Prototype Aqueous Lithium-Ion Battery with a Lithium-Ion Conductive Solid Electrolyte Separator

Hayato Seki, Kazuomi Yoshima, Yasunobu Yamashita, Shinsuke Matsuno, Norio Takami

Abstract: Lithium-ion batteries (LIBs) with a non-aqueous electrolyte are capable of high energy density, high power output, and long cycle performance. These batteries are regarded as the most promising sources of power for electric vehicles (EVs), hybrid electric vehicles (HEVs), and grid storage. However, current LIBs pose a safety risk due to their flammable organic electrolytes. In contrast, lithium-ion batteries with aqueous electrolytes are safer and cost less than current LIBs, but the electrochemical stability window of aqueous electrolytes is narrower than that of the organic electrolytes used in LIBs. The stable operating voltage window of an aqueous electrolyte is approximately 1.23 V thermodynamically, beyond which the electrolysis of H2O occurs along with the evolution of H2 or O2 gas. As illustrated by a Pourbaix diagram, the overall electrochemical stability window of aqueous electrolytes is constant and independent of the pH of the electrolytes. In this study, we report the widening of the overall electrochemical stability window with two electrolytes having different pH values. We utilized a lithium-ion conductive solid electrolyte to separate the electrolytes into the cathode and anode sides of an aqueous lithium-ion battery in order to suppress the evolution of oxygen and hydrogen. In particular, we fabricated an aqueous lithium-ion cell with a lithium-ion conductive solid electrolyte as the separator between two inorganic lithium salt layers. A spinel lithium manganese oxide (LMO) was used as the cathode active material while a spinel lithium titanate oxide (LTO) with a Li+ insertion potential of 1.55 V vs. Li was used as the anode active material, leading to less hydrogen evolution compared with the graphite anodes used in current LIBs. A lithium-ion ceramic plate (LICGC™, Ohara Inc.) with a thickness 150 µm and conductivity 10-4 S/cm at 25°C was used as the separator. The plate was able to separate the different electrolytes into the cathode and anode sides. Then, 2 mol/L Li2SO4 and 12 mol/L LiCl, both of which have higher conductivity than the organic electrolytes of current LIBs, were used as the cathode and anode electrolytes, respectively. The cell was constructed with an LMO cathode electrode (10 mm in diameter, 0.1 mm thick), an LTO anode electrode (approximately the same dimensions as the cathode), the solid electrolyte separator (2.5 ´ 2.5 cm, 150 µm thick), and an aqueous solution with 2 mol/L Li2SO4 and 12 mol/L LiCl as the cathode and anode electrolyte, respectively. The charge/discharge current density was 0.282 mA/cm2 at the 1C rate. Figure 1 shows the charge and discharge curves of the LMO/LTO cell at the 20th cycle (25°C). The aqueous test cell exhibited an average discharge voltage of over 2.4 V and a coulombic efficiency of over 94%. Figure 2 shows the cycling stability and coulombic efficiencies of aqueous LMO/LTO cells at the 1C rate. To prevent drying of the electrolyte in a long-term experiment, 12 mol/L LiCl was used as electrolytes for both the cathode and anode. The retention of discharge capacity and coulombic efficiency was approximately 100% after 1000 cycles. The coulombic efficiency of the initial cycle, in which the pH of the 12 mol/L LiCl electrolyte was neutral (measured with pH test paper), was relatively low. During the 20th cycle, which had relatively low coulombic efficiency, the anode electrolyte changed from acidic to basic and hydrogen evolution with electrolysis of water was suppressed. After the 20th cycle, the electrolyte pH at the anode electrode surface was close to 14, whereas the entire electrolyte pH was close to neutral. The pH of the local electrolyte, situated between the anode electrode surface and the solid electrolyte separator, changed from acidic to basic, resulting in the suppression of oxygen and hydrogen gas generation without changing the pH of the cathode electrolyte. The initial coulombic efficiency was dependent on the anode electrolyte pH due to the lower coulombic efficiency of the anode compared with the cathode. Additional electrochemical tests will be reported in the future. Figure 1


A Review of Lithium-Ion Battery Recycling: Technologies, Sustainability, and Open Issues

Alessandra Zanoletti, Eleonora Carena, Chiara Ferrara, Elza Bontempi

INSTM and Chemistry for Technologies Laboratory, University of Brescia, Via Branze 38, 25123 Brescia, Italy

Fondazione Cariplo through the grant “Tech4Lib–Spent Lithium ion battery recovery”, Fondazione Cariplo through the grant “Tech4Lib–Spent Lithium ion battery recovery”, Fondazione Cariplo through the grant “Tech4Lib–Spent Lithium ion battery recovery”, Fondazione Cariplo through the grant “Tech4Lib–Spent Lithium ion battery recovery”, Fondazione Cariplo through the grant “Cathode Recovery for Lithium-Ion Battery Recycling, COLIBRI”, Fondazione Cariplo through the grant “Cathode Recovery for Lithium-Ion Battery Recycling, COLIBRI”, Fondazione Cariplo through the grant “Cathode Recovery for Lithium-Ion Battery Recycling, COLIBRI”, Fondazione Cariplo through the grant “Cathode Recovery for Lithium-Ion Battery Recycling, COLIBRI”, Regione Lombardia for the project Regional Hub for Circular Economy, R2BATT Laboratory, Regione Lombardia for the project Regional Hub for Circular Economy, R2BATT Laboratory, Regione Lombardia for the project Regional Hub for Circular Economy, R2BATT Laboratory, Regione Lombardia for the project Regional Hub for Circular Economy, R2BATT Laboratory, MUR-PRIN “enhanced metals recovery by coordination chemistry from lithium batteries waste–ERCOLE”, MUR-PRIN “enhanced metals recovery by coordination chemistry from lithium batteries waste–ERCOLE”, MUR-PRIN “enhanced metals recovery by coordination chemistry from lithium batteries waste–ERCOLE”, MUR-PRIN “enhanced metals recovery by coordination chemistry from lithium batteries waste–ERCOLE”, Next-GenerationEU, Next-GenerationEU, Next-GenerationEU, Next-GenerationEU, MICS (Made in Italy–Circular and Sustainable) Extended Partnership, MICS (Made in Italy–Circular and Sustainable) Extended Partnership, MICS (Made in Italy–Circular and Sustainable) Extended Partnership, MICS (Made in Italy–Circular and Sustainable) Extended Partnership

