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Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results. [ABSTRACT FROM AUTHOR]

Abstract Chimeric antigen receptor (CAR)-T-cell therapy is one of the most effective immunotherapies. CAR-T-cell therapy has achieved great success in the treatment of hematological malignancies. However, due to the characteristics of solid malignant tumors, such as on-target effects, off-tumor toxicity, an immunosuppressive tumor microenvironment (TME), and insufficient trafficking, CAR-T-cell therapy for solid tumors is still in the exploration stage. Mesothelin (MSLN) is a molecule expressed on the surface of various solid malignant tumor cells that is suitable as a target of tumor cells with high MSLN expression for CAR-T-cell therapy. This paper briefly described the development of CAR-T cell therapy and the structural features of MSLN, and especially summarized the strategies of structure optimization of MSLN-targeting CAR-T-cells and the enhancement methods of MSLN-targeting CAR-T cell anti-tumor efficacy by summarizing some preclinical experiment and clinical trials. When considering MSLN-targeting CAR-T-cell therapy as an example, this paper summarizes the efforts made by researchers in CAR-T-cell therapy for solid tumors and summarizes feasible treatment plans by integrating the existing research results.

Chimeric antigen receptor T (CAR-T) cell therapy has been proven to be successful against different leukaemias and lymphomas. Its success has led, in recent years, to its use being tested for different solid tumours, including glioblastoma, a type of primary brain tumour, characterised by aggressiveness and recurrence. This paper presents an analytical study of a mathematical model describing the competition of CAR-T and glioblastoma tumour cells, taking into account their immunosuppressive capacity. The model is formulated in a general way, and its basic properties are investigated. However, most of the analysis considers the model with exponential tumour growth, assuming this growth type for simplicity. The existence and stability of steady states are studied, and the subsequent focus is on two different types of treatment: constant and periodic. Finally, protocols for CAR-T cell therapy of glioblastoma are numerically derived; these are aimed at preventing the tumour from reaching a critical size and at prolonging the patients' survival time as much as possible. The analytical and numerical results provide theoretical support for the treatment of glioblastoma using CAR-T cells. [ABSTRACT FROM AUTHOR]

Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR‐T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR‐T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR‐T cell therapy, and considers future outlooks for research development. Significance statement: The necessity and importance of chimeric antigen receptor (CAR) T cells and their therapeutic efficiency in treating diseases other than cancer, mainly cardiovascular diseases, have emerged in recent years. However, there is still room for advancement in the current models of CAR‐T cell therapy. This paper highlights the evolution and roadblocks of CAR‐T technology at different levels, from technical concerns to clinical outcomes, in an attempt to improve the therapeutic efficiency of CAR‐T cell therapy in this area. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy in relapsed/refractory (R/R) hematological malignancies, especially in R/R B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). To prevent disease progression and reduce tumor burden during CAR-T cell manufacturing, bridging therapies prior to CAR-T cell infusion are crucial. At present, it has been demonstrated that targeted therapy, radiotherapy and autologous stem cell transplantation (ASCT) could serve as effective bridging strategies. However, whether cryoablation could serve as a novel bridging strategy is unknown. In this paper, we report 2 cases of R/R B cell malignancies with bulky disease that were successfully treated with a combination of cryoablation and CAR-T cell therapy. Patient 1 was a 65-year-old female who was diagnosed with R/R MM with extramedullary disease (EMD). She was enrolled in the anti-BCMA CAR-T cell clinical trial. Patient 2 was a 70-year-old man who presented with a subcutaneous mass in the right anterior thigh and was diagnosed with primary cutaneous diffuse large B cell lymphoma, leg type (PCLBCL-LT) 1 year ago. He failed multiline chemotherapies as well as radiotherapy. Thus, he requested anti-CD19 CAR-T cell therapy. Unfortunately, they all experienced local progression during CAR-T cell manufacturing. To rapidly achieve local tumor control and reduce tumor burden, they both received cryoablation as a bridging therapy. Patient 1 achieved a very good partial response (VGPR) 1 month after CAR-T cell infusion, and patient 2 achieved a partial response (PR) 1 month after CAR-T cell infusion. In addition, adverse effects were tolerable and manageable. Our study demonstrated the favorable safety and efficacy of combination therapy with cryoablation and CAR-T cell therapy for the first time, and it also indicates that cryoablation could serve as a novel therapeutic strategy for local tumor control in B cell malignancies. [ABSTRACT FROM AUTHOR]

