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Cardio-oncology is a critical field due to the escalating significance of cardiovascular toxicity as a side effect of anticancer treatments. Cancer therapy-related cardiac dysfunction (CTRCD) is a prevalent condition associated with cardiovascular toxicity, necessitating effective strategies for prediction, monitoring, management, and tracking. This comprehensive review examines the definition and risk stratification of CTRCD, explores monitoring approaches during anticancer therapy, and highlights specific cardiovascular toxicities linked to various cancer treatments. These include anthracyclines, HER2-targeted agents, vascular endothelial growth factor inhibitors, immune checkpoint inhibitors, chimeric antigen receptor T-cell therapies, and tumor-infiltrating lymphocytes therapies. Incorporating the Korean data, this review offers insights into the regional nuances in managing CTRCD. Using systematic follow-up incorporating cardiovascular imaging and biomarkers, a better understanding and management of CTRCD can be achieved, optimizing the cardiovascular health of both cancer patients and survivors. [ABSTRACT FROM AUTHOR]

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]

Lung cancer remains one of the leading causes of cancer-related mortality worldwide necessitating the development of innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy represents a promising advancement in the field of oncology offering a novel approach to target and eliminate tumor cells with high specificity and reduced risk of immune-related adverse effects. This paper reviews the mechanism, potential targets, and recent advances in CAR-NK cell therapy for lung cancer, including the design and engineering of CAR-NK cells, preclinical studies, and the outcomes of early-phase clinical trials. We highlight the unique advantages of using NK cells, such as their innate ability to recognize and kill cancer cells and their reduced potential for inducing graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) compared to CAR T-cell therapies. Results from recent studies demonstrate significant antitumor activity in lung cancer models with improved targeting and persistence of CAR-NK cells observed in vitro and in vivo. Finally, we discuss the challenges in optimizing CAR-NK cell therapies, including the potential resistance mechanisms. The paper concludes with an outlook on the future directions of CAR-NK cell research and its implications for lung cancer treatment emphasizing the importance of continued innovation and collaboration in the field. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells, as innate lymphocytes, possess cytotoxic capabilities and engage target cells through a repertoire of activating and inhibitory receptors. Particularly, natural killer group 2, member D (NKG2D) receptor on NK cells recognizes stress‐induced ligands—the MHC class I chain‐related molecules A and B (MICA/B) presented on tumor cells and is key to trigger the cytolytic response of NK cells. However, tumors have developed sophisticated strategies to evade NK cell surveillance, which lead to failure of tumor immunotherapy. In this paper, we summarized these immune escaping strategies, including the downregulation of ligands for activating receptors, upregulation of ligands for inhibitory receptors, secretion of immunosuppressive compounds, and the development of apoptosis resistance. Then, we focus on recent advancements in NK cell immune therapies, which include engaging activating NK cell receptors, upregulating NKG2D ligand MICA/B expression, blocking inhibitory NK cell receptors, adoptive NK cell therapy, chimeric antigen receptor (CAR)‐engineered NK cells (CAR‐NK), and NKG2D CAR‐T cells, especially several vaccines targeting MICA/B. This review will inspire the research in NK cell biology in tumor and provide significant hope for improving cancer treatment outcomes by harnessing the potent cytotoxic activity of NK cells. [ABSTRACT FROM AUTHOR]

Simulation Analysis and Modeling II (SAAM II) is a graphical modeling software used in life sciences for compartmental model analysis, particularly, but not exclusively, appreciated in pharmacokinetics (PK) and pharmacodynamics (PD), metabolism, and tracer modeling. Its intuitive "circles and arrows" visuals allow users to easily build, solve, and fit compartmental models without the need for coding. It is suitable for rapid prototyping of models for complex kinetic analysis or PK/PD problems, and in educating students and non‐modelers. Although it is straightforward in design, SAAM II incorporates sophisticated algorithms programmed in C to address ordinary differential equations, deal with complex systems via forcing functions, conduct multivariable regression featuring the Bayesian maximum a posteriori, perform identifiability and sensitivity analyses, and offer reporting functionalities, all within a single package. After 26 years from the last SAAM II tutorial paper, we demonstrate here SAAM II's updated applicability to current life sciences challenges. We review its features and present four contemporary case studies, including examples in target‐mediated PK/PD, CAR‐T‐cell therapy, viral dynamics, and transmission models in epidemiology. Through such examples, we demonstrate that SAAM II provides a suitable interface for rapid model selection and prototyping. By enabling the fast creation of detailed mathematical models, SAAM II addresses a unique requirement within the mathematical modeling community. [ABSTRACT FROM AUTHOR]

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR‐T cell therapy, many factors were found to be associated with the efficacy of CAR‐T therapy. This paper reviews the factors affecting the effect of CAR‐T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR‐T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies. [ABSTRACT FROM AUTHOR]