Abstract: Lithium-ion batteries (LIBs) are a widely used energy storage technology as they possess high energy density and are characterized by the reversible intercalation/deintercalation of Li ions between electrodes. The rapid development of LIBs has led to increased production efficiency and lower costs for manufacturers, resulting in a growing demand for batteries and their application across various industries, particularly in different types of vehicles. In order to meet the demand for LIBs while minimizing climate-impacting emissions, the reuse, recycling, and repurposing of LIBs is a critical step toward achieving a sustainable battery economy. This paper provides a comprehensive review of lithium-ion battery recycling, covering topics such as current recycling technologies, technological advancements, policy gaps, design strategies, funding for pilot projects, and a comprehensive strategy for battery recycling. Additionally, this paper emphasizes the challenges associated with developing LIB recycling and the opportunities arising from these challenges, such as the potential for innovation and the creation of a more sustainable and circular economy. The environmental implications of LIB recycling are also evaluated with methodologies able to provide a sustainability analysis of the selected technology. This paper aims to enhance the comprehension of these trade-offs and encourage discussion on determining the “best” recycling route when targets are in conflict.


Modeling of analog battery management system for single cell lithium ion battery

CSIR‐Central Electrochemical Research Institute (CECRI) CSIR‐Madras Complex  Chennai India

Abstract: AbstractThe Li‐ion battery is an energy storage system in consumer and industrial applications. Because of their cell and pack level protection, Li‐ion battery requires a battery management system (BMS). The important function of the BMS is to monitor and protect the Li‐ion battery cells and packs from fault conditions, in order to maximize their lifecycle and increase safety features. In this research article, an analog BMS is presented for the protection of nickel manganese cobalt oxide‐chemistry‐based single‐cell Li‐ion battery. The Analog BMS is a battery protection circuit module that includes battery protection integrated circuit to protect batteries from overvoltage, undervoltage, overcurrent charging, and overcurrent discharging conditions. In addition, the semiconductor switches are used for charge and discharge protection control. This protection circuit module is designed for 18650 single‐cell Li‐ion battery and test the performance of analog BMS based on protection parameters. A real‐time experiment is carried out on analog BMS interconnected with 18650 single‐cell Li‐ion battery and tested under different charge and discharge rates using standard constant current‐constant voltage (CC‐CV) charging method. The experimental results show that the developed analog BMS protected single‐cell Li‐ion battery from overvoltage, undervoltage, overcurrent charging, and discharging conditions under different C/5, C/2, and 1C rates.


An insight into lithium-ion transport in germanium-doped lithium titanate anode through NMR spectroscopy and post-carbonization for anode applications in lithium-ion battery

Sreejith O. V., Arunkumar Dorai, Junichi Kawamura, Murugan Ramaswamy

High Energy Density Batteries Research Laboratory, Department of Physics, Pondicherry University 1 , Puducherry 605 014, India

Abstract: Adapting toward lithium titanate as a negative electrode for lithium-ion batteries led to the safest and long-lasting battery technology, especially for electric vehicle applications. However, the poor conductivity and lithium-ion diffusion of lithium titanate have to be addressed for widespread usage in next-generation E-mobility. The lithium-ion motion inside lithium titanate and germanium-doped lithium titanate was investigated through pulsed-field gradient nuclear magnetic resonance spectroscopy and temperature-dependent ionic conductivity studies. The superior charge carrier mobility of germanium enhanced the lithium-ion diffusion in lithium titanate significantly to 1.48 × 10−8 cm2 s−1 in Li4Ge0.1Ti4.9O12 at 500 °C. While germanium improves the ionic diffusion, an ex situ carbon coating was adapted over the sample for electronic conductivity enhancement. Samples with two different carbon contents (5 and 10 wt. %) were examined for electrochemical analysis. Significant improvements in battery performance were observed on carbon-coated germanium-doped lithium titanate. The carbon-coated sample gave superior initial performance (191 and 178 mAh g−1 for 10 and 5 wt. % carbon at 0.1C) than the pristine lithium titanate and preserved the exceptional capacity retention over a thousand cycles at 1C rate.


CAR-T Cell Therapy in Rheumatic Diseases

Hiren Kalyani, P.D Rath, Shwetal Chouhan, Mayank Goyal, Tejaswee Banavathu

Abstract: CAR-T cell (Chimeric Antigen Receptor-T cell) therapy has revolutionized the treatment of various hematologic malignances. CD19 targeted CAR-T cell therapy is coming in a big way in rheumatic diseases. Recent case reports and case series have shown encouraging results in diseases like systemic lupus erythematosus (SLE), systemic sclerosis and antisynthetase syndrome which have been refractory to multiple existing therapies. The dramatic response encompasses objective improvement across multiple clinical domains as well as seroconversion. Side effects of concern with CAR-T cell therapy are related to release of pro-inflammatory cytokines and include cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). The reported side effects of this therapy for autoimmune diseases were of low grade and were managed without any fatality. Several modifications in CAR-T cell therapy have been proposed to maximize the safety and improving the efficacy. This therapy has got the potential to be a major breakthrough in management of rheumatic diseases, especially wherein existing therapies have been refractory.


Hematopoietic Dyscrasias and Stem Cell Transplantation/CAR-T Cell Therapy

Abstract: This chapter describes the epidemiology, clinical presentation, assessment, and management of the many psychosocial issues and neuropsychiatric syndromes that may arise in patients with hematopoietic dyscrasias, including those undergoing hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T (CAR-T) cell therapy. We focus our discussion on adults who are undergoing acute treatment and briefly discuss issues faced by long-term survivors, families, and caregivers. Although an increasing body of literature supports evidence-based management strategies, clinical recommendations for treatment continue to incorporate both empirical evidence and expert opinion. We conclude by proposing directions for future research that will lead to improved care and outcomes for this population.


CAR-T Cell Therapy

Advancements in the Diagnostics and Therapeutics for Non-Small Cell Lung Carcinoma (NSCLC)

G.D. Rungta College of Science and Technology, Bhilai, India

Abstract: There is rising interest in CAR-T therapy as a potential treatment of non-small cell lung cancer (NSCLC) that comprises about 85% of all lung cancer and has a high mortality rate. This is a new technology whereby T cells are engineered to attack certain tumor-specific antigens. However, it tends to be undermined by other factors (i.e., the immunosuppressive tumor microenvironment and antigen heterogeneity). More recent data have found epidermal growth factor receptor (EGFR) and mesothelin as future targets of CAR-T therapy. The development of cars such as dual-targeting CAR improves the efficiency of treatment. However, there also exist some challenges such as safety concerns such as cytokine release syndrome (CRS). To overcome immunosuppressive barriers, CAR-T/immune checkpoint combination therapy can be used as an added advantage. Further research on new CAR-T regimens and trials is needed to improve patient treatment outcomes and survival in patients with NSCLC, a complex and advanced disease.