Purpose of Review: The purpose of our paper is to describe the all-encompassing supportive care for patients with relapsed or refractory lymphoma undergoing cellular therapy, with a focus on the advanced practice provider's (APPs) perspective. Recent Findings: Chimeric antigen receptor-T (CAR-T) cell therapy has become more available for treating relapsed or refractory B-cell hematologic malignancies, requiring proficient and adequate treatment of side effects, complications, and infections that may occur during therapy. APPs often meet these patients during the initial referral and help to support them through the CAR-T cell therapy process. Summary: As APPs acquire a complete understanding and comprehensive knowledge of how to treat, support, and guide patients with B-cell malignancies through CAR-T cell therapy, they play a pivotal role in these patients throughout their treatment. Standardization of supportive care is paramount. [ABSTRACT FROM AUTHOR]

• CAR-T therapy offers durable remissions in refractory hematological malignancies. • Meta-analyses show significant efficacy in various hematologic cancers. • CAR T-cell therapy improves quality of life for blood cancer patients. • Encouraging results in CD22-targeting CAR T-cell therapy for B-cell malignancies. • Long-term studies reveal durable remissions but also persistent adverse effects. Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects. [ABSTRACT FROM AUTHOR]

ABSTRACT: Introduction: Chimeric antigen receptor T (CAR-T) cell therapy is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) that is a multi-step process involving various stakeholders. Appropriate education on the practical logistics is therefore paramount to ensure treatment success. Methods: A group of key opinion leaders met to explore the key elements of setting up and running a CAR-T center in Brazil. For each step in the CAR-T cell therapy process, the experts agreed on basic requirements, gave their key recommendations from practical experience, and considered any remaining unanswered questions. Results: This paper presents best-practice recommendations and advice on how to overcome common challenges for each step in the CAR-T cell therapy process, with a focus on the current situation in Brazil. Key themes throughout the process are collaboration within the multidisciplinary team and with the referring physician, along with communication and education for patients and their caregivers. Conclusion: We believe that the expert insights presented in this paper, in particular on optimal patient selection and timing of CAR-T cell therapy, will deepen understanding of the CAR-T process and aid implementation of this novel therapy for patients with RRMM in Brazil.

Background: Cellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application. Methods: We manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro. Results: In this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them. Conclusions: We successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density. [ABSTRACT FROM AUTHOR]

Background: Previously, we discovered that human solid tumours, but not normal human tissues, preferentially overexpress interleukin‐13Receptor alpha2, a high binding receptor for IL‐13. To develop novel anti‐cancer approaches, we constructed a chimeric antigen receptor construct using a high binding and codon optimised scFv‐IL‐13Rα2 fragment fused with CD3ζ and co‐stimulatory cytoplasmic domains of CD28 and 4‐1BB. Methods: We developed a scFv clone, designated 14‐1, by biopanning the bound scFv phages using huIL‐13Rα2Fc chimeric protein and compared its binding with our previously published clone 4‐1. We performed bioinformatic analyses for complementary determining regions (CDR) framework and residue analyses of the light and heavy chains. This construct was packaged with helper plasmids to produce CAR‐lentivirus and transduced human Jurkat T or activated T cells from peripheral blood mononuclear cells (PBMCs) to produce CAR‐T cells and tested for their quality attributes in vitro and in vivo. Serum enzymes including body weight from non‐tumour bearing mice were tested for assessing general toxicity of CAR‐T cells. Results: The binding of 14‐1 clone is to IL‐13Rα2Fc‐chimeric protein is ∼5 times higher than our previous clone 4‐1. The 14‐1‐CAR‐T cells grew exponentially in the presence of cytokines and maintained phenotype and biological attributes such as cell viability, potency, migration and T cell activation. Clone 14‐1 migrated to IL‐13Rα2Fc and cell free supernatants only from IL‐13Rα2+ve confluent glioma tumour cells in a chemotaxis assay. scFv‐IL‐13Rα2‐CAR‐T cells specifically killed IL‐13Rα2+ve but not IL‐13Rα2‐ve tumour cells in vitro and selectively caused significant release of IFN‐γ only from IL‐13Rα2+ve co‐cultures. These CAR‐T cells regressed IL‐13Rα2+ve glioma xenografts in vivo without any general toxicity. In contrast, the IL‐13Rα2 gene knocked‐down U251 and U87 xenografts failed to respond to the CAR‐T therapy. Conclusion: Taken together, we conclude that the novel scFv‐IL‐13Rα2 CAR‐T cell therapy may offer an effective therapeutic option after designing a careful pre‐clinical and clinical study. [ABSTRACT FROM AUTHOR]