Surgery, chemotherapy, and endocrine therapy have improved the overall survival and postoperative recurrence rates of Luminal A, Luminal B, and HER2-positive breast cancers but treatment modalities for triple-negative breast cancer (TNBC) with poor prognosis remain limited. The effective application of the rapidly developing chimeric antigen receptor (CAR)-T cell therapy in hematological tumors provides new ideas for the treatment of breast cancer. Choosing suitable and specific targets is crucial for applying CAR-T therapy for breast cancer treatment. In this paper, we summarize CAR-T therapy's effective targets and potential targets in different subtypes based on the existing research progress, especially for TNBC. CAR-based immunotherapy has resulted in advancements in the treatment of breast cancer. CARmacrophages, CAR-NK cells, and CAR-mesenchymal stem cells (MSCs) may be more effective and safer for treating solid tumors, such as breast cancer. However, the tumor microenvironment (TME) of breast tumors and the side effects of CAR-T therapy pose challenges to CAR-based immunotherapy. CAR-T cells and CAR-NK cells-derived exosomes are advantageous in tumor therapy. Exosomes carrying CAR for breast cancer immunotherapy are of immense research value and may provide a treatment modality with good treatment effects. In this review, we provide an overview of the development and challenges of CAR-based immunotherapy in treating different subtypes of breast cancer and discuss the progress of CAR-expressing exosomes for breast cancer treatment. We elaborate on the development of CAR-T cells in TNBC therapy and the prospects of using CAR-macrophages, CAR-NK cells, and CARMSCs for treating breast cancer. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, represented by immune checkpoint blocking and chimeric antigen receptor (CAR) T cell therapy, has achieved promising results in clinical applications. However, it faces challenges that hinder its further development, such as limited response rates and poor tumor permeability. The efficiency of tumor immunotherapy is also closely linked to the structure and function of the immune microenvironment where the tumor resides. Recently, nanoparticle‐based tumor immune microenvironment (TIME) modulation strategies have attracted a great deal of attention in cancer immunotherapy. This is primarily due to the distinctive physical characteristics of nanoparticles, which enable them to effectively infiltrate the TIME and selectively modulate its key constituents. This paper reviews recent advances in nanoparticle engineering to improve anti‐cancer immunotherapy. Emerging nanoparticle‐based approaches for modulating immune cells, tumor stroma, cytokines and immune checkpoints are discussed, aiming to overcome current challenges in the clinic. In addition, integrating immunotherapy with various treatment modalities such as chemotherapy and photodynamic therapy can be facilitated through the utilization of nanoparticles, thereby enhancing the efficacy of cancer treatment. The future challenges and opportunities of using nanomaterials to reeducate the suppressive immune microenvironment of tumors are also discussed, with the aim of anticipating further advancements in this growing field. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost and important organisational impact. The literature has focused on their assessment, appraisal and market access solutions. No evidence on the costs sustained to implement CAR-T is available and a few studies reported the cost of the CAR-T clinical pathway, including the activities that are remunerated through inpatient or outpatient fee-for-service/episode. This paper aims at filling the information gap, assessing the cost of implementing CAR-T activity and the full cost of managing the CAR-T clinical pathway. Methods: Cost analysis relied on the Activity Based Costing approach, which was applied to two Italian healthcare organisations, both CAR-T Centres authorized by the regional governments with a minimum of 20 patients treated with the first two CAR-T therapies launched on the market. Results: The cost of implementing CAR-T was estimated at €1.31 million (calculated for one of the organizations with complete data). Most of these costs (77%) were generated by quality assurance activity. The mean cost per patient entering the CAR-T pathway (59 and 27) and surviving at follow-up (21 and 5) ranges from €48K to €57K and from €96K to €106K, respectively. Fees for hospitalization and infusion of gene therapy accounts for more than 70% of these costs. The actual hospitalisation cost varies greatly across patients and is in general lower than the fee-for-episode paid by the region to the hospital. Conclusions: Despite its limitations (exploratory nature; the time spent by staff on activities which are not remunerated through fees was estimated through interviews with the CAR-T coordinators; cost items are not fully comparable), this research highlighted the relevant organisational and economic impact of CAR-T and provided important insights for policy makers and healthcare managers: the necessity to invest resources in CAR-T implementation; the need for assessing activities which are not remunerated through fees for service / episode; the opportunity to shift from fee-for-episode / service to bundled payments for CAR-T clinical pathway. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its longterm efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

The tumor microenvironment, particularly the immune microenvironment, plays an indispensable role in the malignant progression and metastasis of gastric cancer (GC). As our understanding of the GC microenvironment continues to evolve, we are gaining deeper insights into the biological mechanisms at the single-cell level. This, in turn, has offered fresh perspectives on GC therapy. Encouragingly, there are various monotherapy and combination therapies in use, such as immune checkpoint inhibitors, adoptive cell transfer therapy, chimeric antigen receptor T cell therapy, antibody-drug conjugates, and cancer vaccines. In this paper, we review the current research progress regarding the GC microenvironment and summarize promising immunotherapy research and targeted therapies. [ABSTRACT FROM AUTHOR]

Although the efficacy of chimeric antigen receptor (CAR)-T cell therapy has been widely demonstrated, its clinical application is hampered by the complexity and fatality of its side effects. Cytokine release syndrome (CRS) is the most common toxicity following CAR-T cell infusion, and its symptoms substantially overlap with those of infection. Whereas, current diagnostic techniques for infections are time-consuming and not highly sensitive. Thus, we are aiming to develop feasible and efficient models to optimize the differential diagnosis in clinical practice. This study included 191 febrile patients from our center, including 85 with CRS-related fever and 106 with infectious fever. By leveraging the serum cytokine profile at the peak of fever, we generated differential models using a classification tree algorithm and a stepwise logistic regression analysis, respectively. The first model utilized three cytokines (IFN-β, CXCL1, and CXCL10) and demonstrated high sensitivity (90% training, 100% validation) and specificity (98.44% training, 90.48% validation) levels. The five-cytokine model (CXCL10, CCL19, IL-4, VEGF, and CCL20) also showed high sensitivity (91.67% training, 95.65% validation) and specificity (98.44% training, 100% validation). These feasible and accurate differentiation models may prompt early diagnosis of infections during immune therapy, allowing for early and appropriate intervention. [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]