Honing the safety and delivery of CAR T-cell therapy

Victoria University of Wellington Library

Abstract: Chimeric antigen receptor (CAR) T-cell therapy is an emerging and evolving therapy for haematological malignancies, with the potential for broader use for other malignancies and autoimmune conditions. Although this therapy is now standard of care in many countries for B-cell non-Hodgkin lymphoma, the clinical delivery of this therapy continues to be refined, as its clinical application catches up to the impressive underlying science. In this thesis I present three projects on the theme of improving the clinical delivery of CAR T-cell therapy for B-cell non-Hodgkin lymphoma. The first project is a a clinical audit report including a new audit tool for reviewing nursing assessments of cytokine release syndrome and immune effector cell neurotoxicity syndrome, two of the primary characteristic risks seen after CAR T-cell therapy. The second study, RE-TELL, is a qualitative research study of Aotearoa New Zealand CAR T-cell patients, support persons, clinicians and administrators, to identify future improvements in CAR T-cell delivery. Lastly, I present THERMAL, a study of wearable temperature monitors for the detection of neutropenic fevers, a key risk with CAR T-cell therapy. These three projects represent attempts to enhance the safe clinical delivery of CAR T-cell therapy for B-cell non-Hodgkin lymphoma, from the patient level to the service design level, which could be readily translated into CAR T-cell service delivery in the future, both in Aotearoa New Zealand and internationally.


Nonviral gene delivery vectors for transfection of the CAR gene for CAR-T cell therapy

Abstract: The introduction of the CAR gene via retrovirus is the most widely used and most successful technique for CAR-T cell therapy. However, the limitations and risks associated with viral gene therapy continue to motivate the development of nonviral gene delivery technologies that are potentially safer, less expensive, and quicker. In terms of safety and efficacy, electroporation has emerged as the most promising non-viral technology, albeit more optimization testing and clinical trials are required before it can be directly compared to retroviral CAR gene delivery techniques. But these findings suggest that non-viral gene delivery to T cells (and other related cells, such as natural killer cells) is feasible and is quickly emerging as a viable alternative to CAR-T cell therapy and other gene therapies.


An Overview of CAR T Cell Mediated B Cell Maturation Antigen Therapy

Abstract: Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.


The major advantages and early clinical obstacles of CAR-NK compared to CAR-T cell therapy

Abstract: Chimeric Antigen Receptor T-Cells (CAR-T) are genetically engineered T cells designed to recognize and attack specific cancer cells, thereby offering a targeted approach to cancer immunotherapy. Chimeric Antigen Receptor Natural Killer (CAR-NK) cells are a novel form of such cell therapy where NK cells are genetically modified to express specific receptors, enabling them to identify and eliminate targeted cancer cells. This mini-review discussed the major advantages of CAR-NK compared to CAR-T, issues that limit the clinical translation of CAR-NK cells, and approaches to overcome these early obstacles.


The Latest Research Progress of CAR-T Cell Therapy v1

Abstract: CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy), achimeric antigen receptor T cellimmunotherapy, has been in use for many years but has only been used in clinical practice in recent years. It has significant curative effect in the treatment of acute leukemia and non-Hodgkin'slymphoma,and is considered as one of the most promising approaches totreatmentof cancer. As with all technologies, CAR-T technology has also undergone a long evolutionary process. It is during this series of evolution that CAR-T technology has gradually matured.


Empowering CAR T Cell Therapy

Abstract: Chimeric antigen receptors (CAR) T cell therapies have already demonstrated favourable clinical outcomes, however tumor resistance mechanisms remain a major obstacle. This thesis focuses on the primary function of CAR T cells in cancer therapy: the mechanisms by which they kill tumor cells. By gaining a fundamental understanding of how CAR T cells induce tumor cell death and how tumors resist this cytotoxicity, we can design new strategies to overcome resistance while avoiding systemic side effects. The main mechanism by which CAR T cells eliminate tumor cells is through the release of cytotoxic granule contents into the target cell. The key effector protein that induces regulated cell death (apoptosis) is granzyme B. In human biology, Serpin B9 is known as a specific inhibitor of granzyme B. Chapter 2 identifies Serpin B9 as a novel intrinsic resistance mechanism to CD19- and CD20-directed CAR T cell therapy. Previous studies have shown that preclinical inhibition of MCL-1 can effectively eliminate multiple myeloma (MM) cells. However, clinical trials have revealed severe systemic toxicity associated with MCL-1 inhibition, halting further clinical development. To make this potentially effective strategy feasible, we investigated synergistic combinations of clinically available agents. Chapter 3 demonstrates that inhibition of P70S6K1 and MCL-1 has a synergistic effect, thereby allowing treatment with lower doses of MCL-1 inhibitors and minimizing adverse effects. In Chapter 4, we explore innovative methods to specifically target MCL-1 in MM. To this end, we developed a strategy to express the MCL-1 antagonist NOXA within the cytotoxic granules of BCMA-targeted CAR T cells. We show that NOXA can be directed to the granules by fusing it to granzyme B. Upon recognition of an MM cell, NOXA is released into the tumor cell. This arming of BCMA CAR T cells with a pro-apoptotic NOXA, enhances their antitumor activity. Besides we also reveal MCL-1 expression by MM cells as a CAR T resistance mechanism. Chapter 5 describes an international patent filing related to fusion proteins based on the NOXA scaffold. In this approach, the effector BH3 domain of NOXA can be exchanged with BH3 domains from other pro-apoptotic BCL-2 family proteins. This design could support personalized therapies tailored to tumor-specific dependencies on survival proteins. Cytotoxic T cells mainly induce apoptosis. This clean form of cell death does not release inflammatory mediators such as damage-associated molecular patterns (DAMPs). In Chapter 6, we take the first steps toward using our CARgo delivery method to induce immunogenic cell death in vitro. We anticipate that inducing an immunogenic form of tumor cell death could shift the balance in favor of tumor-clearing CAR T cells, especially in solid tumor settings where T cell infiltration is limited. Collectively, this thesis provides new insights into intrinsic tumor resistance mechanisms involving Serpin B9 and MCL-1, and presents innovative strategies using CAR T cells to deliver pro-apoptotic or immunogenic cell death–inducing proteins to tumor cells. Together, these studies mark a step forward in overcoming resistance and advancing the next generation of CAR T cell therapies.