Infections due to pathogenic fungi are endemic in particular area with increased morbidity and mortality. More than a thousand people are infected per year and the way of treatment is of high demand having a significant impact on the population health. Medical practitioners confront various troublesome analytic and therapeutical challenges in the administration of immunosuppressed sufferer at high danger of expanding fungal infections. An upgraded antimycosal treatment is fundamental for a fruitful result while treating intrusive mycoses. A collection of antimycosal drugs keeps on developing with their specific antifungal targets including cell membrane, mitochondria, cell wall, and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) or protein biosynthesis. Some fundamental classes of ordinarily directed medications are the polyenes, amphotericin B, syringomycin, allylamines, honokiol, azoles, flucytosine, echinocandins etc. However, few immunotherapy processes and vaccinations are being developed to mark this need, although one presently can't seem to arrive at the conclusion. In this review article, there has been a trial to give details upgradation about the current immune therapeutic techniques and vaccination strategies against prevention or treatment of mycosis as well as the difficulties related with their turn of events. There has been also a visualization in the mentioned review paper about the various assorted drugs and their specific target analysis along with therapeutic interventions.

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Introduction: CAR-T cell therapy is a novel approach in the treatment of hematological tumors. However, it is associated with life-threatening side effects, such as the severe cytokine release syndrome (sCRS). Therefore, predicting the occurrence and development of sCRS is of great significance for clinical CAR-T therapy. The study of existing clinical data by artificial intelligence may bring useful information. Methods: By analyzing the heat map of clinical factors and comparing them between severe and non-severe CRS, we can identify significant differences among these factors and understand their interrelationships. Ultimately, a decision tree approach was employed to predict the timing of severe CRS in both children and adults, considering variables such as the same day, the day before, and initial values. Results: We measured cytokines and clinical biomarkers in 202 patients who received CAR-T therapy. Peak levels of 25 clinical factors, including IFN-g, IL6, IL10, ferritin, and D-dimer, were highly associated with severe CRS after CAR T cell infusion. Using the decision tree model, we were able to accurately predict which patients would develop severe CRS consisting of three clinical factors, classified as same-day, day-ahead, and initial value prediction. Changes in serum biomarkers, including C-reactive protein and ferritin, were associated with CRS, but did not alone predict the development of severe CRS. Conclusion: Our research will provide significant information for the timely prevention and treatment of sCRS, during CAR-T immunotherapy for tumors, which is essential to reduce the mortality rate of patients. [ABSTRACT FROM AUTHOR]

Introduction: The devastation of hospitals and the severing of international links has made paediatric haematopoietic stem cell transplantation (HSCT) in Ukraine impossible. The aim of our study was to present the activity of Polish paediatric bone marrow transplant units in saving the lives of child war refugees. Material and methods: The data collected from 6 units on the treatment of child war refugees from Ukraine with HSCT were analysed. Results: From 24 February 2022 up to the end of 2022, 18 children from Ukraine underwent HSCT and one received chimeric antigen receptor T-cell (CAR-T) therapy. This project was possible due to great organisational support from non-governmental organisations (NGOs), international cooperation ("SAFER Ukraine" enterprise), and financial coverage by the Polish national insurance system. Twelve patients were treated in Wrocław, 3 in Lublin, 2 in Bydgoszcz, one in Poznań, and one in Kraków. The group consisted of 10 boys and 9 girls, aged 1.3--17.9 years, 16 of whom suffered from haematological malignancy (acute lymphoblastic leukaemia n = 9, acute myeloblastic leukaemia n = 5, juvenile myelomonocytic leukaemia n = 2) and 3 from non-neoplastic disease (severe aplastic anaemia n = 2 and severe combined immunodeficiency syndrome n = 1). Despite poor preparation, numerous pre-existing comorbidities, a high rate of acute complications, and long hospital stays, the overall results were satisfactory. Only 2 patients (10%) died during the first 100 days after transplantation, both due to severe infection. The total number of allogeneic-HSCTs performed in Poland on Ukrainian children during wartime was not substantially lower than in previous years in their home country. Moreover, this specific war situation allowed the prescribing of CAR-T therapy to one of the first paediatric patients from this country. Conclusions: Saving the lives of seriously ill child war refugees with the use of HSCT and CAR-T therapy is effective provided that all entities responsible for it cooperate in a coordinated manner and support the activities of NGOs. [ABSTRACT FROM AUTHOR]

