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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]

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]

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]

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]

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]

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]

Kaiser et al. offer management recommendations for transplant‐eligible, high‐risk multiple myeloma (HRMM), derived from recent trials exploring treatment intensification in the various phases of front‐line therapy. The definition of HRMM continues to evolve with emergence of novel genomic insights and impact of modern therapies, underscoring the need to expand beyond traditional interphase fluorescence in situ hybridization cytogenetics and International Staging System staging for a precise risk assessment. Despite progress, ongoing challenges in treatment delivery and tolerability underscore the urgency for exploring novel approaches like T‐cell redirecting bispecific antibodies and chimeric antigen receptor T‐cell to enhance outcomes in this complex patient population.Commentary on: Kaiser et al. Diagnosis and initial treatment of transplant‐eligible high‐risk myeloma patients: A British Society for Haematology/UK Myeloma Society Good Practice Paper. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19623 [ABSTRACT FROM AUTHOR]

Background: The AABB compiles an annual synopsis of the published literature covering important developments in the field of transfusion medicine. An abridged version of this work is being made available in TRANSFUSION, with the full-length report available as Appendix S1 (available as supporting information in the online version of this paper).Study Design and Methods: Papers published in late 2017 and 2018 are included, as well as earlier papers cited for background. Although this synopsis is comprehensive, it is not exhaustive, and some papers may have been excluded or missed.Results: The following topics are covered: "big data" and "omics" studies, emerging infections and testing, platelet transfusion and pathogen reduction, transfusion therapy and coagulation, transfusion approach to hemorrhagic shock and mass casualties, therapeutic apheresis, and chimeric antigen receptor T-cell therapy.Conclusion: This synopsis may be a useful educational tool. [ABSTRACT FROM AUTHOR]

In their paper, the authors present their experience with the use of chimeric antigen receptor T cells targeting CD7 as a bridge to allogeneic haematopoietic cell transplantation in patients with relapsed/refractory T‐cell acute lymphoblastic leukaemia/lymphoblastic lymphoma. Commentary on: Cao et al. A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T‐cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T‐cell therapy. Br J Haematol 2024;204:2351‐2364. [ABSTRACT FROM AUTHOR]

Coherent anti‐Stokes Raman scattering (CARS) is a versatile technique for vibrational imaging that can be realized by a simple setup using a single femtosecond laser oscillator. For such a layout, supercontinuum generation in a photonic crystal fiber (PCF) is commonly used to produce a broadband Stokes beam in the so‐called multiplex CARS spectroscopy; accordingly, characterization of the supercontinuum beam is a necessary requirement to perform controlled experiments. In this paper, we first perform simulations and characterizations of the supercontinuum spectra produced by a PCF in conditions encountered in a typical single‐oscillator multiplex CARS setup. Good agreement between the experimental and simulated supercontinuum spectra is obtained in the whole emission band and for different PCF working conditions, by accurate choice of the simulation input parameters and by accounting for the input beam chirp in the numerical code. The influence of PCF working conditions on the CARS signal measured on a reference sample is also shown. To this regard, we also study the long‐term stability of the Stokes beam and of the associated CARS signal, using the Allan variance to determine a limit to the acquisition time in CARS measurements. We show that Stokes and CARS long‐term spectral fluctuations are on a timescale of some minutes in our setup, setting an indicative limit to the practical acquisition time for reliable CARS measurements. Based on this work, good control over the measurement of vibrational bands by CARS microscopy can be achieved in view of optimized performances in specific spectral bands. [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]

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]

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs. [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]

Summary: CD19‐directed treatment in B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) frequently leads to the downmodulation of targeted antigens. As multicolour flow cytometry (MFC) application for minimal/measurable residual disease (MRD) assessment in BCP‐ALL is based on B‐cell compartment study, CD19 loss could hamper MFC‐MRD monitoring after blinatumomab or chimeric antigen receptor T‐cell (CAR‐T) therapy. The use of other antigens (CD22, CD10, CD79a, etc.) as B‐lineage gating markers allows the identification of CD19‐negative leukaemia, but it could also lead to misidentification of normal very‐early CD19‐negative BCPs as tumour blasts. In the current study, we summarized the results of the investigation of CD19‐negative normal BCPs in 106 children with BCP‐ALL who underwent CD19 targeting (blinatumomab, n = 64; CAR‐T, n = 25; or both, n = 17). It was found that normal CD19‐negative BCPs could be found in bone marrow after CD19‐directed treatment more frequently than in healthy donors and children with BCP‐ALL during chemotherapy or after stem cell transplantation. Analysis of the antigen expression profile revealed that normal CD19‐negative BCPs could be mixed up with residual leukaemic blasts, even in bioinformatic analyses of MFC data. The results of our study should help to investigate MFC‐MRD more accurately in patients who have undergone CD19‐targeted therapy, even in cases with normal CD19‐negative BCP expansion. [ABSTRACT FROM AUTHOR]