Developing logic-gated CAR T cells for saferT-cell lymphoma therapy

Agence Bibliographique de l'Enseignement Supérieur

Abstract: CAR T cells à circuits intégrés pour améliorer leur sécurité dans le traitement des lymphomes T La thérapie par cellules T à récepteur antigénique chimérique (CAR) est apparue comme l'une des percées les plus convaincantes dans le traitement du cancer au cours de la dernière décennie. Cependant, les résultats remarquables obtenus dans les hémopathies B ne se sont pas encore étendus aux lymphomes T (LT) où l'éventuelle toxicité « on-target off-tumor » a limité le développement d'approches similaires.Dans ce travail, nous avons développé une plateforme NOT-gate, tirant parti de la perte d'expression du CD7 dans les LT pour distinguer les cellules T tumorales des cellules T normales. Cette plateforme associe un CAR 4-28^1 XX activateur ciblant le CD4, un antigène T fortement exprimé dans les LT, à un CAR 7PD1 inhibiteur ciblant le CD7. Les nouvelles cellules CAR T 4-28(1XX, éditées CD4 pour limiter le fratricide, ont démontré une activité antitumorale robuste contre les cellules tumorales CD4-positives in vitro et in vivo dans des modèles murins de LT disséminé. Cependant, la perte du CD4 a démasqué un phenotype hyperproliferatif reponsable d'une infiltration tissulaire létale, dont les mécanismes exacts restent à élucider. L'ajout d'un CAR inhibiteur 7PD1 a permis de réduire la sécrétion de cytokines et la dégranulation des cellules T CAR4-28C1XX, mais il a été plus difficile d'obtenir une inhibition de la cytotoxicité globale. De nombreux paramètres doivent être optimisés pour une plateforme NOT- gate plus efficace, comprenant principalement le rapport stoechiométrique CAR/cible et l'intensité du signal médié par chaque CAR.


CAR-T CELL THERAPY IN LARGE B CELL LYMPHOMA

Hematology Section, Dept. of Radiological Science and Hematology, Catholic University, Rome, Italy

Mediterranean Journal of Hematology and Infectious Diseases

Ugo Testa, Germana Castelli, Giuseppe Leone, Elvira Pelosi, Germana Castelli, Stefan Hohaus

Abstract: Large B-cell lymphomas (LBCLs) are among the most frequent (about 30%) non-Hodgkin’s lymphoma. Despite the aggressive behavior of these lymphomas, more than 60% of patients can be cured with first-line chemoimmunotherapy using the R-CHOP regimen. Patients with refractory or relapsing disease show a poor outcome even when treated with second-line therapies. CD19-targeted chimeric antigen receptor (CAR) T-cells are emerging as an efficacious second-line treatment strategy for patients with LBCL. Three CD19-CAR-T-cell products received FDA and EMA approval. The use of CAR-T cell therapy has also been explored for the treatment of high-risk LBCL patients in the first-line setting and for patients with central nervous system involvement. Although CD19-CAR-T therapy has transformed the care of refractory/relapsed LBCL, about 60% of these patients will ultimately progress or relapse following CD19-CAR-T: therefore, it is fundamental to identify predictive criteria of response to CAR-T therapy and to develop salvage therapies for patients relapsing after CD19-CAR-T therapies. Moreover, ongoing clinical trials are evaluating bispecific CAR-T cells targeting both CD19 and CD20 or CD19 and CD22 as a tool to improve the therapeutic efficacy and to reduce the number of refractory/relapsing patients.


CAR T Cell Therapy for Rheumatoid Arthritis

Abstract: Chimeric Antigen Receptor (CAR) T cell therapy had revolutionised the treatment of relapsed/refractory B cell leukaemia, lymphoma and multiple myeloma. A growing body of evidence has recently demonstrated that these cell-based therapies can target autoimmune diseases including systemic lupus erythematosus, systemic sclerosis and Rheumatoid Arthritis. This review highlights how CAR T cell therapy has been used to treat Rheumatoid Arthritis patients with treatment refractory disease. To date, seven patients have been treated with CAR T cells targeting CD19 and/or CD20 antigens on B cells, and all patients have shown remarkable responses, including depletion of circulating B cells, ablation of autoantibody levels and drug-free remission. The review also highlights emerging in-vitro and animal model studies where T cell subsets have been engineered with CARs to fine-tune their immune responses, including targeting of autoreactive B cells, autoreactive T cells or fibroblasts. CAR T cell therapy holds enormous promise for the treatment of difficult-to-treat Rheumatoid Arthritis, but more research and clinical trials are needed to confirm its efficacy and safety.


CAR-T Cell Therapy in Primary Mediastinal B-cell Lymphoma

Abstract: A specific type of CAR-T cell therapy, the CAR19 therapy has demonstrated notable efficacy for relapsed or refractory (R/R) hematologic cancers, including B-cell lymphomas. After the recent reclassification of the rare subtype Primary Mediastinal B-cell Lymphoma (PMBCL) from general Diffuse Large B-cell Lymphoma (DLBCL), questions have been raised about the application of immunotherapies in this cancer, including the most discussed CAR-T cell therapy. The CAR-T cell therapy, more specifically the CAR19, exerts anti-tumor effects in multiple mechanisms, including different cytotoxic pathways—apoptosis triggering via perforin–granzyme release and Fas/FasL-pathway—driven by calcium-dependent signaling MAPK, PI3K/Akt, and NF-κB. Multiple extant clinical trials have evaluated the response of PMBCL patients to CAR19, specifically the Axi-cel, Liso-cel, and Tisa-cel therapies, focusing the rates of complete response (CR), progression-free survival (PFS), and the overall survival (OS). Studies exclusive to PMBCL patients showed that bridging therapies and other first-line treatments did not influence CAR19 effectiveness, while post-relapse application of Pembrolizumab yielded durable CRs in some patients, and allo-HSCT was associated with high mortality. The CAR-SIE trial in Italy, comparing Axi-cel CAR19 in PMBCL cancer with other B-cell lymphomas, demonstrated a better result in PMBCL patients with higher ORR, CR, and PFS. This paper integrates the underlying mechanisms of CAR19 with clinical trials, aiming to demonstrate both the potential and the limitations of this therapy in PMBCL cancer.