Objectives: As emerging adoptive immunotherapy after CAR-T cell therapy, CAR-NK cell therapy has been developing rapidly in recent years. Presently, the research on CAR-NK cells has become a hotspot in the field of tumor immunotherapy. Methods: In this descriptive study, CtieSpace and VOSviewer were used to perform the bibliometric and scientific knowledge-map analysis of articles and reviews related to CAR-NK cells. Results: 5371 authors from 715 institutions in 65 countries published 1028 papers about CAR-NK cells in 346 journals. The number of publications related to CAR-NK cells was increasing overall, especially from 2018 to 2021. The United States was in a leading position. The most active institution was Univ Texas, MD Anderson Cancer Center (USA). The journal with the most publications was Frontiers in immunology, and the most co-cited journal was Blood. The researcher with the most published papers was Winfried S. Wels, while the most co-cited researcher was Shannon L Maude. The research of CAR-NK cells in hematological malignancies and solid tumors (especially the selection of targets and the evaluation of efficacy and safety) was a research hotspot in this field. The emerging topics mainly included three aspects. First, further improve the proliferation and persistence of NK cells in vivo. Secondly, optimizing and improving the CAR structure for NK cells to improve the antitumor ability of CAR-NK cells. Thirdly, the related research of CRISPR/Cas9 gene-editing technology in constructing engineered immune cells. Conclusion: In this study, a bibliometric and scientific knowledge-map study provided a unique and objective perspective for the CAR-NK cell field. This information would provide a helpful reference for researchers interested in this field. [ABSTRACT FROM AUTHOR]

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]

Autologous Chimeric antigen receptor (CAR‐T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long‐term response. Low CAR‐T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR‐T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose‐exposure relationships do not seem to exist for any of the currently approved CAR‐T cell products. In other words, dose increases have not led to a commensurate increase in the measurable in vivo frequency of transferred CAR‐T cells. Therefore, alternative approaches beyond dose titration are needed to optimize CAR‐T cell exposure. In this paper, we provide examples of actionable variables – design elements in CAR‐T cell discovery, development, and clinical practice, which can be modified to optimize autologous CAR‐T cell exposure. Most of these actionable variables can be assessed throughout the various stages of discovery and development as part of a well‐informed research and development program. Model‐informed drug development approaches can enable such study and program design choices from discovery through to clinical practice and can be an important contributor to cell therapy effectiveness and efficiency. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability. [ABSTRACT FROM AUTHOR]

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC. [ABSTRACT FROM AUTHOR]

Purpose: Chimeric antigen receptor T-cell (CART) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute and long-term toxicities. To understand the patient perspective, we measured a patient-reported outcome (PRO), specifically, health-related quality of life (HRQoL), at multiple time points over one year. Methods: This was a prospective feasibility study of a cohort of patients who were eligible for standard of care CART therapy, tisagenlecleucel. Demographic data and disease characteristics were collected. HRQoL was measured using FACT-Lym at baseline, and months 1, 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma subscale. Results: Thirty-four of 35 patients approached, consented to participate. Two of them did not receive their infusion due to progressive disease. 50% were female and median age was 62 (23–77). Twenty-nine patients (91%) completed baseline FACT-Lym and 20 of 21 (95%) eligible patients completed 12-month FACT-Lym. 52% completed all 4 post-baseline FACT-Lym measures. Exploratory analyses for changes in FACT-Lym scores are reported. Conclusion: It is feasible to measure longitudinal PROs in patients who receive CART therapy. This study will inform future studies in evaluating the patient perspective on CART therapy. [ABSTRACT FROM AUTHOR]

The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system, a groundbreaking innovation in genetic engineering, has revolutionized our approach to surmounting complex diseases, culminating in CASGEVY™ approved for sickle cell anemia. Derived from a microbial immune defense mechanism, CRISPR/Cas9, characterized as precision, maneuverability and universality in gene editing, has been harnessed as a versatile tool for precisely manipulating DNA in mammals. In the process of applying it to practice, the consecutive exploitation of novel orthologs and variants never ceases. It's conducive to understanding the essentialities of diseases, particularly cancer, which is crucial for diagnosis, prevention, and treatment. CRISPR/Cas9 is used not only to investigate tumorous genes functioning but also to model disparate cancers, providing valuable insights into tumor biology, resistance, and immune evasion. Upon cancer therapy, CRISPR/Cas9 is instrumental in developing individual and precise cancer therapies that can selectively activate or deactivate genes within tumor cells, aiming to cripple tumor growth and invasion and sensitize cancer cells to treatments. Furthermore, it facilitates the development of innovative treatments, enhancing the targeting efficiency of reprogrammed immune cells, exemplified by advancements in CAR-T regimen. Beyond therapy, it is a potent tool for screening susceptible genes, offering the possibility of intervening before the tumor initiative or progresses. However, despite its vast potential, the application of CRISPR/Cas9 in cancer research and therapy is accompanied by significant efficacy, efficiency, technical, and safety considerations. Escalating technology innovations are warranted to address these issues. The CRISPR/Cas9 system is revolutionizing cancer research and treatment, opening up new avenues for advancements in our understanding and management of cancers. The integration of this evolving technology into clinical practice promises a new era of precision oncology, with targeted, personalized, and potentially curative therapies for cancer patients. [ABSTRACT FROM AUTHOR]

This editorial, titled "Pharmacology of gangliosides," explores the potential of gangliosides as therapeutic targets and diagnostic biomarkers. Gangliosides are glycosphingolipids found on the surfaces of vertebrate cells and are involved in various diseases, including cancer, neurological disorders, infections, metabolic disorders, autoimmune diseases, and cardiovascular diseases. The editorial provides an overview of recent research on gangliosides, including their role as cancer biomarkers, targeted therapies, enhanced effect of immunotherapy, and drug delivery systems. It highlights the importance of further research into gangliosides in tumor biology and the exploration of other gangliosides beyond GD2 and GD3. The author contributions, funding, acknowledgments, conflict of interest, and publisher's note are also mentioned. [Extracted from the article]

Introduction: Fibroblast activation protein (FAP) overexpression on cancerassociated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP+ stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy. Methods: In this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAPpositive cells (hFAP-HT1080 cells and a variety of primary CAFs) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model. Results: Results showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT. Discussion: Taken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells. [ABSTRACT FROM AUTHOR]

Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model. Proton RT significantly increased MSLN expression in tumor cells and caused a significant increase in CAR T cell infiltration into tumors. The combination therapy reshaped the immunosuppressive TME, promoting antitumorigenic M1 polarized macrophages and reducing myeloid-derived suppressor cells (MDSC). In a flank PDAC model, the combination therapy demonstrated superior attenuation of tumor growth and improved survival compared to individual treatments alone. In an orthotopic PDAC model treated with image-guided proton RT, tumor growth was significantly reduced in the combination group compared to the RT treatment alone. Further, the combination therapy induced an abscopal effect in a dual-flank tumor model, with increased serum interferon-γ levels and enhanced proliferation of extratumoral CAR T cells. In conclusion, combining proton RT with MSLN-targeting CAR T therapy proves effective in modulating the TME, enhancing CAR T cell trafficking, and exerting systemic antitumor effects. Thus, this combinatorial approach could present a promising strategy for improving outcomes in unresectable PDAC. [ABSTRACT FROM AUTHOR]

T cell engagers (TCE) such as chimeric antigen receptor (CAR) T cell therapy and bispecific antibodies (BiAbs) for the treatment of multiple myeloma (MM) have significantly improved clinical outcomes, but have also raised awareness for ensuing post-treatment secondary immunodeficiency and hypogammaglobulinemia (HG). As patients with MM live longer, recurrent infections become a significant component of therapy-associated morbidity and mortality. Treatment of HG with immunoglobulin G replacement therapy (IgG-RT) has been a mainstay of the primary immunodeficiency (PI) world, and extrapolation to MM has recently started to show promising clinical outcomes. However, IgG-RT initiation, dosing, route, timing, monitoring, and management in MM has not been standardized in the setting of TCE. Progress in MM treatment will involve greater recognition and screening of underlying secondary immunodeficiency, identification of risk-stratification markers, optimizing IgG-RT management, and implementing other approaches to decrease the risk of infection. In this review, we summarize infection risk, risk of HG, and management strategies for IgG-RT in patients with relapsed MM after TCE. [ABSTRACT FROM AUTHOR]

Cell and gene therapies are an innovative solution to various severe diseases and unfulfilled needs. Adoptive cell therapy (ACT), a form of cellular immunotherapies, has been favored in recent years due to the approval of chimeric antigen receptor CAR-T products. Market research indicates that the industry’s value is predicted to reach USD 24.4 billion by 2030, with a compound annual growth rate (CAGR) of 21.5%. More importantly, ACT is recognized as the hope and future of effective, personalized cancer treatment for healthcare practitioners and patients worldwide. The significant global momentum of this therapeutic approach underscores the urgent need to establish it as a practical and standardized method. It is essential to understand how cell culture conditions affect the expansion and differentiation of T-cells. However, there are ongoing challenges in ensuring the robustness and reproducibility of the manufacturing process. The current study evaluated various adoptive T-cell culture platforms to achieve large-scale production of several billion cells and high-quality cellular output with minimal cell death. It examined factors such as bioreactor parameters, media, supplements and stimulation. This research addresses the fundamental challenges of scalability and reproducibility in manufacturing, which are essential for making adoptive T-cell therapy an accessible and powerful new class of cancer therapeutics. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains. We hypothesized that CAPs and CAR-TKs would be more potent than CARs because they would bypass both the steps that define the signaling threshold of TCRζ and the inhibitory regulation of upstream molecules. CAPs were too potent and exhibited high tonic signaling in vitro. In contrast, CAR-TKs exhibited high antitumor efficacy and significantly enhanced long-term tumor clearance in leukemia-bearing NSG mice as compared with the conventional CD19-28ζ-CAR-T cells. CAR-TKs were activated in a manner independent of the kinase Lck and displayed slower phosphorylation kinetics and prolonged signaling compared with the 28ζ-CAR. Lck inhibition attenuated CAR-TK cell exhaustion and improved long-term function. The distinct signaling properties of CAR-TKs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an antitumor chimeric receptor. Editor's summary: T cells that express chimeric antigen receptors (CARs) are therapeutically effective against only some types of cancers. Noting that downstream signaling molecules are recruited inefficiently to current CARs, Balagopalan et al. instead incorporated domains from these signaling proteins into the CAR itself. Inclusion of the kinase domain of ZAP70 to generate CAR tyrosine kinases resulted in cells with enhanced antitumor efficacy in mice compared with that of current CAR T cells. Thus, the signaling properties of CAR tyrosine kinases could be explored to enhance antitumor T cell efficacy. —John F. Foley [ABSTRACT FROM AUTHOR]

In recent years, in the development of emerging immunotherapy, B7‐H3 is also termed as CD276 and has become a novel chimeric antigen receptor (CAR)‐T target against glioma and other tumours, and aroused extensive attention. However, B7‐H3 has three isoforms (2, 3 and 4Ig) with the controversial expression and elusive function in tumour especially glioma. The current study mainly focuses on the regulatory factors and related mechanisms of generation of different B7‐H3 isoforms. First, we have determined that 2Ig is dominant in glioma with high malignancy, and 4Ig is widely expressed, whereas 3Ig shows negative expression in all glioma. Next, we have further found that RNA binding protein annexin A2 (ANXA2) is essential for B7‐H3 isoform maintenance, but fail to determine the choice of 4Ig or 2Ig. RNA methyltransferase NOP2/Sun RNA methyltransferase 2 (NSUN2) and 5‐methylcytosine reader Y‐box binding protein 1 (YBX1) facilitate the production of 2Ig. Our findings have uncovered a series of factors (ANXA2/NSUN2/YBX1) that can determine the alternative generation of different isoforms of B7‐H3 in glioma. Our result aims to help peers gain a clearer understanding of the expression and regulatory mechanisms of B7H3 in tumour patients, and to provide better strategies for designing B7H3 as a target in immunotherapy. [ABSTRACT FROM AUTHOR]