Currently, a major focus of biomedical research and clinical application are the so-called advanced therapy medicinal products (ATMPs), which are highly complex medicines that enable the targeted and personalised treatment of patients. The potential of ATMPs in future cancer treatment is invaluable. However, this novel class of treatments is often extremely expensive. Consequently, these therapies push established reimbursement models to their limits. Because of the high costs, as well as the lack of appropriate reimbursement models, access to these potentially lifesaving therapies is currently not guaranteed to all patients. This paper analyses the current legal framework in Switzerland and critically evaluates existing reimbursement models, particularly with respect to their adaptation for ATMPs. As a promising reimbursement arrangement, this paper proposes a model combining outcome-based instalment payments with aspects of the pay for performance and the annuity payment model. According to this performance-based shared risk model, instalment payments are due when defined treatment goals are achieved.

Introduction: Chimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since "ontarget/ off-tumor" cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no "on-target/off-tumor" cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts. Methods: Using the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2nd generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8+ T cells upon co-cultivation with CD176+ tumor cell lines as models for CD176+ blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity. Results: Specific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-kB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176+ cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e.g. interferon-g, granzyme B and perforin), mediated cytotoxicity against CD176+ cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176-control cells, their response proved to be target-specific. Discussion: Genetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding "on-target/off-tumor" cytotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: CAR-T cell therapy is a novel approach in the treatment of hematological tumors. However, it is associated with life-threatening side effects, such as the severe cytokine release syndrome (sCRS). Therefore, predicting the occurrence and development of sCRS is of great significance for clinical CAR-T therapy. The study of existing clinical data by artificial intelligence may bring useful information. Methods: By analyzing the heat map of clinical factors and comparing them between severe and non-severe CRS, we can identify significant differences among these factors and understand their interrelationships. Ultimately, a decision tree approach was employed to predict the timing of severe CRS in both children and adults, considering variables such as the same day, the day before, and initial values. Results: We measured cytokines and clinical biomarkers in 202 patients who received CAR-T therapy. Peak levels of 25 clinical factors, including IFN-g, IL6, IL10, ferritin, and D-dimer, were highly associated with severe CRS after CAR T cell infusion. Using the decision tree model, we were able to accurately predict which patients would develop severe CRS consisting of three clinical factors, classified as same-day, day-ahead, and initial value prediction. Changes in serum biomarkers, including C-reactive protein and ferritin, were associated with CRS, but did not alone predict the development of severe CRS. Conclusion: Our research will provide significant information for the timely prevention and treatment of sCRS, during CAR-T immunotherapy for tumors, which is essential to reduce the mortality rate of patients. [ABSTRACT FROM AUTHOR]

Keywords: CAR-T cell therapy; Viral infections; Immunotherapy; Chimeric antigen receptors; Viral antigens EN CAR-T cell therapy Viral infections Immunotherapy Chimeric antigen receptors Viral antigens 1839 1842 4 08/02/23 20230901 NES 230901 Dear Editor, The emergence of chimeric antigen receptor T (CAR-T) cell therapy has ushered in a new era of optimism in the realm of viral infection treatment. Balancing challenges and opportunities: an exploration of CAR-T cell therapy in viral infecti... While CAR-T cell therapy exhibits promising potential for treating viral infections, several substantial challenges still exist. Originally designed for cancer therapy [[1]], CAR-T cell therapy employs the genetic modification of a patient's T cells to express chimeric antigen receptors (CARs) that precisely identify and potentially target viral antigens, thereby eradicating cells infected with the virus. [Extracted from the article]

Simple Summary: FMC63-CAR-T cell therapy, an immunotherapy against CD19 protein expressed on malignant B cells, is effective in diffuse large B-cell lymphoma (r/r DLBCL) with complete response in half of the treated patients. Remarkably, there are two germline CD19 antigen variants due to the single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen, which is present in half of the global population. We present evidence that this single nucleotide polymorphism in CD19 has a clinical impact on the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy. Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63–84% and complete response observed in 43–54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome. [ABSTRACT FROM AUTHOR]

