efficacity can lead to applying those novel therapies as standalone therapeutic options for pediatric ALL. [ABSTRACT FROM AUTHOR]

Simple Summary: The primary issue of adoptive cell therapy is the poor in vivo persistence. In this context, it is necessary to clarify the fundamental mechanisms of T cell dysfunction. Here we review common dysfunctional states, including exhaustion and senescence, and discuss the challenges associated with phenotypical characterization of these T cell subsets. We overview the heterogeneity among exhausted T cells as well as mechanisms by which T cells get reinvigorated by checkpoint inhibitors. We emphasize that some cancers not responding to such treatment may activate distinct T cell dysfunction programs. Finally, we describe the dysfunction-promoting mechanisms specific for CAR-T cells and the ways to mitigate them. Immunotherapy using chimeric antigen receptor (CAR) T cells is a promising option for cancer treatment. However, T cells and CAR-T cells frequently become dysfunctional in cancer, where numerous evasion mechanisms impair antitumor immunity. Cancer frequently exploits intrinsic T cell dysfunction mechanisms that evolved for the purpose of defending against autoimmunity. T cell exhaustion is the most studied type of T cell dysfunction. It is characterized by impaired proliferation and cytokine secretion and is often misdefined solely by the expression of the inhibitory receptors. Another type of dysfunction is T cell senescence, which occurs when T cells permanently arrest their cell cycle and proliferation while retaining cytotoxic capability. The first section of this review provides a broad overview of T cell dysfunctional states, including exhaustion and senescence; the second section is focused on the impact of T cell dysfunction on the CAR-T therapeutic potential. Finally, we discuss the recent efforts to mitigate CAR-T cell exhaustion, with an emphasis on epigenetic and transcriptional modulation. [ABSTRACT FROM AUTHOR]

The landscape of pediatric oncology has dramatically changed over the course of the past several decades with five-year survival rates surpassing 80%. Anthracycline therapy has been the cornerstone of many chemotherapy regimens for pediatric patients since its introduction in the 1960s, and recent improved survival has been in large part due to advancements in chemotherapy, refinement of supportive care treatments, and development of novel therapeutics such as small molecule inhibitors, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors. Unfortunately, many cancer-targeted therapies can lead to acute and chronic cardiovascular pathologies. The range of cardiotoxicity can vary but includes symptomatic or asymptotic heart failure, arrhythmias, coronary artery disease, valvar disease, pericardial disease, hypertension, and peripheral vascular disease. There is lack of data guiding primary prevention and treatment strategies in the pediatric population, which leads to substantial practice variability. Several important future research directions have been identified, including as they relate to cardiac disease, prevention strategies, management of cardiovascular risk factors, risk prediction, early detection, and the role of genetic susceptibility in development of cardiotoxicity. Continued collaborative research will be key in advancing the field. The ideal model for pediatric cardio-oncology is a proactive partnership between pediatric cardiologists and oncologists in order to better understand, treat, and ideally prevent cardiac disease in pediatric oncology patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are bone marrow cancers that have a poor prognosis. They have traditionally been treated with chemotherapy with limited success, and stem cell transplant, which many patients are too frail to receive. Perturbations in the immune system play a role in the development of MDS and AML. Recently, there has been progress in understanding how the immune system can be harnessed to treat these cancers. Effective immune therapies for MDS and AML have been developed at a rapid pace, including novel immune checkpoint inhibitor antibodies, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and natural killer cells. This review article highlights advances in this field for the practicing clinician to aid in understanding new developments for treating patients with MDS and AML. Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Designer T and NK cells are a modality within immunotherapy that manipulates receptor-ligand interactions to enhance cells of the immune system to destroy cancer more effectively. Patient's own immune cells are isolated, genetically modified to improve responses against cancers cells, expanded, and subsequently reintroduced into the individual. Several clinical trials to investigate immunotherapy strategies that may garner lasting benefit even for cancer patients with glioblastoma (GBM), a deadly brain cancer with limited treatment options, are underway. Therapeutic potential for gene editing technologies in limiting rejection and adverse reactions to improve treatment responses in preclinical models is now translating into enduring efficacy in GBM patients. Glioblastoma (GBM) is the most prevalent, aggressive primary brain tumour with a dismal prognosis. Treatment at diagnosis has limited efficacy and there is no standardised treatment at recurrence. New, personalised treatment options are under investigation, although challenges persist for heterogenous tumours such as GBM. Gene editing technologies are a game changer, enabling design of novel molecular-immunological treatments to be used in combination with chemoradiation, to achieve long lasting survival benefits for patients. Here, we review the literature on how cutting-edge molecular gene editing technologies can be applied to known and emerging tumour-associated antigens to enhance chimeric antigen receptor T and NK cell therapies for GBM. A tight balance of limiting neurotoxicity, avoiding tumour antigen loss and therapy resistance, while simultaneously promoting long-term persistence of the adoptively transferred cells must be maintained to significantly improve patient survival. We discuss the opportunities and challenges posed by the brain contexture to the administration of the treatments and achieving sustained clinical responses. [ABSTRACT FROM AUTHOR]