CAR T cells are widely applied for relapsed hematological cancer patients. With six approved cell therapies, for Multiple Myeloma and other B-cell malignancies, new insights emerge. Profound evidence shows that patients who fail CAR T-cell therapy have, aside from antigen escape, a more glycolytic and weakened metabolism in their CAR T cells, accompanied by a short lifespan. Recent advances show that CAR T cells can be metabolically engineered towards oxidative phosphorylation, which increases their longevity via epigenetic and phenotypical changes. In this review we elucidate various strategies to rewire their metabolism, including the design of the CAR construct, co-stimulus choice, genetic modifications of metabolic genes, and pharmacological interventions. We discuss their potential to enhance CAR T-cell functioning and persistence through memory imprinting, thereby improving outcomes. Furthermore, we link the pharmacological treatments with their anti-cancer properties in hematological malignancies to ultimately suggest novel combination strategies. [ABSTRACT FROM AUTHOR]

Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells. Editor's summary: Commonly used T cell therapies such as engineered T cell receptors (TCRs) and chimeric antigen receptors (CARs) have greatly improved outcomes for many patients; however, both still have their associated drawbacks. To overcome some of these limitations, Mog et al. have developed high-affinity antibody–expressing T cells that use a receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. They further show in vivo that these Co-STARs induce T cell expansion and induce long-term regression in mouse models with low densities of antigen, representing a promising strategy that requires further evaluation. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Tumor immune microenvironment (TIME) consists of intra-tumor immunological components and plays a significant role in tumor initiation, progression, metastasis, and response to therapy. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the cancer treatment paradigm. Although CAR-T cell immunotherapy has emerged as a successful treatment for hematologic malignancies, it remains a conundrum for solid tumors. The heterogeneity of TIME is responsible for poor outcomes in CAR-T cell immunotherapy against solid tumors. The advancement of highly sophisticated technology enhances our exploration in TIME from a multi-omics perspective. In the era of machine learning, multi-omics studies could reveal the characteristics of TIME and its immune resistance mechanism. Therefore, the clinical efficacy of CAR-T cell immunotherapy in solid tumors could be further improved with strategies that target unfavorable conditions in TIME. Herein, this review seeks to investigate the factors influencing TIME formation and propose strategies for improving the effectiveness of CAR-T cell immunotherapy through a multi-omics perspective, with the ultimate goal of developing personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to unprecedented treatment outcomes. Among CAR T therapies available, ciltacabtagene autoleucel (cilta-cel) is a good candidate for outpatient administration due to its generally predictable safety profile. There are multiple advantages of outpatient administration of cilta-cel, including reduced healthcare burden, expanded access, and patient autonomy. This mixed methods qualitative study aimed to identify key factors for outpatient administration of CAR T and best practice recommendations by combining a targeted literature review with expert interviews and panels. Methods: The targeted review (Phase 1) aimed to identify factors for outpatient CAR T administration in the US and determine key topics for the exploratory interviews (Phase 2) and expert panels (Phase 3), which aimed to inform on best practices and challenges of outpatient CAR T administration (focusing on ciltacel). Participants in clinical and administrative positions based in treatment centers that had experience with real-world outpatient administration of ciltacel were recruited. Results: Seventeen studies were identified in Phase 1. Key factors for outpatient administration included the development of protocols for CAR T complications, education for caregivers, outpatient specialists, hospital staff, and emergency services staff for identification and referral after possible adverse events, the creation of multidisciplinary teams for effective communication and management, straightforward patient intake processes encompassing financial eligibility review and provision of patient education materials, and close patient monitoring throughout the treatment journey. In Phase 2, 5 participants from 2 centers were interviewed. In Phase 3, 14 participants across 6 treatment centers were interviewed. Two 90-minute virtual panel discussions took place. All participants agreed that cilta-cel can be safely and effectively administered in an outpatient setting. Key recommendations included the creation of educational resources for patients and caregivers, the development of standard operating procedures, dedicated outpatient infrastructure and establishment of interdisciplinary teams, outpatient monitoring for toxicity management, and monitoring of the reimbursement landscape. Discussion: This study offers a comprehensive understanding of the feasibility of outpatient cilta-cel administration in participating CAR T centers and provides actionable recommendations while acknowledging existing challenges. [ABSTRACT FROM AUTHOR]