Modelling CAR T-cell Therapy with Patient Preconditioning

Abstract: A bstract The Federal Drug Administration (FDA) approved the first Chimeric Antigen Receptor T-cell (CAR T-cell) therapies for the treatment of several blood cancers in 2017, and efforts are underway to broaden CAR T technology to address other cancer types. Standard treatment protocols incorporate a preconditioning regimen of lymphodepleting chemotherapy prior to CAR T-cell infusion. However, the connection between preconditioning regimens and patient outcomes is still not fully understood. Optimizing patient preconditioning plans and reducing the CAR T-cell dose necessary for achieving remission could make therapy safer. In this paper, we test treatment regimens consisting of sequential administration of chemotherapy and CAR T-cell therapy on a system of differential equations that models the tumor-immune interaction. We use numerical simulations of treatment plans from within the scope of current medical practice to assess the effect of preconditioning plans on the success of CAR T-cell therapy. Model results affirm clinical observations that preconditioning can be crucial for some patients, not just to reduce side effects, but to even achieve remission at all. We demonstrate that preconditioning plans using the same CAR T-cell dose and the same total concentration of chemotherapy can lead to different patient outcomes due to different delivery schedules. Results from sensitivity analysis of the model parameters suggest that making small improvements in the effectiveness of CAR T-cells in attacking cancer cells, rather than targeting the recruitment and longevity of CAR T-cells, will significantly reduce the minimum dose required for successful treatment. Our modeling framework represents a starting point for evaluating the efficacy of patient preconditioning in the context of CAR T-cell therapy.


Chimeric Antigen Receptor T-Cell Therapy (Car T-Cells) in Solid Tumors, Resistance and Success

Bioequivalence & Bioavailability International Journal

Abstract: CARs are chimeric synthetic antigen receptors that can be introduced into an immune cell to retarget its cytotoxicity toward a specific tumor antigen. CAR T-cells immunotherapy demonstrated significant success in the management of hematologic malignancies. Nevertheless, limited studies are present regarding its efficacy in solid and refractory tumors. It is well known that the major concerns regarding this technique include the risk of relapse and the resistance of tumor cells, in addition to high expenses and limited affordability. Several factors play a crucial role in improving the efficacy of immunotherapy, including tumor mutation burden (TMB), microsatellite instability (MSI), loss of heterozygosity (LOH), the APOBEC Protein Family, tumor microenvironment (TMI), and epigenetics. In this minireview, we address the current and future applications of CAR T-Cells against solid tumors and their measure for factors of resistance and success.


Enhancing CAR-T therapy development: harnessing cell selection flexibility

Abstract: Clinical advancements in personalized cell therapy, particularly CAR-T cell therapy, have created a demand for innovative, closed, automated, and space-efficient manufacturing methods. Given that each therapeutic product requires a unique manufacturing process, flexibility in automation platforms is essential to accommodate these varying needs. This article will explore recent developments in the Cocoon® Platform, an automated system for CAR-T manufacturing, highlighting the ability to adapt to different processes including positively or negatively selecting T cells directly from apheresis. Enabling direct cell isolation from the input material eliminates the need for additional upstream processing equipment, thus reducing costs, time, and space requirements. Automatic transfer to an expansion chamber for extended culture enables further reduction in manual processing.


CAR-T CELL THERAPY FOR T-CELL MALIGNANCIES

Ugo Testa, Patrizia Chiusolo, Elvira Pelosi, Germana Castelli, Giuseppe Leone

Abstract: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell lymphoid neoplasia and, in some instances, improved disease outcomes. Thus, six FDA-approved commercial CAR-T cell products that target antigens preferentially expressed on malignant B-cells or plasma cells have been introduced in the therapy of B-cell lymphomas, B-ALLs and multiple myeloma. These therapeutic successes have triggered the application of CAR-T cell therapy to other hematologic tumors, including T-cell malignancies. However, the success of CAR-T cell therapies in T-cell neoplasms was considerably more limited to the existence of some limiting factors, such as the sharing of mutual antigens between normal T-cells and CAR-T cells, and malignant cells, determining fratricide events and severe T-cell aplasia; contamination of CAR-T cells used for CAR transduction with contaminating malignant T-cells. Allogeneic CAR-T products can avoid tumor contamination but raise other problems related to immunological incompatibility. In spite of these limitations, there has been significant progress in CD7- and CD5-targeted CAR-T cell therapy of T-cell malignancies in the last few years.


Defining the differential contributions of CD4+ and CD8+ T cells to CAR T cell therapy against B cell malignancies

Abstract: Définir les contributions différentielles des lymphocytes T CD4+ et CD8+ à la thérapie par cellules CAR T contre les cancers hématologiques Les cellules CAR T (de l'anglais Chimeric Antigen Receptor T cells) sont apparues comme étant une thérapie potentiellement curative pour le traitement de certains lymphomes et leucémies. Au cours d'essais cliniques, les cellules CAR T anti-CD19 ont atteint des taux de rémission initiaux allant jusqu'à 86%, mais seuls 50% des patients ayant une réponse durable à long terme. La survenue d'événements indésirables graves, dont le syndrome de relargage des cytokines (CRS), représente une limitation importante à la thérapie par cellules CAR T. Les produits de cellules CAR T comprennent un mélange de lymphocytes T CD4+ et CD8+ et ainsi diffèrent grandement d'un patient à l'autre avec, notamment, d'importantes différences dans la représentation des divers phénotypes de lymphocytes T. Le succès de la thérapie par cellules CAR T est généralement attribué à l'activité d'un grand nombre d'effecteurs cytotoxiques ciblant la tumeur. Par conséquent, nous ne savons pas précisément si les cellules CAR T agissent de manière autonome ou si elles nécessitent des interactions avec le microenvironnement tumoral. Dans la littérature, les cellules CD4+ CAR T présentent une activité anti-tumorale variable selon les modèles précliniques. Ainsi, les mécanismes qui déterminent quand et comment les cellules CD4+ CAR T favorisent la régression tumorale ne sont pas complètement compris. Enfin, nous ne savons pas si la variabilité interindividuelle de la composition des cellules CAR T contribue au développement du CRS. Durant mon doctorat, j'ai étudié le mode d'action et les contributions différentielles des cellules CD4+ et CD8+ CAR T à l'efficacité anti-tumorale et aux toxicités liées à la thérapie dans le contexte d'hémopathies lymphoïdes B. En utilisant le séquençage des ARN de cellules uniques, nous avons montré que la thérapie par cellules CAR T induit un remodelage considérable du microenvironnement tumoral. La production d'interféron-g (IFN-g) par les cellules CAR T puis la production subséquente d'interleukine 12 (IL-12) par les cellules hôtes ont non seulement renforcé l'activité des lymphocytes T et NK endogènes, mais ont également été essentiels au maintien de la cytotoxicité des cellules CAR T. En comparaison des cellules CD8+ CAR T, les cellules CD4+ CAR T sont très efficaces pour l'activation immunitaire endogène mais présentent une activité cytotoxique moindre. À l'aide de l'imagerie intravitale biphotonique, nous avons mis en évidence que la production d'IFN-g, plutôt que la cytotoxicité médiée par la perforine, était le mécanisme dominant pour l'élimination tumorale par les cellules CD4+ CAR T. Mécaniquement, l'IFN-g dérivé des cellules CD4+ CAR T est capable de diffuser largement pour agir sur les cellules tumorales à distance, tuant sélectivement les tumeurs sensibles à la mort induite par cytokine. La sensibilité intrinsèque de la tumeur à l'activité pro-apoptotique de l'IFN-g est donc un déterminant majeur de l'efficacité des lymphocytes CD4+ CAR T. Enfin, nous montrons que les cellules CD4+ CAR T, mais pas les cellules CD8+ CAR T, sont principalement responsables du CRS. Notamment, le CRS s'est développé indépendamment de l'IFN-g produit par les cellules CAR T, et uniquement en condition de charge tumorale élevée. En ce sens, nous proposons que l'ajustement du ratio de cellules CD4:CD8 CAR T à la charge tumorale du patient permette d'atténuer les toxicités associées aux cellules CAR T. En conclusion, les cellules CAR T n'agissent pas seules in vivo, mais reposent plutôt sur des interactions cellulaires et moléculaires au sein du microenvironnement tumoral pour leur efficacité optimale et éliminent les cellules tumorales à travers plusieurs mécanismes complémentaires. Identifier et tirer parti des forces et des faiblesses uniques des cellules CD4+ et CD8+ CAR T représentent une étape importante vers la conception rationnelle de thérapies cellulaires améliorées tout en atténuant les toxicités associées aux cellules CAR T.