Immunotherapy is a promising therapeutic domain for the treatment of gliomas. However, clinical trials of various immunotherapeutic modalities have not yielded significant improvements in patient survival. Preclinical models for glioma research should faithfully represent clinically observed features regarding glioma behavior, mutational load, tumor interactions with stromal cells, and immunosuppressive mechanisms. In this review, we dive into the common preclinical models used in glioma immunology, discuss their advantages and disadvantages, and highlight examples of their utilization in translational research. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapies have revolutionized the management of hematological malignancies and solid organ cancers. These new treatments present numerous infectious complications. We aim to present the main infectious complications related to immune checkpoint inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase inhibitors (PI3K), antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors and CAR-T cell infusion treatments. The knowledge of complications allows the physician to better identify patients at risk in order to implement diagnostic and therapeutic strategies, or to discuss the implementation of preventive measures. Background: Infections are well known complications of some targeted drugs used to treat solid organ cancer and hematological malignancies. Furthermore, Individual patient risk factors are associated with underlying pathologies, concomitant immunosuppressive treatment, prior treatment and use of anti-infective prophylaxis. Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Objectives: In this narrative review, we present the current state of knowledge concerning the infectious complications occurring in patients treated with immune checkpoint inhibitors (ICIs), Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, antiapoptotic protein BCL-2 inhibitors, Janus kinase inhibitors or CAR-T cell infusion. Sources: We searched for studies treating infectious complications of ICIs, BTK inhibitors, PI3K inhibitors, antiapoptotic protein BCL-2 inhibitors and CAR-T cell therapy. We included randomized, observational studies and case reports. Content: Immune-related adverse events (irAEs) are frequent among patients treated with new targeted drugs. Treatment of irAEs with corticosteroids and other immunosuppressive agents can lead to opportunistic infections. Bruton's tyrosine kinase (BTK) inhibitors are associated with higher rate of infections, including invasive fungal infections. Implications: Infections, particularly fungal ones, are common in patients treated with BTK inhibitors even though most of the complications occurring among patients treated by ICIs or CART-cells infusion are associated with the treatment of side effects related to the use of these new treatments. The diagnosis of these infectious complications can be difficult and may require extensive investigations. [ABSTRACT FROM AUTHOR]

Simple Summary: Mantle Cell Lymphoma (MCL) is a lymphoproliferative disorder which represents less than 10% of all non-Hodgkin Lymphomas. The typical course of MCL is characterized by several relapses ("remitting-relapsing" course), and since its identification it has been considered an incurable disease. Allogeneic stem cell transplantation (allo-SCT) has represented in the past years the only treatment which could ensure prolonged remissions, at least in younger patients. In our paper, we critically revised the available data on the use of allo-SCT in MCL. The aim of our review is to identify the subgroups of patients who could best benefit from this therapeutic strategy, the optimal timing for transplantation and the best ways to bridge patients to allo-SCT, in an era in which many novel agents have been developed. MCL is an uncommon lymphoproliferative disorder that has been regarded as incurable since its identification as a distinct entity. Allogeneic transplantation for two decades has represented the only option capable of ensuring prolonged remissions and possibly cure. Despite its efficacy, its application has been limited by feasibility limitations and substantial toxicity, particularly in elderly patients. Nevertheless, the experience accumulated over time has been wide though often scattered among retrospective and small prospective studies. In this review, we aimed at critically revise and discuss available evidence on allogeneic transplantation in MCL, trying to put available evidence into the 2020 perspective, characterized by unprecedented development of novel promising therapeutic agents and regimens. [ABSTRACT FROM AUTHOR]