In late 2017, the Food and Drug Administration (FDA) approved CD19 CAR T-cell therapy for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Since 2017, two anti-CD19 CAR T-cell therapy products, axicabtagene ciloleucel and tisagenlecleucel, have been approved by the FDA for the treatment of relapsed or refractory large B-cell lymphoma after the failure of two lines of systemic therapy (Nair & Neelapu, [15]). CAR T-cell therapy's potential for the treatment of autoimmune diseases such as APLS is based on its ability to specifically target the B cells that produce the autoantibodies causing these diseases. In conclusion, we report a patient with refractory DLBCL who was also undergoing lifelong anticoagulation therapy for APLS, and whose DLBCL and APLS remissions are likely attributable to CAR T-cell therapy. [Extracted from the article]

Background: Little was known on infection and mortality rates, still less the risk factors of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) omicron variant in B‐cell lymphoma patients following CD19 targeted chimeric antigen receptor T cell (CAR‐T). Aims: We performed a retrospective multicenter study and analyzed the details of relapsed/refractory (R/R) B‐cell lymphoma patients who received CD19 targeted CAR‐T heretofore in five cellular immunotherapy centers in China during the omicron wave. Materials & Methods: One hundred fifty‐four patients were enrolled in this study. Results: Among them, 52 patients (33.8%) were uninfected, 74 patients (48.1) had ambulatory mild disease (including nine patients of asymptomatic infection), 22 patients (14.3%) had moderate disease and six patients (3.9%) had severe disease when data collected up. Three patients with severe disease died from COVID‐19, the death rate was 1.9% for all enrolled patients, and 2.9% for infected patients. We also found that patients over 60 years old or with diabetes mellitus (DM) tend to develop severe disease (p = 0.0057 and p = 0.0497, respectively). Patients had CAR‐T infusion within 6 months also tend to have severe disease (p = 0.0011). In multivariate logistic regression model, CAR‐T infusion within 6 months (relative risk (RR) 40.92; confidence interval (CI) 4.03–415.89; p = 0.002) were associated with significantly higher risk of severe disease. Conclusion: Through this study, we conclude that the outcome for B‐cell lymphoma patients following CD19 targeted CAR‐T therapy when facing omicron infection was improved, but aggressive precautionary measures were particularly crucial for patients with high risk factors. [ABSTRACT FROM AUTHOR]

Background: The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR‐T) cells in the management of acute lymphoblastic leukemia (ALL) and non‐Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR‐T‐cell persistence are the leading causes of progressive disease following single‐antigen targeting, we evaluated CD22/CD19 dual‐targeting CAR‐T‐cell therapy efficacy and safety in relapsed/refractory B‐cell malignancies. Methods: The Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B‐cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19‐dual‐targeting CAR‐T‐cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random‐effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis. Results: Fourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1‐year proportions of overall survival (OS) and progression‐free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1‐year OS and 1‐year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual‐targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19‐CAR‐T cells and third‐generation CAR‐T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment‐related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively. Conclusions: Our meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies. This meta‐analysis demonstrates very high responses by using dual‐targeting CAR‐T therapy with a tolerable safety profile in treating R/R B‐cell hematologic malignancies.Although further studies are warranted, these findings may help immunologists and clinicians design proper CAR structure and/or combine with important target therapies to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

The robust and stable expression of CD38 in T‐cell acute lymphoblastic leukemia (T‐ALL) blasts makes CD38 chimeric antigen receptor (CAR)‐T/natural killer (NK) a potential therapy for T‐ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR‐T/NK cells. Here a "2‐in‐1" gene editing strategy is developed to generate fratricide‐resistant locus‐specific CAR‐T/NK cells. CD38‐specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI) or exogenous EF1α promoter (CD38KO/KIEF1α). CD38 knockout reduces fratricide and allows the expansion of CAR‐T cells. Meanwhile, CD38KO/KIEF1α results in higher CAR expression than CD38KO/KI in both CAR‐T and CAR‐NK cells. In a mouse T‐ALL model, CD38KO/KIEF1α CAR‐T cells eradicate tumors better than CD38KO/KI CAR‐T cells. Surprisingly, CD38KO/KI CAR‐NK cells show superior tumor control than CD38KO/KIEF1α CAR‐NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR‐T and CAR‐NK cells differently. Therefore, these results support the efficacy of CD38 CAR‐T/NK against T‐ALL and demonstrate that the "2‐in‐1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy (ACT) is a rapidly growing anti-cancer strategy that has shown promise in treating various cancer types. The concept of ACT involves activating patients' own immune cells ex vivo and then transferring them back to the patients to recognize and eliminate cancer cells. Currently, the commonly used ACT includes tumor-infiltrating lymphocytes (TILs), genetically engineered immune cells, and dendritic cells (DCs) vaccines.With the advancement of cell culture and genetic engineering techniques, ACT has been used in clinics to treat malignant hematological diseases and many new ACT-based regimens are in different stages of clinical trials. Here, representative ACT approaches are introduced and the opportunities and challenges for clinical translation of ACT are discussed. [ABSTRACT FROM AUTHOR]