Unmasking the invisible: CAR T-cell therapy for intravascular large B-cell lymphoma

Ferrata Storti Foundation (Haematologica)

Abstract: Not available.


CAR-T Cell Therapy in Acute Lymphoblastic Leukemia

Abstract: Acute Lymphoblastic Leukemia (ALL) is a common blood malignancy tumor that originates from the uncontrolled growth of immature lymphocytes. This process destabilizes normal hematopoiesis and gradually deteriorates the health of patients. There are some conventional treatments such as chemotherapy and hematopoietic stem cell transplantation can improve survival for some patients. However, regarding Relapsed or Refractory (R/R) cases, their efficacy remains very limited, which is a significant challenge in clinical practice. To address these challenges, Chimeric Antigen Receptor T-cell (CAR-T) therapy has unveiled an innovative immunotherapeutic therapy. By carrying out genetic engineering on autologous T cells of patients, this strategy allows them to accurately identify and eradicate malignant lymphoblasts. Among these strategies, CD19-directed CAR-T therapy has accomplished notable clinical breakthroughs. Research shows that 70% to 90% of patients suffering from R/R ALL achieve total remission after receiving CAR-T therapy. In most cases, minimal residual disease becomes undetectable within a relatively short period. These findings also reflect this therapy can induce rapid remission and offer patients improved long-term survival outlook. At the same time, research in this field is expanding. But, in relation to safety hurdles including Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), the risk of relapse in certain patients, and the logistical challenges posed by complex manufacturing and high costs. This research explores recent research on CAR-T therapy in ALL, highlighting both its treatment developments and existing limitations. The purpose is to provide a thorough understanding that may advise future clinical practice and translational research.


B cell targeting in CAR T cell therapy: Side effect or driver of CAR T cell function?

American Association for the Advancement of Science (AAAS)

Gregory M. Chen, Jan Joseph Melenhorst, Kai Tan

Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA.

Abstract: Chimeric antigen receptor (CAR) T cell therapies targeting CD19 and CD22 have been successful for treating B cell cancers, but CAR T cells targeting non–B cell cancers remain unsuccessful. We propose that rather than being strictly a side effect of therapy, the large number of CAR interactions with normal B cells may be a key contributor to clinical CAR T cell responses.


Bridging viral immunology and CAR-T therapy: leveraging natural T cell responses to enhance engineered cell therapies

Senior Vice President and Chief Research Officer, Children’s National Hospital, Washington, DC USA

Abstract: “Success ultimately requires thoughtful clinical trial design that evaluates how...immunoengineered products...perform against exhaustion and TME suppression in comparable patient populations.” Ashling Cannon (Editor, BioInsights) speaks to Catherine Bollard (Chief Research Officer and Senior Vice President, Children’s National Hospital) about translating insights from natural viral antigen-specific T cell responses into improved CAR-T design and clinical performance. They explore how virus-specific T cells demonstrate superior persistence compared to current CAR-T therapies, strategies for preventing T cell exhaustion through TGF-beta resistance, innovative combination approaches merging antigen-specific T cells with CAR-T platforms, and critical regulatory considerations for advancing these therapeutic approaches from bench to clinic.


CAR-T cell therapy in T-cell malignancies: Is success a low-hanging fruit?

Pouya Safarzadeh Kozani, Pooria Safarzadeh Kozani, Fatemeh Rahbarizadeh

Abstract: AbstractChimeric antigen receptor T-cell (CAR-T) therapy has been prosperous in the treatment of patients with various types of relapsed/refractory (R/R) B-cell malignancies including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic leukemia (B-ALL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and multiple myeloma (MM). However, this type of therapy has faced serious hindrances in combating T-cell neoplasms. R/R T-cell malignancies are generally associated with poor clinical outcomes, and the available effective treatment approaches are very limited. CAR-T therapy of T-cell malignancies has unique impediments in comparison with that of B-cell malignancies. Fratricide, T-cell aplasia, and product contamination with malignant T cells when producing autologous CAR-Ts are the most important challenges of CAR-T therapy in T-cell malignancies necessitating in-depth investigations. Herein, we highlight the preclinical and clinical efforts made for addressing these drawbacks and also review additional potent stratagems that could improve CAR-T therapy in T-cell malignancies.


The Black Hole: CAR T cell Therapy in AML

Abstract: Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed-refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything, considering only around 30% of patients show a response but with consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T and CAR-NK therapies; approaches to tailor the microenvironment and target neoantigens; and allogeneic approaches.


Separating dose schedule from disease biology in CD19 CAR T-cell therapy. Comment on: "A novel dose-dense strategy for CD19-directed CAR T-cell therapy is associated with durable responses without increased toxicity in patients with B-cell non-Hodgkin lymphoma"

Abstract: Not available.