Metastatic melanoma is the most aggressive and difficult to treat type of skin cancer, with a survival rate of less than 10%. Metastatic melanoma has conventionally been considered very difficult to treat; however, recent progress in understanding the cellular and molecular mechanisms involved in the tumorigenesis, metastasis and immune escape have led to the introduction of new therapies. These include targeted molecular therapy and novel immune-based approaches such as immune checkpoint blockade (ICB), tumor-infiltrating lymphocytes (TILs), and genetically engineered T-lymphocytes such as chimeric antigen receptor (CAR) T cells. Among these, CAR T cell therapy has recently made promising strides towards the treatment of advanced hematological and solid cancers. Although CAR T cell therapy might offer new hope for melanoma patients, it is not without its shortcomings, which include off-target toxicity, and the emergence of resistance to therapy (e.g., due to antigen loss), leading to eventual relapse. The present review will not only describe the basic steps of melanoma metastasis, but also discuss how CAR T cells could treat metastatic melanoma. We will outline specific strategies including combination approaches that could be used to overcome some limitations of CAR T cell therapy for metastatic melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor (CAR) T-cells are powerful therapeutic tools that have revolutionized the treatment of several hematological malignancies. However, their therapeutic application in acute myeloid leukemia (AML) remains challenging. In this review, the authors aimed to dissect how AML-leukemic stem cell and AML-bone marrow niche features can impact on the success of CAR T-cell therapy. The clinical implementation of some of the newly developed approaches discussed in this review may lead to the development of safe and effective CAR T-cell strategies for AML, accounting for the disease heterogeneity. Current treatment outcome for acute myeloid leukemia (AML) patients is unsatisfactory and characterized by high rates of relapse and poor overall survival. Increasing evidence points to a crucial role of leukemic stem cells (LSC) and the bone marrow (BM) leukemic niche, in which they reside, in AML evolution and chemoresistance. Thus, future strategies aiming at improving AML therapeutic protocols are likely to be directed against LSC and their niche. Chimeric antigen receptor (CAR) T-cells have been extremely successful in the treatment of relapsed/refractory acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma and comparable results in AML are highly desirable. At present, we are at the dawn of CAR T-cell application in AML, with several preclinical studies and few early phase clinical trials. However, the lack of leukemia-specific targets and the genetic and phenotypic heterogeneity of the disease combined with the leukemia-induced remodeling of the BM microenvironment are limiting CAR T-cell exploitation in AML. Here, we reviewed AML-LSC and AML-BM niche features in the context of their therapeutic targeting using CAR T-cells. We summarized recent progress in CAR T-cell application to the treatment of AML, and we discussed the remaining therapeutic challenges and promising novel strategies to overcome them. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) has long been at the forefront of the battle with cancer that began last century with the therapeutic application of tumor-infiltrating lymphocytes (TILs) against melanoma. The development of novel ACT approaches led researchers and clinicians to highly efficient technologies based on genetically engineered T lymphocytes, with chimeric antigen receptor (CAR)-T cells as the most prominent example. CARs consist of an extracellular domain that represents the single-chain variable fragment (scFv) of a monoclonal antibody (mAb) responsible for target recognition and the intracellular domain, which was built from up to several signaling motifs that mediated T cell activation. The number of potential targets amenable for CAR-T cell therapy is expanding rapidly, which means that the tremendous success of this approach in oncology could be further translated to treating other diseases. In this review, we outlined modern trends and recent developments in CAR-T cell therapy from an unusual point of view by focusing on diseases beyond cancer, such as autoimmune disorders and viral infections, including SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Despite the progress during the last decade, patients with advanced gastric and esophageal cancers still have poor prognosis. Finding optimal therapeutic strategies represents an unmet need in this field. Several prognostic and predictive factors have been evaluated and may guide clinicians in choosing a tailored treatment. Data from large studies investigating the role of immunotherapy in gastrointestinal cancers are promising but further investigations are necessary to better select those patients who can mostly benefit from these novel therapies. This review will focus on the treatment of metastatic esophageal and gastric cancer. We will review the standard of care and the role of novel therapies such as immunotherapies and CAR-T. Moreover, we will focus on the analysis of potential predictive biomarkers such as Modify as: Microsatellite Instability (MSI) and PD-L1, which may lead to treatment personalization and improved treatment outcomes. A multidisciplinary point of view is mandatory to generate an integrated approach to properly exploit these novel antiproliferative agents. [ABSTRACT FROM AUTHOR]

In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies. [ABSTRACT FROM AUTHOR]