Aims: Mesothelin (MSLN) is a cancer‐associated antigen that is overexpressed in malignancies such as mesothelioma, pancreatic and ovarian cancer. It is also a target for novel personalised therapies, including antibodies, antibody–drug conjugates and chimeric antigen receptor T cells. Immunohistochemistry may predict those who would best respond to anti‐mesothelin therapies and guide decisions in therapeutic strategy. This study aimed to assess the intensity and distribution of MSLN immunostaining in mesothelioma, and to determine the prognostic value of MSLN expression by histochemical‐score (H‐score). Methods and results: The MN1 anti‐MSLN antibody was used to stain a formalin‐fixed paraffin‐embedded tissue microarray of histologically confirmed mesothelioma from 75 consecutive patients who had undergone pleurectomy with or without decortication. MSLN positivity, the staining intensity, distribution of staining and H‐score were evaluated. The correlation of H‐score with prognosis was investigated. Sixty‐six per cent of epithelioid tumours were MSLN‐positive (with expression in > 5% tumour cells). Of MSLN‐expressing epithelioid tumours, 70.4% had moderate (2+) or strong (3+) intensity MSLN immunostaining, although only 37% of samples had staining in ≥ 50% of tumour cells. In multivariate analysis, MSLN H‐score as a continuous variable and an H‐score ≥ 33 were independent predictors of improved survival (P = 0.04 and P < 0.001, respectively). Conclusions: MSLN expression was more heterogenous in epithelioid mesothelioma than reported previously. Therefore, it would be appropriate to perform an immunohistochemical assessment of MSLN expression to stratify and assess patient suitability for mesothelin‐targeted personalised therapies, such as chimeric antigen receptor T cells. [ABSTRACT FROM AUTHOR]

Summary: For successful chimeric antigen receptor T (CAR‐T) cell therapy, CAR‐T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR‐T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B‐cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104/μL; p = 0.01) and CD4/CD8 T‐cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (

Summary: Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T‐cell therapy, an emerging therapy for relapsed or refractory diffuse large B‐cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the 'niche'. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271+ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T‐cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271+ niche cells were severely impaired after CAR T‐cell infusion in patients with PC. Cytokine analyses after CAR T‐cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation‐related cytokines on day 28 after CAR T‐cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation‐related cytokines in the BM following CAR T‐cell infusion are associated with subsequent PC. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8–13.6] vs. 14.1 [95% CI: 10–18.1] months, p =.126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5–18.2] vs. 18.4 [95% CI 14.8–22.1] months, p =.100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9–15.5] vs. 4.28 months [95% CI 0.6–7.9], p =.010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4–19.6] vs. 8.7 months [95% CI 4.6–12.8], p =.05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p =.021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis. [ABSTRACT FROM AUTHOR]

Despite substantial advancements in development of cancer treatments, lack of standardized and physiologically‐relevant in vitro testing platforms limit the early screening of anticancer agents. A major barrier is the complex interplay between the tumor microenvironment and immune response. To tackle this, a dynamic‐flow based 3D bioprinted multi‐scale vascularized breast tumor model, responding to chemo and immunotherapeutics is developed. Heterotypic tumors are precisely bioprinted at pre‐defined distances from a perfused vasculature, exhibit tumor angiogenesis and cancer cell invasion into the perfused vasculature. Bioprinted tumors treated with varying dosages of doxorubicin for 72 h portray a dose‐dependent drug response behavior. More importantly, a cell based immune therapy approach is explored by perfusing HER2‐targeting chimeric antigen receptor (CAR) modified CD8+ T cells for 24 or 72 h. Extensive CAR‐T cell recruitment to the endothelium, substantial T cell activation and infiltration to the tumor site, resulted in up to ≈70% reduction in tumor volumes. The presented platform paves the way for a robust, precisely fabricated, and physiologically‐relevant tumor model for future translation of anti‐cancer therapies to personalized medicine. [ABSTRACT FROM AUTHOR]