Metastasis causes greater than 90% of cancer-associated deaths, presenting huge challenges for detection and efficient treatment of cancer due to its high heterogeneity and widespread dissemination to various organs. Therefore, it is imperative to combat cancer metastasis, which is the key to achieving complete cancer eradication. Immunotherapy as a systemic approach has shown promising potential to combat metastasis. However, current clinical immunotherapies are not effective for all patients or all types of cancer metastases owing to insufficient immune responses. In recent years, immunological nanomaterials with intrinsic immunogenicity or immunomodulatory agents with efficient loading have been shown to enhance immune responses to eliminate metastasis. In this review, we would like to summarize various types of immunological nanomaterials against metastasis. Moreover, this review will summarize a series of immunological nanomaterial-mediated immunotherapy strategies to combat metastasis, including immunogenic cell death, regulation of chemokines and cytokines, improving the immunosuppressive tumour microenvironment, activation of the STING pathway, enhancing cytotoxic natural killer cell activity, enhancing antigen presentation of dendritic cells, and enhancing chimeric antigen receptor T cell therapy. Furthermore, the synergistic anti-metastasis strategies based on the combinational use of immunotherapy and other therapeutic modalities will also be introduced. In addition, the nanomaterial-mediated imaging techniques (e.g., optical imaging, magnetic resonance imaging, computed tomography, photoacoustic imaging, surface-enhanced Raman scattering, radionuclide imaging, etc.) for detecting metastasis and monitoring anti-metastasis efficacy are also summarized. Finally, the current challenges and future prospects of immunological nanomaterial-based anti-metastasis are also elucidated with the intention to accelerate its clinical translation. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T (CAR‐T) cell therapy has emerged as a potent treatment for relapsed or refractory multiple myeloma, demonstrating significant clinical efficacy. Despite these advances, treatment‐related toxicities, particularly infections, pose a significant challenge to patient safety. Methods: This review synthesizes current knowledge on the mechanisms underlying post‐CAR‐T therapy infections, focusing on the interplay between immune dysfunction, host factors, and treatment‐induced toxicity. It provides a comprehensive analysis of the temporal and individual variability in infection characteristics and the confounding clinical presentation of cytokine release syndrome. Results: The review identifies that patients receiving CAR‐T cells are at increased risk of concurrent infections due to the heterogeneity in infection characteristics across different time periods, individuals, and patient groups. It highlights the diagnostic and therapeutic complexities introduced by the overlapping symptoms of infection and cytokine release syndrome. Conclusion: To enhance the infection control post‐CAR‐T therapy, this review proposes preventive strategies tailored to the early and long‐term management of patients. It underscores the need for a nuanced understanding of infection mechanisms and the importance of personalized prevention plans to improve clinical outcomes in multiple myeloma treatment. [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor-expressing T cells (CAR T cells) have revolutionized cancer treatment, particularly in B cell malignancies. However, the use of autologous T cells for CAR T therapy presents several limitations, including high costs, variable efficacy, and adverse effects linked to cell phenotype. Methods: To overcome these challenges, we developed a strategy to generate universal and safe anti-CD19 CAR T cells with a defined memory phenotype. Our approach utilizes CRISPR/Cas9 technology to target and eliminate the B2M and TRAC genes, reducing graft-versus-host and host-versus-graft responses. Additionally, we selected less differentiated T cells to improve the stability and persistence of the universal CAR T cells. The safety of this method was assessed using our CRISPRroots transcriptome analysis pipeline, which ensures successful gene knockout and the absence of unintended off-target effects on gene expression or transcriptome sequence. Results: In vitro experiments demonstrated the successful generation of functional universal CAR T cells. These cells exhibited potent lytic activity against tumor cells and a reduced cytokine secretion profile. The CRISPRroots analysis confirmed effective gene knockout and no unintended off-target effects, validating it as a pioneering tool for on/off-target and transcriptome analysis in genome editing experiments. Discussion: Our findings establish a robust pipeline for manufacturing safe, universal CAR T cells with a favorable memory phenotype. This approach has the potential to address the current limitations of autologous CAR T cell therapy, offering a more stable and persistent treatment option with reduced adverse effects. The use of CRISPRroots enhances the reliability and safety of gene editing in the development of CAR T cell therapies. Conclusion: We have developed a potent and reliable method for producing universal CAR T cells with a defined memory phenotype, demonstrating both efficacy and safety in vitro. This innovative approach could significantly improve the therapeutic landscape for patients with B cell malignancies. [ABSTRACT FROM AUTHOR]

Approximately 50% of patients with hematologic malignancies relapse after chimeric antigen receptor (CAR) T cell treatment; mechanisms of failure include loss of CAR T persistence and tumor resistance to apoptosis. We hypothesized that both of these challenges could potentially be overcome by overexpressing one or more of the Bcl-2 family proteins in CAR T cells to reduce their susceptibility to apoptosis, both alone and in the presence of BH3 mimetics, which can be used to activate apoptotic machinery in malignant cells. We comprehensively investigated overexpression of different Bcl-2 family proteins in CAR T cells with different signaling domains as well as in different tumor types. We found that Bcl-xL and Bcl-2 overexpression in CAR T cells bearing a 4-1BB costimulatory domain resulted in increased expansion and antitumor activity, reduced exhaustion, and decreased apoptotic priming. In addition, CAR T cells expressing either Bcl-xL or a venetoclax-resistant Bcl-2 variant led to enhanced antitumor efficacy and survival in murine xenograft models of lymphoma and leukemia in the presence or absence of the BH3 mimetic venetoclax, a clinically approved BH3 mimetic. In this setting, Bcl-xL overexpression had stronger effects than overexpression of Bcl-2 or the Bcl-2(G101V) variant. These findings suggest that CAR T cells could be optimally engineered by overexpressing Bcl-xL to enhance their persistence while opening a therapeutic window for combination with BH3 mimetics to prime tumors for apoptosis. Editor's summary: A major issue with chimeric antigen receptor (CAR) T cell therapy is poor persistence of the CAR T cells. To address this, Korell et al. developed CAR T cells overexpressing members of the Bcl-2 family, proteins involved in protection from apoptosis. The authors found that overexpression of Bcl-xL in particular improved CAR T cell persistence and function in vivo and could be combined with the BH3 mimetic venetoclax to further improve tumor control in mice. Together, these data highlight a potential strategy to improve CAR T cell therapies as well as suggest a combination therapy with BH3 mimetics. —Courtney Malo [ABSTRACT FROM AUTHOR]

Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells. When used in CAR-T cell processing, the plant alkaloid berbamine prolongs the survival of leukemic animals by boosting CAR-T cell viability, memory phenotype, and persistence by modulating cellular metabolism, including mitochondrial respiration. [ABSTRACT FROM AUTHOR]

