Search

Chimeric antigen receptor (CAR) T cell therapy has transformed cancer immunotherapy. However, significant challenges limit its application beyond B cell-driven malignancies, including limited clinical efficacy, high toxicity, and complex autologous cell product manufacturing. Despite efforts to improve CAR T cell therapy outcomes, there is a growing interest in utilizing alternative immune cells to develop CAR cells. These immune cells offer several advantages, such as major histocompatibility complex (MHC)-independent function, tumor microenvironment (TME) modulation, and increased tissue infiltration capabilities. Currently, CAR products from various T cell subtypes, innate immune cells, hematopoietic progenitor cells, and even exosomes are being explored. These CAR products often show enhanced antitumor efficacy, diminished toxicity, and superior tumor penetration. With these benefits in mind, numerous clinical trials are underway to access the potential of these innovative CAR cells. This review aims to thoroughly examine the advantages, challenges, and existing insights on these new CAR products in cancer treatment. [ABSTRACT FROM AUTHOR]

Biallelic mutations in the ACP5 gene cause spondyloenchondrodysplasia with immune dysregulation (SPENCDI). SPENCDI is characterized by the phenotypic triad of skeletal dysplasia, innate and adaptive immune dysfunction, and variable neurologic findings ranging from asymptomatic brain calcifications to severe developmental delay with spasticity. Immune dysregulation in SPENCDI is often refractory to standard immunosuppressive treatments. Here, we present the cases of two patients with SPENCDI and recalcitrant autoimmune cytopenias who demonstrated a favorable clinical response to targeted JAK inhibition over a period of more than 3 years. One of the patients exhibited steadily rising IgG levels and a bone marrow biopsy revealed smoldering multiple myeloma. A review of the literature uncovered that approximately half of the SPENCDI patients reported to date exhibited increased IgG levels. Screening for multiple myeloma in SPENCDI patients with rising IgG levels should therefore be considered. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-T (CAR-T) cell therapy based on functional immune cell transfer is showing a booming situation. However, complex manufacturing processes, high costs, and disappointing results in the treatment of solid tumors have limited its use. Encouragingly, it has facilitated the development of new strategies that fuse immunology, cell biology, and biomaterials to overcome these obstacles. In recent years, CAR-T engineering assisted by properly designed biomaterials has improved therapeutic efficacy and reduced side effects, providing a sustainable strategy for improving cancer immunotherapy. At the same time, the low cost and diversity of biomaterials also offer the possibility of industrial production and commercialization. Here, we summarize the role of biomaterials as gene delivery vehicles in the generation of CAR-T cells and highlight the advantages of in-situ construction in vivo. Then, we focused on how biomaterials can be combined with CAR-T cells to better enable synergistic immunotherapy in the treatment of solid tumors. Finally, we describe biomaterials' potential challenges and prospects in CAR-T therapy. This review aims to provide a detailed overview of biomaterial-based CAR-T tumor immunotherapy to help investigators reference and customize biomaterials for CAR-T therapy to improve the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) respond to pathogen constituents, such as microbial lipids and nucleic acids (NAs). TLRs recognize NAs in endosomal compartments. Structural and functional studies have shown that recognition of NAs by TLRs depends on NA processing by RNases and DNases. DNase II-dependent DNA degradation is required for TLR9 responses to single-stranded DNAs, whereas RNase T2-dependent RNA degradation enables TLR7 and TLR8 to respond to nucleosides and oligoribonucleotides. In contrast, RNases and DNases negatively regulate TLR responses by degrading their ligands. RNase T2 negatively regulates TLR3 responses to degrading the TLR3 ligand double-stranded RNAs. Therefore, NA metabolism in the endosomal compartments affects the endosomal TLR responses. Dysregulation of NA metabolism in the endosomal compartment drives the TLR-dependent pathologies in human diseases. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages. [ABSTRACT FROM AUTHOR]

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient's personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient's humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses. [ABSTRACT FROM AUTHOR]

Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials. [ABSTRACT FROM AUTHOR]