Cell‐based immunotherapy, for example, chimeric antigen receptor T (CAR‐T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR‐based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR‐T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR‐T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR‐T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME‐associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME‐associated factors. Lastly, the future directions for engineering efficient CAR‐T cells for solid tumour therapy will be discussed. [ABSTRACT FROM AUTHOR]

In December 2021, three phase III trials investigating Chimeric Antigen Receptor (CAR) T‐cell for large B‐cell lymphoma were published, only one of which showed no treatment effect on Event‐Free Survival (EFS). All compared anti‐CD19 CAR T‐cell as second‐line treatment with immunochemotherapy plus autologous stem cell transplant if an adequate response to chemotherapy was achieved. In this letter, we discuss the methodological reasons that partially explain the discrepant results observed between the ZUMA‐7, TRANSFORM and BELINDA trials. A raw comparison shows that BELINDA simultaneously had the worst experimental arm and the best control arm among the three trials. This could be partially related to differences in the event definition and time of assessment. Stable Disease was considered an event as early as W9 in TRANSFORM, W12 in BELINDA and only W21 in ZUMA‐7. Since tisa‐cel had the longest manufacturing time, the time window may have been too short to assess its full potential compared with axi‐cel and liso‐cel. In comparison, a patient with stable disease in ZUMA‐7 would not be considered an event until W21. On the other hand, a second salvage regimen was allowed before considering stable disease as an event only in the BELINDA control arm which could have delayed EFS. Many of these issues could be avoided if progression‐free survival was preferred to EFS and if the time to manufacture CAR‐T cells was shortened, as long delays can result in a higher tumor volume and more refractory diseases at the time of infusion. [ABSTRACT FROM AUTHOR]

Genetically arming new chimeric antigen receptors (CARs) on T cells is a prevalent method to fulfill CAR‐T immunotherapy. However, this approach fails to completely address the poor infiltration, complex immunosuppressive tumor microenvironment (ITM), and insufficient immune cells, which are recognized as the three dominant hurdles to discouraging the trafficking and persistence of CAR‐T and immune checkpoint blockade (ICB) immunotherapies against solid tumors. To address the three hurdles, a sonoimmunity‐engineered nanoplatform is designed in which a rattle‐type‐structured carrier enables intraparticle‐double‐scattering to generate massive reactive oxygen species (ROS) during the sonodynamic process. Abundant ROS accumulation can directly kill tumor cells, release antigens, and activate systematic immune responses for expanding effector T or CAR‐T cells, while alleviating ITM via immunosuppressive macrophage polarization and reduction in pro‐tumorigenic cytokine secretion. Furthermore, the co‐loaded phosphodiesterase‐5 inhibitors release nitric oxide (NO) to impel vascular normalization and open the infiltration barrier (IB) for allowing more T cells to enter into the tumor. Systematic experiments demonstrate the feasibility of such intraparticle‐double‐scattering‐decoded sonogenetics in the sonoimmunity‐engineered nanoplatforms for expanding effector T or CAR‐T cells, thereby promoting their infiltration into tumors and alleviating ITM. These compelling actions lead to excellent CAR‐T and ICB immunotherapies against solid tumors with repressed tumor metastasis. [ABSTRACT FROM AUTHOR]

Advances in immuno‐oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno‐therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non‐solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno‐therapies, especially CAR‐T cells. Here, we summarize the current knowledge of TCR and CAR‐T cell immunotherapy with particular focus on the structure of CAR‐T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR‐T cell therapies are described. [ABSTRACT FROM AUTHOR]

Summary: Treatment with high‐dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered standard of care (SOC) second‐line treatment for relapsed or refractory large B‐cell lymphoma (LBCL). However, outcomes remain suboptimal. A systematic review and meta‐analysis of randomised controlled trials comparing efficacy and safety of SOC versus chimeric antigen receptor T‐cell (CAR‐T) therapy as second‐line for patients with LBCL refractory or relapsing within 12 months. Outcomes included overall survival (OS), event‐free survival (EFS), overall response rate (ORR) and safety. Three trials published in 2021 (involving 865 participants) fulfilled the eligibility criteria. EFS as well as OS were significantly improved with CAR‐T therapy as compared to SOC, hazard ratio (HR) 0.57 (95% confidence interval [CI] 0.49–0.68) and HR 0.77 (95% CI 0.60–0.98) respectively. CAR‐T therapy was associated with significantly better ORR, relative risk (RR) 1.55 (95% CI 1.12–2.13, p = 0.001). The risk of Grade III/IV adverse event was comparable between the two arms, RR 1.03 (95% CI 0.93–1.14). In summary, CAR‐T therapy has superior outcomes as compared to SOC in patients with LBCL refractory or relapsing within 12 months, without excess of toxicity. Longer follow‐up is needed to confirm these results and determine the optimal sequencing of CAR‐T therapy in the management of LBCL. [ABSTRACT FROM AUTHOR]