T-Cell Lymphoma From CAR T-Cell Therapy—A New Safety Notice

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco

Abstract: This Viewpoint outlines a recent safety signal identified by the FDA concerning CAR T-cell therapy for pediatric cancer, including what is known and likely implications.


Exploring BiTE-Integrated CAR T-Cell Therapy to Overcome Tumor Antigen Escape and Reinforce CAR-T Therapy in Mantle Cell Lymphoma

Grace Glass Crutchfield, Yang Liu, Fangfang Yan, Xiaolin Li, Heng-Huan Lee, Michael Wang, Yixin Yao

1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX

Abstract: Background T cell engagers (BiTEs) are bispecific T-cell engaging antibodies that redirect T cells to target antigen-expressing tumor cells. Combining a second antigen-targeted bispecific T cell engager (BiTE) with CAR T cells or incorporating bispecific engaging antibody-secreting T cells (engager-T cells) is expected to augment T-cell activation and proliferative capacity, and antitumor cytotoxicity, even towards tumor cells expressing tumor antigens heterogeneously. Here, we report a BiTE-integrated T-cell therapeutic strategy to overcome tumor antigen escape and reinforce the efficacy of CAR-T therapy in mantle cell lymphoma (MCL). Methods CD20-directed bispecific T-cell engager (CD20-BiTE) was constructed with a publicly available VHH fragment from an anti-CD20 single-domain antibody, and anti-CD3 scFv from OKT3 monoclonal antibody. CD19-directed CAR construct is comprised of anti-CD19 scFv from publicly available FMC63 monoclonal antibody, CD8 transmembrane-, 4-1BB costimulatory-, and CD3ζ signaling-domains. Human primary pan-T cells were isolated from PBMC derived from normal human donors (MD Anderson Blood Bank) or patients with MCL. Activated T cells were used for effector functional assay or transduced with lentivirus to produce CAR T or engager-T cells. Effector function of bispecific antibodies and T cells was determined via T-cell activation, cytokine release, and T-cell-dependent cytotoxicity assay in a co-culture model. Results Treatment with CD20-BiTE enhances the effector function of naïve T cells: the BiTE-Fc fusion protein was ectopically expressed in Expi293 and purified by immobilized Protein-A. The binding specificity of scFv(s) of CD20-BiTE was confirmed to bind strongly and specifically to CD20-expressing cells. In vitro functional analyses demonstrated that co-culture of naïve T cells with CD20-exressing cells in the presence of CD20-BiTE induced antigen-specific activation of the T cells (increase in the expression of CD25 and CD69). In the presence of naïve T cells and antigen-positive MCL cells, CD20-BiTE enhanced the secretion of cytokines (IFNγ and TNFα, &gt; 2-fold increase) and CD8 T-cell cytotoxic molecule granzyme B by T cells, in a BiTE-dependent and CD20-specific manner. The enhanced effector function translated into improved antitumor cytotoxicity, as activated T cells treated with CD20-BiTE exerted 43- 72% increase in the killing efficacy of JeKo-1 BTK-KD cells. CD20-BiTE-combined CAR T cells endowed with enhanced antitumor activity overcome tumor antigen escape and resistance to current CD19-CAR T cell therapy: when primary T cells and CD19-CAR T cells were co-cultured with MCL cells, addition of CD20-BiTE potentiated T cell-dependent cytotoxicity ( p &lt; 0.001). Since both CD19-dependent and -independent CAR T cell-resistance often develop during adoptive cell therapy in MCL, we sought to overcome the resistance in MCL by combining a second antigen-targeted CD20-BiTE with CAR T cells or incorporating CD20-BiTE secreting T cells (engager-T cells). Remarkably, when combined with CD19-CAR T cells, CD20-BiTE mediates significant increase in the antitumor cytotoxicity, compared to T cells alone ( p ≤ 0,001 and p &lt; 0.001 for 2nM and 5nM of the BiTE, respectively), in a CD20-specific fashion, in both MCL cells with diminished CD19 expression, and CD19-CAR T-resistant primary MCL cells. Importantly, in a transwell assay, CD19-CAR T cells demonstrated restored potent killing (&gt;3-fold increase over CAR T cells alone) of the CD19-low or CAR T therapy resistant tumor cells, but only when the engager-T cells were present in the insert, suggesting the engaging molecules were able to redirect CD19-CAR T cells to CD20-positive tumor cells regardless of their CD19 expression. The anti-lymphoma efficacy of engager-CAR T cell therapy will be further evaluated in our well-established unique PDX model for MCL. In summary, we have successfully generated a CD20-directed bispecific T-cellengaging antibody and CD20-BiTE engager-T cells that could be combined with CAR T cell therapy, which was demonstrated effective in overcoming tumor antigen escape and resistance to current CD19-CAR T cell therapy in MCL.


Toward clinical-scale nonviral gene-edited CAR-NK cells for cell therapy

Director, R&D, Cell Biology, Thermo Fisher Scientific, Carlsbad, CA, USA

Abstract: Improving the accessibility and effectiveness of cell therapies is essential to meet the growing demand for cancer treatments. Engineered natural killer (NK) cells represent a promising modality, offering safety, effectiveness, and the possibility of allogeneic use. This article highlights gene editing techniques such as CRISPR-Cas9 for enhancement of NK cell functionality, and explores nonviral transfection methods and scalable manufacturing processes. Additionally, a case study on anti-Meso3 CAR-NK cells targeting ovarian cancer cell line is explored, showcasing the enhanced efficacy of engineered CAR-NK cells for killing cancer cells and their potential for clinical scale applications.


Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany

Nawid Albinger, Jessica Hartmann, Evelyn Ullrich

Abstract: AbstractChimeric antigen receptor (CAR)-T cell therapies are on the verge of becoming powerful immunotherapeutic tools for combating hematological diseases confronted with pressing medical needs. Lately, CAR-NK cell therapies have also come into focus as novel therapeutic options to address hurdles related to CAR-T cell therapies, such as therapy-induced side effects. Currently, more than 500 CAR-T and 17 CAR-NK cell trials are being conducted worldwide including the four CAR-T cell products Kymriah, Yescarta, Tecartus and Breyanzi, which are already available on the market. Most CAR-T cell-based gene therapy products that are under clinical evaluation consist of autologous enriched T cells, whereas CAR-NK cell-based approaches can be generated from allogeneic donors. Besides modification based on a second-generation CAR, more advanced CAR-immune cell therapeutics are being tested, which utilize precise insertion of genes to circumvent graft-versus-host disease (GvHD) or employ a dual targeting approach and adapter CARs in order to avoid therapy resistance caused by antigen loss. In this review, we are going to take a closer look at the commercial CAR-T cell therapies, as well as on CAR-T and CAR-NK cell products, which are currently under evaluation in clinical trials, that are being conducted in Germany.