Osteoclasts (OCLs) are key players in controlling bone remodeling. Modifications in their differentiation or bone resorbing activity are associated with a number of pathologies ranging from osteopetrosis to osteoporosis, chronic inflammation and cancer, that are all characterized by immunological alterations. Therefore, the 2000s were marked by the emergence of osteoimmunology and by a growing number of studies focused on the control of OCL differentiation and function by the immune system. At the same time, it was discovered that OCLs are much more than bone resorbing cells. As monocytic lineage-derived cells, they belong to a family of cells that displays a wide heterogeneity and plasticity and that is involved in phagocytosis and innate immune responses. However, while OCLs have been extensively studied for their bone resorption capacity, their implication as immune cells was neglected for a long time. In recent years, new evidence pointed out that OCLs play important roles in the modulation of immune responses toward immune suppression or inflammation. They unlocked their capacity to modulate T cell activation, to efficiently process and present antigens as well as their ability to activate T cell responses in an antigen-dependent manner. Moreover, similar to other monocytic lineage cells such as macrophages, monocytes and dendritic cells, OCLs display a phenotypic and functional plasticity participating to their anti-inflammatory or pro-inflammatory effect depending on their cell origin and environment. This review will address this novel vision of the OCL, not only as a phagocyte specialized in bone resorption, but also as innate immune cell participating in the control of immune responses. [ABSTRACT FROM AUTHOR]

Viral infections have a major impact on morbidity and mortality of immunosuppressed solid organ transplant (SOT) patients because of missing or failure of adequate pharmacologic antiviral treatment. Adoptive antiviral T-cell therapy (AVTT), regenerating disturbed endogenous T-cell immunity, emerged as an attractive alternative approach to combat severe viral complications in immunocompromised patients. AVTT is successful in patients after hematopoietic stem cell transplantation where T-cell products (TCPs) are manufactured from healthy donors. In contrast, in the SOT setting TCPs are derived from/applied back to immunosuppressed patients. We and others demonstrated feasibility of TCP generation from SOT patients and first clinical proof-of-concept trials revealing promising data. However, the initial efficacy is frequently lost long-term, because of limited survival of transferred short-lived T-cells indicating a need for next-generation TCPs. Our recent data suggest that Rapamycin treatment during TCP manufacture, conferring partial inhibition of mTOR, might improve its composition. The aim of this study was to confirm these promising observations in a setting closer to clinical challenges and to deeply characterize the next-generation TCPs. Using cytomegalovirus (CMV) as model, our next-generation Rapamycin-treated (Rapa-)TCP showed consistently increased proportions of CD4+ T-cells as well as CD4+ and CD8+ central-memory T-cells (TCM). In addition, Rapamycin sustained T-cell function despite withdrawal of Rapamycin, showed superior T-cell viability and resistance to apoptosis, stable metabolism upon activation, preferential expansion of TCM, partial conversion of other memory T-cell subsets to TCM and increased clonal diversity. On transcriptome level, we observed a gene expression profile denoting long-lived early memory T-cells with potent effector functions. Furthermore, we successfully applied the novel protocol for the generation of Rapa-TCPs to 19/19 SOT patients in a comparative study, irrespective of their history of CMV reactivation. Moreover, comparison of paired TCPs generated before/after transplantation did not reveal inferiority of the latter despite exposition to maintenance immunosuppression post -SOT. Our data imply that the Rapa-TCPs, exhibiting longevity and sustained T-cell memory, are a reasonable treatment option for SOT patients. Based on our success to manufacture Rapa-TCPs from SOT patients under maintenance immunosuppression, now, we seek ultimate clinical proof of efficacy in a clinical study. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects. [ABSTRACT FROM AUTHOR]

Autoinflammatory disease was introduced as a concept in 1999, demarcating an entirely new group of diseases in clinical, immunological, and conceptual terms. During recent years, the preconditions for the definition of autoinflammatory conditions have changed. This includes the recent discovery of a number of monogenic autoinflammatory conditions with complex phenotypes that combine autoinflammation with defects of the adaptive and/or innate immune system, resulting in the occurrence of infection, autoimmunity, and/or uncontrolled hyperinflammation in addition to autoinflammation. Further, there are strong indications that classical IL-1-driven autoinflammatory diseases are associated with activation of adaptive immunity. As suggested by this development, we are of the opinion that an all-encompassing definition of autoinflammatory diseases should regard autoinflammatory conditions and innate dysregulation as inseparable and integral parts of the immune system as a whole. Hence, in this article, we try to advance the conceptual understanding of autoinflammatory disease by, proposing a modification of the definition by Daniel Kastner et al., which allows for a congruent and precise description of conditions that expand the immunological spectrum of autoinflammatory disease. [ABSTRACT FROM AUTHOR]