Background: Kidney cancer is one of the most common solid tumors. The advancement of human kidney cancer research and treatment has been hindered by a lack of research models that faithfully recapitulate the diversity of the disease. Methods: We established an effective three‐dimensional culture system for generating kidney cancer organoids from clinical renal cell carcinoma samples. Renal cell carcinoma (RCC) organoids were characterized by H&E staining, immunofluorescence, whole‐exome sequencing, RNA sequencing and single‐cell RNA sequencing. The use of RCC organoids in personalized cancer therapy was assessed by testing their responses to treatment drugs and chimeric antigen receptor T cells. Results: Using this organoid culture system, 33 kidney cancer organoid lines from common kidney cancer subtypes, including clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC), were generated. RCC organoids preserved the histological architectures, mutational landscapes, and transcriptional profile of the parental tumor tissues. Single‐cell RNA‐sequencing revealed inter‐ and intra‐tumoral heterogeneity in RCC organoids. RCC organoids allowed for in vitro drug screening and provided a tool for assessing the efficacy of chimeric antigen receptor T cells. Conclusions: Patient‐derived RCC organoids are valuable pre‐clinical models for academic research and personalized medicine. [ABSTRACT FROM AUTHOR]

Advances made in chimeric antigen receptor (CAR) T cell therapy have revolutionized the treatment and management of certain cancers. Currently, B cell malignancies have been among the few cancers to which CAR T cells have shown persistent and resilient anti‐tumor responses. A growing body of evidence suggests that the persistence of CAR T cells within patients following infusion is linked to the mitochondrial fitness of the CAR T cell, which could affect clinical outcomes. Analysis of CAR T cells from patients undergoing successful treatment has shown an increase in mitochondrial mass and fusion events, and a reduction in aerobic metabolism, highlighting the importance of mitochondria in CAR T cell function. Consequently, there has been recent interest and investment in approaches that focus on mitochondrial programming. In this regard, miRNAs are promising agents in mitochondrial reprogramming for several reasons: (1) natural and artificial miRNAs are non‐immunogenic, (2) one miRNA can simultaneously modulate the expression of multiple genes within a pathway, (3) the small size of a sequence required for producing mature miRNA is ideal for use in viral vectors and (4) different precursor miRNAs (pre‐miRNAs) hairpins can be incorporated into a polycistronic miRNA cluster to create a miRNA cocktail. In this perspective, we describe the latest genetic engineering strategies that can be used to achieve the optimal expression of candidate miRNAs alongside a CAR construct. In addition, we include an in silico analysis of rational candidate miRNAs that could promote the mitochondrial fitness of CAR T cells. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T (CAR‐T) cell successes have encouraged continued clinical study. Apheresis collection of starting material for CAR‐T cell therapy product manufacturing is critical but described approaches suggest variability and clinical guidelines are currently lacking. The goal of this study was to gather and assess variability in apheresis collection descriptions in publicly available CAR T‐cell therapy clinical trials. Study design: We searched clinicaltrials.gov (a publicly available clinical trial database) for "chimeric antigen receptor T cells" on July 01, 2020 and studies accessed July 30, 2020‐August 15, 2020. Data collected included date posted, study characteristics, apheresis mentions (number, location, and context), laboratory parameters and transfusion allowances. Apheresis context was analyzed using a qualitative inductive approach of grounded theory method with open coding. Text was classified into 37 context codes, grouped into 12 categories, and then consolidated into patient, procedure, product, and miscellaneous themes. Results: Apheresis was mentioned 1044 times in 322 (51.9%) of 621 total studies. Laboratory parameters mentioned included white blood cells (100 studies), absolute neutrophil count (220 studies), absolute lymphocyte count (102 studies), CD3+ cell (38 studies), hemoglobin (233 studies, 54 studies specified transfusion allowance), and platelet (269 studies, 48 studies specified transfusion allowance). Conclusions: Apheresis collection of CAR‐T cell products is not well‐defined in clinical study descriptions and the context is inconsistent. Laboratory parameters useful for apheresis collection are variably present and do not consistently align with current practices. Further exploration, and clinical guideline development will encourage alignment of apheresis collections for CAR‐T cell products. [ABSTRACT FROM AUTHOR]