Background: The specific cytotoxic effects of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy have led to impressive outcomes in individuals previously treated for B-cell malignancies. However, the specific biological role of CD19(+) target cells, which exert antitumor immunity against some solid tumors, remains to be elucidated. Methods: We collected information regarding the level of CD19 mRNA and protein expression from various databases including The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA) for both tumor and normal samples. To evaluate the patient's prognosis according to CD19 expression, a Kaplan-Meier (KM) analysis and univariate Cox regression were performed. Furthermore, using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using the Expression Data (ESTIMATE) algorithm, we estimated the ratio of immune cells infiltrating malignant tumor tissues. Afterward, the GSCALite repository was employed to evaluate the vulnerability of tumors expressing CD19 to drugs used in chemotherapy. To validate the results in clinical samples of certain cancer types, immunohistochemistry was then performed. Results: Most tumor types exhibited CD19 expression differently, apart from colon adenocarcinoma (COAD). The early diagnostic value of CD19 has been demonstrated in 9 different tumor types, and the overexpression of CD19 has the potential to extend the survival duration of patients. Multiple tumors showed a positive correlation between CD19 expression and tumor mutation burden (TMB), microsatellite instability (MSI), and ESTIMATE score. Furthermore, a direct association was discovered between the expression of CD19 and the infiltration of immune cells, particularly in cases of breast invasive carcinoma (BRCA). Moreover, CD19 is highly sensitive to a variety of chemotherapy drugs. Conclusion: The study reveals the potential of CD19 as both a predictive biomarker and a target for different cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Lymphocyte collection by apheresis for CAR-T production usually does not include blood mobilized using granulocyte colony stimulating factor (G-CSF) due to the widespread knowledge that it causes a decrease in the number and functionality of lymphocytes. However, it is used for stem cell transplant, which is a common treatment for hematological malignancies. The growing demand for CAR therapies (CAR-T and NK-CAR), both in research and clinics, makes it necessary to evaluate whether mobilized PBSC products may be potential candidates for use in such therapies. This review collects recent works that experimentally verify the role and functionality of T and NK lymphocytes and the generation of CAR-T from apheresis after G-CSF mobilization. As discussed, T cells do not vary significantly in their phenotype, the ratio of CD4+ and CD8+ remains constant, and the different sub-populations remain stable. In addition, the expansion and proliferation rates are invariant regardless of mobilization with G-CSF as well as the secretion of proinflammatory cytokines and the cytotoxic ability. Therefore, cells mobilized before apheresis are postulated as a new alternative source of T cells for adoptive therapies that will serve to alleviate high demand, increase availability, and take advantage of the substantial number of existing cryopreserved products. [ABSTRACT FROM AUTHOR]

The anaplastic lymphoma kinase (ALK, CD247) is a potential target for antibody-based therapy. However, no antibody-based therapeutics targeting ALK have entered clinical trials, necessitating the development of novel antibodies with unique therapeutic merits. Single-domain antibodies (sdAb) bear therapeutic advantages compared to the full-length antibody including deeper tumor penetration, cost-effective production and fast washout from normal tissues. In this study, we identified a human immunoglobulin heavy chain variable domain (VH domain) (VH20) from an in-house phage library. VH20 exhibits good developability and high specificity with no off-target binding to ~6000 human membrane proteins. VH20 efficiently bound to the glycine-rich region of ALK with an EC50 of 0.4 nM and a KD of 6.54 nM. Both VH20-based bispecific T cell engager (TCE) and chimeric antigen receptor T cells (CAR Ts) exhibited potent cytolytic activity to ALK-expressing tumor cells in an ALK-dependent manner. VH20 CAR Ts specifically secreted proinflammatory cytokines including IL-2, TNFα and IFNγ after incubation with ALK-positive cells. To our knowledge, this is the first reported human single-domain antibody against ALK. Our in vitro characterization data indicate that VH20 could be a promising ALK-targeting sdAb with potential applications in ALK-expressing tumors, including neuroblastoma (NBL) and non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66–12.42) and liso-cel (OR:4.26; 95%CrI:2.33–7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37–0.79) and tisa-cel (HR:0.47; 95%CrI:0.26–0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel. [ABSTRACT FROM AUTHOR]

Tumor immune escape refers to the inability of the immune system to clear tumor cells, which is one of the major obstacles in designing effective treatment schemes for cancer diseases. Although clinical studies have led to promising treatment outcomes, it is imperative to design theoretical models to investigate the long-term treatment effects. In this paper, we develop a mathematical model to study the interactions among tumor cells, immune escape tumor cells, and T lymphocyte. The chimeric antigen receptor (CAR) T-cell therapy is also described by the mathematical model. Bifurcation analysis shows that there exists backward bifurcation and saddle-node bifurcation when the immune intensity is used as the bifurcation parameter. The proposed model also exhibits bistability when its parameters are located between the saddle-node threshold and backward bifurcation threshold. Sensitivity analysis is performed to illustrate the effects of different mechanisms on the backward bifurcation threshold and basic immune reproduction number. Simulation studies confirm the bifurcation analysis results and predict various types of treatment outcomes using different CAR T-cell therapy strengths. Analysis and simulation results show that the immune intensity can be used to control the tumor size, but it has no effect on the control of the immune escape tumor size. The introduction of the CAR T-cell therapy will reduce the immune escape tumor size and the treatment effect depends on the CAR T-cell therapy strength. [ABSTRACT FROM AUTHOR]

Tumour spheroids are widely used in immune cell cytotoxicity assays and anticancer drug testing, providing a physiologically relevant model replicating the tumour microenvironment. However, co-culture of immune and tumour cells complicates quantification of immune cell killing efficiency. We present a novel 3D hanging spheroid-filter plate that efficiently facilitates spheroid formation and separates unbound/dead cells during cytotoxicity assays. Optical imaging directly measures the cytotoxic effects of anti-cancer drugs on tumour spheroids, eliminating the need for live/dead fluorescent staining. This approach enables cost-effective evaluation of T-cell cytotoxicity with specific chimeric antigen receptors (CARs), enhancing immune cell-based assays and drug testing in three-dimensional tumour models. [ABSTRACT FROM AUTHOR]