As genetically engineered cells, chimeric antigen receptor (CAR)-T cells express specific receptors on their surface to target and eliminate malignant cells. CAR proteins are equipped with elements that enhance the activity and survival of T cells. Once injected, CAR-T cells act as a "living drug" against tumor cells in the body. Up to now, CAR-T cell therapy has been demonstrated as a robust adoptive cell transfer (ACT) immunotherapeutic modality for eliminating tumor cells in refractory hematological malignancies. CAR-T cell therapy modality involves several steps, including the collecting of the blood from patients, the isolation of peripheral blood mononuclear cells (PBMCs), the enrichment of CD4+/CD8+ T cell, the genetic reprogramming, the expansion of modified T cells, and the injection of genetically engineered T cells. The production of CAR-T cells is a multi-step procedure, which needs precise and safety management systems, including good manufacturing practice (GMP), and in-line quality control and assurance. The current study describes the structure of CARs and concentrates on the next generations of CARs that are engaged in enhancing the anti-tumor responses and safety of the engineered T cells. This paper also highlights the important concerns in quality control and nonclinical research of CAR-T cells, as well as general insights into the manufacture, reprogramming, and application of CAR-T cells based on new and enhanced techniques for treating hematological malignancies. Besides, the application of the CRISPR-Cas9 genome editing technology and nanocarrier-based delivery systems containing CAR coding sequences to overcome the limitations of CAR-T cell therapy has also been explained. [Display omitted] [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) is a traditional therapeutic regime that focuses on ionizing radiation, however, RT maintains largely palliative due to radioresistance. Factors such as hypoxia, the radiosensitivity of immune cells, and cancer stem cells (CSCs) all come into play in influencing the significant impact of radioresistance in the irradiated tumor microenvironment (TME). Due to the substantial advances in the treatment of malignant tumors, a promising approach is the genetically modified T cells with chimeric antigen receptors (CARs) to eliminate solid tumors. Moreover, CAR-T cells targeting CSC-related markers would eliminate radioresistant solid tumors. But solid tumors that support an immune deserted TME, are described as immunosuppressive and typically fail to respond to CAR-T cell therapy. And RT could overcome these immunosuppressive features; thus, growing evidence supports the combination of RT with CAR-T cell therapy. In this review, we provide a deep insight into the radioresistance mechanisms, advances, and barriers of CAR-T cells in response to solid tumors within TME. Therefore, we focus on how the combination strategy can be used to eliminate these barriers. Finally, we show the challenges of this therapeutic partnership. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-T cell therapy is effective in the treatment of refractory/relapsed (r/r) hematological malignancies (r/r B-cell lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma). In addition, it is being explored as a treatment option for solid tumors. As of 31 March 2022, seven CAR-T therapies for hematological malignancies have been approved worldwide. Although CAR-T therapy is an effective treatment for many malignancies, it also causes adverse effects. The incidence of cytokine release syndrome (CRS), the most common adverse reaction after infusion of CAR-T cells, is as high as 93%.CRS, is the leading risk factor of immune effector cell-associated neurotoxicity syndrome (ICANS), as well as cardiovascular, hematological, hepatorenal, skin, pulmonary, and gastrointestinal toxicity. Severe adverse reactions complicated by CRS severely impede the widespread application of CAR-T therapy. The CAR-T product was initially approved in 2017; however, only limited studies have investigated the adverse reactions owing to CAR-T therapy compared to that of clinically approved drugs. Thus, we aimed to elucidate the mechanisms, risk factors, diagnostic criteria, and treatment of toxicities concurrent with CRS, thereby providing a valuable reference for the safe, effective, and widespread application of CAR-T therapy. [ABSTRACT FROM AUTHOR]

The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators). Usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death. Not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies. Due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered. [ABSTRACT FROM AUTHOR]

Treatment targeting CD19 by a chimeric antigen receptor expressed on T cells (anti-CD19 CAR-T) has led to a breakthrough in the management and treatment of relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). After infusion, the efficacy of anti-CD19 CAR-T is monitored by bone marrow negative minimal residual disease and the absence of peripheral CD19+ B lymphocytes (B-cell aplasia). In patients who have received an allogenic Hematopoietic Stem Cell Transplantation (HSCT) prior to treatment with anti-CD19 CAR-T, monitoring lineage-specific chimerism could be helpful. We found that on 4 patients who received anti-CD19 CAR-T cells after HSCT and achieved early complete response, CD19+ lineage mixed chimerism but not CD3+ lineage mixed chimerism monitored by molecular techniques anticipated earlier than B-cell aplasia determined by flow cytometry, lack of effectiveness of anti-CD19 CAR-T and leukemia relapse. Donor lymphocyte infusions (DLIs) did not prevent relapse but recovered CD3+ full donor chimerism. We suggest that continuous lineage chimerism analysis should be done routinely in patients who receive anti-CD19 CAR-T cells after HSCT and achieve complete remission because it can support early treatment intervention. However, the role of DLI in this setting is unclear, so further prospective studies should be developed. [ABSTRACT FROM AUTHOR]

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4–6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44–0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31–0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria. [ABSTRACT FROM AUTHOR]