Although chimeric antigen receptor (CAR) T cells have demonstrated significant promise in suppressing hematopoietic cancers, their applications in treating solid tumors have been limited by onset of CAR T cell exhaustion that accompanies continuous CAR T cell exposure to tumor antigen. To address this limitation, we have exploited the abilities of recently designed universal CARs to bind fluorescein and internalize a fluorescein‐TLR7 agonist conjugate by CAR‐mediated endocytosis. We demonstrate here that anti‐fluorescein CAR‐mediated uptake of a fluorescein‐TLR7‐3 conjugate can reactivate exhausted CAR T cells, leading to dramatic reduction in T cell exhaustion markers (PD‐1+Tim‐3+) and shrinkage of otherwise resistant tumors without inducing systemic activation of the immune system. We conclude that CAR T cell exhaustion can be reversed by administration of a CAR‐targeted TLR7 agonist, thereby enabling the CAR T cells to successfully treat solid tumors without incurring the systemic toxicity that commonly accompanies administration of nontargeted TLR7 agonists. [ABSTRACT FROM AUTHOR]

As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR‐T cells that is achievable through regulatory display of CARs. By embedding the hepatitis C virus NS3 protease (HCV‐NS3) between the single‐chain variable fragment (scFv) and the hinge domain, we showed that the display of anti‐CD19 scFv on CAR‐T cells was positively correlated to the presence of a clinical HCV‐NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti‐CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically reversible chemical switch. We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR‐T activation during cancer treatment. [ABSTRACT FROM AUTHOR]

The development of gene editing technologies over the past years has allowed the precise and efficient insertion of transgenes into the genome of various cell types. Knock‐in approaches using homology‐directed repair and designer nucleases often rely on viral vectors, which can considerably impact the manufacturing cost and timeline of gene‐edited therapeutic products. An attractive alternative would be to use naked DNA as a repair template. However, such a strategy faces challenges such as cytotoxicity from double‐stranded DNA (dsDNA) to primary cells. Here, we sought to study the kinetics of transcription activator‐like effector nuclease (TALEN)‐mediated gene editing in primary T cells to improve nonviral gene knock‐in. Harnessing this knowledge, we developed a rapid and efficient gene insertion strategy based on either short single‐stranded oligonucleotides or large (2 Kb) linear naked dsDNA sequences. We demonstrated that a time‐controlled two‐step transfection protocol can substantially improve the efficiency of nonviral transgene integration in primary T cells. Using this approach, we achieved modification of up to ˜ 30% of T cells when inserting a chimeric antigen receptor (CAR) at the T‐cell receptor alpha constant region (TRAC) locus to generate 'off‐the shelf' CAR‐T cells. [ABSTRACT FROM AUTHOR]

Despite remarkable advances in different types of cancer therapies, an effective therapeutic strategy is still a major and significant challenge. One of the most promising approaches in this regard is immunotherapy, which takes advantage of the patients' immune system; however, the many mechanisms that cancerous cells harbor to extend their survival make it impossible to gain perfect eradication of tumors. The response rate to cancer immunotherapies, especially checkpoint inhibitors and adoptive T cell therapy, substantially differs in various cancer types with the highest rates in advanced melanoma and non‐small cell lung cancer. Indeed, the lack of response in many tumors indicates primary resistance that can originate from either tumor cells (intrinsic) or tumor microenvironment (extrinsic). On the other hand, some tumors show an initial response to immunotherapy followed by relapse in few months (acquired resistance). Understanding the underlying molecular mechanisms of immunotherapy resistance makes it possible to develop effective strategies to overcome this hurdle and boost therapy outcomes. In this review, we take a look at immunotherapy strategies and go through a number of primary and acquired resistance mechanisms. Also, we present various ongoing methods to overcoming resistance and introduce some promising fields to improve the outcome of immunotherapy in patients affected with cancer. [ABSTRACT FROM AUTHOR]

The characteristics of infections following chimeric antigen receptor T (CAR‐T) cells targeting CD19 in real‐word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B‐cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR‐T cells. ECOG performance status (PS) was 2‐3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram‐negative rod, n = 5; Gram‐positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti‐CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell‐associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P =.018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P =.074). Age or PS was not associated with increased risk of bacterial infection. Increase in C‐reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR‐T‐cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs), a group of tumour cells with stem cell characteristics, have the ability of self‐renewal, multi‐lineage differentiation and tumour formation. Since CSCs are resistant to conventional radiotherapy and chemotherapy, their existence may be one of the root causes of cancer treatment failure and tumour progression. The elimination of CSCs may be effective for eventual tumour eradication. Because of the good therapeutic effects without major histocompatibility complex (MHC) restriction and the unique characteristics of CSCs, chimeric antigen receptor T‐cell (CAR‐T) therapy is expected to be an important method to eliminate CSCs. In this review, we have discussed the feasibility of CSCs‐targeted CAR‐T therapy for cancer treatment, summarized current research and clinical trials of targeting CSCs with CAR‐T cells and forecasted the challenges and future direction from the perspectives of toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, and tumour heterogeneity. [ABSTRACT FROM AUTHOR]