Leukocyte recruitment from blood to tissue is a process that occurs at the level of capillary vessels during both physiological and pathological conditions. This process is also relevant for evaluating novel adoptive cell therapies, in which the trafficking of therapeutic cells such as chimeric antigen receptor (CAR)-T cells throughout the capillaries of solid tumors is important. Local variations in blood flow, mural cell concentration, and tissue stiffness contribute to the regulation of capillary vascular permeability and leukocyte trafficking throughout the capillary microvasculature. We developed a platform to mimic a biologically functional human arteriole–venule microcirculation system consisting of pericytes (PCs) and arterial and venous primary endothelial cells (ECs) embedded within a hydrogel, which self-assembles into a perfusable, heterogeneous microvasculature. Our device shows a preferential association of PCs with arterial ECs that drives the flow-dependent formation of microvasculature networks. We show that PCs stimulate basement membrane matrix synthesis, which affects both vessel diameter and permeability in a manner correlating with the ratio of ECs to PCs. Moreover, we demonstrate that hydrogel concentration can affect capillary morphology but has no observed effect on vascular permeability. The biological function of our capillary network was demonstrated using an inflammation model, where significantly higher expression of cytokines, chemokines, and adhesion molecules was observed after tumor necrosis factor-alpha (TNF-α) treatment. Accordingly, T cell adherence and transendothelial migration were significantly increased in the immune-activated state. Taken together, our platform allows the generation of a perfusable microvasculature that recapitulates the structure and function of an in vivo capillary bed that can be used as a model for developing potential immunotherapies. [ABSTRACT FROM AUTHOR]

During pre-approval clinical trials, the safety of axi-cel, a second-generation CAR-T-cell therapy directed against CD19, which dramatically improved the prognosis of intractable B-cell lymphomas, has been investigated only in about 400 patients. Therefore, additional information on this issue is urgently needed. In the present paper, we evaluated the 2905 ICSRs with axi-cel as the suspected drug that had been uploaded in the EudraVigilance database from 1 January 2018 to 31 December 2022. About 80% of the reported adverse events were serious, and about 20% of them did not fully resolve or caused death. The adverse events most-frequently reported were Nervous system disorders (25.6%) and, among them, immune-effector-cell-associated neurotoxicity syndrome, followed by Immune system disorders (23.1%), General disorders and administration site conditions (12.0%), Blood and lymphatic system disorders (7.2%), and Infections and infestations (5.8%). Disproportionality analysis showed that the frequency of reported adverse events related to the nervous system was higher with axi-cel than with the other approved CAR-T-cells, except brexu-cel. In conclusion, real-world pharmacovigilance data showed that nervous system and immune system disorders are the adverse events most reported in axi-cel-related ICSRs and suggest that axi-cel could be more neurotoxic than other CAR-T-cells. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising modality for anti-cancer treatment. Its efficacy is quite remarkable in hematological tumors. Owing to their excellent clinical results, gene- modified cell therapies, including T cells, natural killer (NK) cells, and macrophages, are being actively studied in both academia and industry. However, the protocol to make CAR immune cells is too complicated, so it is still unclear how to efficiently produce the potent CAR immune cells. To manufacture effective CAR immune cells, we need to be aware of not only how to obtain highly infective viral particles, but also how to transduce CAR genes into immune cells. In this paper, we provide detailed information on spinoculation, which is one of the best known protocols to transduce genes into immune cells, in a methodological view. Our data indicate that gene transduction is significantly dependent on speed and duration of centrifugation, concentration and number of viral particles, the concentration of polybrene, and number of infected immune cells. In addition, we investigated on the optimal polyethylene glycol (PEG) solution to concentrate the viral supernatant and the optimized DNA ratios transfected into 293T cells to produce high titer of viral particles. This study provides useful information for practical production of the gene-modified immune cells using viral vectors. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T cells treatment targeting B cell maturation antigen (BCMA) is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) and has demonstrated outstanding outcomes in clinical studies. Objective: The aim of this comprehensive review and meta-analysis was to summarize the effectiveness and safety of anti-BCMA CAR-T treatment for patients with relapsed/refractory multiple myeloma (RRMM). Our research identifies variables influencing outcome measures to provide additional evidence for CAR-T product updates, clinical trial design, and clinical treatment guidance. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard was followed for conducting this comprehensive review and meta-analysis, which was submitted to PROSPERO (CRD42023390037). From the inception of the study until 10 September 2022, PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and WanFang databases were searched for eligible studies. Stata software (version 16.0) was used to assess effectiveness and safety outcomes. Results: Out of 875 papers, we found 21 relevant trials with 761 patients diagnosed as RRMM and were given anti-BCMA CAR-T treatment. The overall response rate (ORR) for the entire sample was 87% (95% CI: 80-93%) complete response rate (CRR) was 44% (95% CI: 34-54%). The minimal residual disease (MRD) negativity rate within responders was 78% (95% CI: 65-89%). The combined incidence of cytokine release syndrome was 82% (95% CI: 72-91%) and neurotoxicity was 10% (95% CI: 5%-17%). The median progression-free survival (PFS) was 8.77 months (95% CI: 7.48-10.06), the median overall survival (OS) was 18.87 months (95% CI: 17.20-20.54) and the median duration of response (DOR) was 10.32 months (95% CI: 9.34-11.31). Conclusion: According to this meta-analysis, RRMM patients who received anti-BCMA CAR-T treatment have demonstrated both effectiveness and safety. Subgroup analysis confirmed the anticipated inter-study heterogeneity and pinpointed potential factors contributing to safety and efficacy, which may help with the development of CAR-T cell studies and lead to optimized BCMA CART-cell products. [ABSTRACT FROM AUTHOR]

This paper introduces a new approach to evaluate the influence of anti‐reflective and anti‐glare surface treatments on the readability of automotive displays. A car simulator was equipped with an illumination setup to mimic real ambient light scenarios. During the experiments we measured the ability of the driver to collect information from the display while driving. Our results validate this approach and demonstrate that the choice of surface treatment depends on the scenarios considered by the car manufacturers. [ABSTRACT FROM AUTHOR]