Impressive outcomes have been achieved by chimeric antigen receptor (CAR)‐T cell therapy using murine‐derived single‐chain variable fragment (scFv) FMC63 specific for CD19 in patients with B cell malignancies. However, evidence suggests that human anti‐mouse immune responses might be responsible for poor persistence and dysfunction of CAR‐T cells, leading to poor outcomes or early tumor recurrence. Substituting a fully human scFv for murine‐derived scFv may address this clinically relevant concern. In this study, we discovered two human anti‐CD19 scFv candidates through an optimized protein/cell alternative panning strategy and evaluated their function in CAR‐T cells and CD19/CD3 bispecific antibody formats. The two clones exhibited excellent cytotoxicity in CAR‐T cells and bispecific antibodies in vitro compared with the benchmarks FMC63 CAR‐T cells and blinatumomab. Furthermore, Clone 78‐BBz CAR‐T cells exhibited similar in vivo antitumor activity to FMC63‐BBz CAR‐T cells. Our results indicate that Clone 78‐BBz CAR has excellent efficacy and safety profile and is a good candidate for clinical development. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has greatly advanced in recent years, with chimeric antigen receptor (CAR) T cells emerging as an innovative technology that harnesses the immune system to fight malignant diseases. These genetically engineered T‐cells have shown encouraging results for B‐cell lymphoid malignancies and are now being explored for other cancer types. However, this novel adoptive cell therapy is associated with a new spectrum of immune‐mediated adverse events and toxicities. As CAR T cells recognize and engage tumour cells, cytokines are secreted and activate other immune cells, frequently leading to rapid development of cytokine release syndrome, which can result in acute deterioration of the patient's clinical condition. In many patients, cytokine release syndrome is mild and easy to manage, but others experience persistent fevers accompanied by hypotension and hypoxia, which require management with immune‐modulatory agents. Another deleterious effect of cytokines released by effector cells is immune effector cell–associated neurotoxicity syndrome. This syndrome, caused by a disruption of the blood–brain barrier as a consequence of the immune process, can result in rapid deterioration in cognitive function. This is often associated with subtle changes in handwriting, often progressing to loss of memory and concentration and reduced ability to name objects or follow commands. In some cases, the neurological state is further compromised by seizures and in rare instances with fulminant life‐threatening cerebral oedema. In this review, we discuss these toxicities, as well as other CAR T‐cell–related immune phenomenon, and address their clinical manifestations, grading, and management options. [ABSTRACT FROM AUTHOR]

Aims: Advanced therapy medicinal products (ATMPs) represent a new category of medicinal products with a potential for transformative improvements in health outcomes but at exceptionally high prices. Routine adoption of ATMPs requires robust evidence of their cost‐effectiveness. Methods: A systematic literature review of economic evaluations of ATMPs, including gene therapies, somatic cell therapies and tissue‐engineered products, was conducted. Literature was searched using MedLine, Embase, PubMed, Cochrane Register, the NHS Economic Evaluation Database and the grey literature of health technology assessment organisations with search terms relating to ATMPs and economic evaluations. Titles were screened independently by 2 reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed. Study findings were appraised critically. Results: 4514 articles were identified, of which 23 met the inclusion criteria. There was some evidence supporting the cost‐effectiveness of: chimeric antigen receptor T‐cell therapy axicabtagene–ciloleucel (Yescarta), embryonic neural stem cells, tumour infiltrating lymphocytes, in vitro expanded myoblast, autologous chondrocyte implantation, ex vivo gene therapy (Strimvelis) and voretigene neparvovec (Luxturna). However, estimates of cost‐effectiveness were associated with significant uncertainty and high likelihood of bias, resulting from largely unknown long‐term outcomes, a paucity of evidence on health state utilities and extensive modelling assumptions. Conclusion: There are critical limitations to the economic evidence for ATMPs, most notably in relation to evidence on the durability of treatment effect, and the reliability of opinion‐based assumptions necessary when evidence is absent. [ABSTRACT FROM AUTHOR]

Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses. [ABSTRACT FROM AUTHOR]

Objectives: The increasing success of Chimeric Antigen Receptor (CAR) T cell therapy in haematological malignancies is reinvigorating its application in many other cancer types and with renewed focus on its application to solid tumors. We present a novel CAR against glioblastoma, an aggressive, malignant glioma, with a dismal survival rate for which treatment options have remained unchanged for over a decade. Methods: We use the human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a novel single‐chain variable fragment (scFv) that recognises epidermal growth factor receptor mutant variant III (EGFRvIII), a common and tumor‐specific mutation found in glioblastoma. We use both in vitro functional assays and an in vivo orthotopic xenograft model of glioblastoma to examine the function of our novel CAR, called GCT02, targeted using murine CAR T cells. Results: Our EGFRvIII‐specific scFv was found to be of much higher affinity than reported comparators reverse‐engineered from monoclonal antibodies. Despite the higher affinity, GCT02 CAR T cells kill equivalently but secrete lower amounts of cytokine. In addition, GCT02‐CAR T cells also mediate rapid and complete tumor elimination in vivo. Conclusion: We present a novel EGFRvIII‐specific CAR, with effective antitumor functions both in in vitro and in a xenograft model of human glioblastoma. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell therapy with axicabtagene ciloleucel (axi‐cel) has considerably improved survival in adults with relapsed/refractory large B‐cell lymphoma. This study reports patient‐reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi‐cel (N = 103, mean age = 61, 39% female) completed SF‐36 or PROMIS‐29 QOL questionnaires prior to treatment and 90 days after. PRO‐Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient‐reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient‐reported toxicities. [ABSTRACT FROM AUTHOR]

Using T‐cell chimeric antigen receptors (CAR‐T) to activate and redirect T cells to tumors expressing the cognate antigen represents a powerful approach in cancer therapy. However, normal tissues with low expression of tumor‐associated antigens (TAAs) can be mistargeted, resulting in severe side effects. An approach using a collection of T cells expressing a diverse, 106‐member combinatorial cellular library of CARs, in which members can be specifically enriched based on avidity for cell membrane antigens, is reported. Using CD38 as the target antigen, an efficient and effective selection of CARs specifically recognizing CD38+ tumor cells is demonstrated. These selected CAR‐T's produce cytokines known to be associated with T cell activation in a CD38 expression‐dependent manner. This avidity‐based selection endows the engineered T cells with minimal off‐tumor effects, while retaining robust antitumor efficacy both in vitro and in vivo. The described method may facilitate the application of CAR‐T therapy to TAAs previously considered undruggable. [ABSTRACT FROM AUTHOR]

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are an important arm of the innate immune system. They constitutively express the NKp30 receptor. NKp30‐mediated responses are triggered by the binding of specific ligands e.g. tumour cell‐derived B7‐H6 and involve the secretion of cytotoxic mediators including TNF‐α, IFN‐γ, perforins and granzymes. The latter two constitute a target cell‐directed response that is critical in the process of immunosurveillance. The structure of NKp30 is presented, focusing on the ligand‐binding site, on the ligand‐induced structural changes and on the experimental data available correlating structure and binding affinity. The translation of NKp30 structural changes to disease progression is also reviewed. NKp30 role in immunotherapy has been explored in chimeric antigen receptor T‐cell (CAR‐T) therapy. However, antibodies or small ligands targeting NKp30 have not yet been developed. The data reviewed herein unveil the key structural aspects that must be considered for drug design in order to develop novel immunotherapy approaches. [ABSTRACT FROM AUTHOR]

Despite major advances in the treatment of multiple myeloma (MM), it remains a largely incurable disease with long‐term control often dependent on continuous therapy. More effective, better tolerated treatments are therefore required to achieve durable remissions and to improve the quality of life of MM patients. Adoptive immunotherapy employing T cells expressing chimeric antigen receptors (CAR) is currently among the most promising treatment approaches in cancer. Within the target portfolio for MM immunotherapy, B‐cell maturation antigen (BCMA) is among the most widely studied target antigens. BCMA is consistently expressed on MM cells and, importantly, is not expressed in critical healthy tissue. For this reason, it is an ideal target for MM immunotherapy. Several clinical trials evaluating different BCMA‐targeting CAR constructs have been initiated and early results are very promising. However, in this rapidly developing clinical landscape, the ultimate role of BCMA‐specific CAR‐T cell therapy remains unclear. In this review, we will summarize currently available clinical data on BCMA‐directed CAR‐T cells and discuss potential future perspective for this promising treatment approach in MM. [ABSTRACT FROM AUTHOR]