Employing the tumor microenvironment to regulate CAR expression in engineered lymphocytes for safer cell therapy

Abstract: Exploitation du microenvironnement tumoral pour réguler l'expression du CAR dans les lymphocytes génétiquement modifiés pour une thérapie cellulaire sécurisée Résumé non disponible


CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences

Vinmec Research Institute of Stem Cell and Gene Technology, College of Health Sciences, VinUniversity, Hanoi, Vietnam.

Abstract: Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.


CRISPR Meets CAR T-cell Therapy

American Association for Cancer Research (AACR)

Abstract: Abstract Using CRISPR/Cas9 technology, researchers have devised a method to deliver a CAR gene to a specific locus, TRAC, in T cells. This targeted approach yielded therapeutic cells that were more potent even at low doses; in a mouse model of acute lymphoblastic leukemia, they outperformed CAR T cells created with a randomly integrating retroviral vector.


CAR-T Cell Therapy for HIV Cure

AIDS Research Institute, IrsiCaixa, 08916 Barcelona, Spain

Abstract: The HIV-1 latent reservoir is considered the major barrier to achieve the eradication, although some evidences indicate that curing HIV-1 is a feasible goal [...]


First CAR T-Cell Therapy Approved for Solid Tumors

Abstract: Abstract: China has approved the first CAR T-cell therapy that targets solid tumors, satricabtagene autoleucel (satri-cel), for patients with claudin 18.2–positive, HER2-negative gastric or gastro-esophageal junction cancer. The approval stems from a phase II trial that found the cells increased progression-free survival and overall survival. Scientists are excited about the decision but caution that more research is necessary to improve the effectiveness of CAR T cells against solid tumors.


Combined nanoparticle-mediated photothermal therapy to enhance CAR-T cell immunotherapy efficacy in stiff cholangiocarcinoma

Abstract: Thérapie photothermique médiée par des nanoparticules pour améliorer l'efficacité de l'immunothérapie CAR-T dans le cholangiocarcinome rigide Le cholangiocarcinome (CCA) est un cancer des voies biliaires présentant une forte résistance aux traitements conventionnels. Cette résistance est principalement attribuée aux fibroblastes associés au cancer (CAF) qui produisent une matrice extracellulaire (MEC) dense et rigide, constituant une barrière physique limitant l'accès des thérapies et des cellules immunitaires aux cellules tumorales. Pour surmonter cet obstacle, nous avons proposé l'utilisation d'une thérapie photothermique (PTT) médiée par des nanoparticules (NPs) métalliques pour moduler le microenvironnement tumoral (TME), déstabiliser la MEC et faciliter l'infiltration des cellules immunitaires. Les macrophages étant des régulateurs clés du TME, nous avons étudié les effets combinés de différentes NPs, avec ou sans activation laser, sur leur polarisation et l'inflammation. Nous avons développé un test prédictif rapide, basé sur une analyse en composantes principales (ACP), pour classifier les réponses immunitaires. En utilisant la lignée THP-1 DUAL différenciée en macrophages M0, M1 et M2, nous avons analysé des marqueurs inflammatoires clés et observé les changements d'expression génique induits par ces traitements. L'ACP nous a permis d'identifier des réponses distinctes des macrophages aux différents traitements avec des NPs métalliques. Les GIONF induisent initialement une polarisation des macrophages vers un profil M2, mais après exposition au laser, ces macrophages adoptent un phénotype de type M1. De plus, la PTT médiée par les GIONF favorise un sous-type de macrophages M1 distinct des macrophages M1 classiques, car ils n'activent pas la voie du facteur régulateur de l'interféron (IRF) mais induisent plutôt l'expression du gène de la synthase inductible de l'oxyde nitrique (iNOS). Ces résultats révèlent l'interaction complexe de la PTT médiée par les NPs sur le comportement des macrophages. La deuxième partie de cette thèse se concentre sur le développement d'un modèle de sphéroïde multicellulaire de CCA in vitro visant à reproduire le plus fidèlement possible le microenvironnement du CCA et ses barrières physiques. Ce modèle a ensuite été utilisé pour évaluer l'efficacité de l'immunothérapie par cellules T à récepteur antigénique chimérique (CAR-T) sur des sphéroïdes de CCA traités par la PTT médiée par des NPs. Afin de mimer les CAF, nous avons utilisé des cellules stellaires hépatiques immortalisées (hTERT-HSC), capables de sécréter du collagène de type 1 et pour le CCA, nous avons utilisé la lignée cellulaire humaine EGI-1. Cette étude a démontré une interaction protectrice synergique entre ces deux lignées cellulaires perturbée par l'exposition aux NPs et au laser, entraînant une augmentation de la mort cellulaire tumorale. Après validation du modèle sphéroïde multicellulaire 3D de CCA humain, nous avons introduit des cellules T non transduites et des cellules CAR-T ciblant les récepteurs EGFR. En cinq jours, les cellules CAR-T EGFR ont induit une destruction notable des sphéroïdes tumoraux, particulièrement dans les sphéroïdes EGI-1, par rapport aux sphéroïdes hTERT-HSC ou cocultivées. De plus, la combinaison des NPs GIONF, du laser et des cellules CAR-T EGFR a entraîné la destruction tumorale la plus significative. Ces résultats ont soutenu l'intérêt de mener des investigations précliniques in vivo. Pour valider les prédictions des études in vitro, nous sommes passés à un modèle in vivo. La dernière partie de ma thèse présente des résultats préliminaires sur les effets des NPs GIONF, suivis d'une hyperthermie modérée induite par la PTT et de la thérapie par cellules CAR-T EGFR, sur un modèle murin de CCA. Ce traitement combiné a provoqué une désorganisation notable des structures de collagène et a favorisé l'infiltration des cellules CAR-T, ralentissant efficacement la croissance tumorale.


Targeting Cancer at its Core: Cellular and Genetic Approaches Via CAR-T Cell Therapy CAR-T Cell Therapy of Cancer

International Journal of Innovative Science and Research Technology

Bandaru Aashritha, Ambati Akshara, Nandini Kongara, P. Veeresh Babu

Abstract: Cancer has recently overtaken other conditions as the foremost cause of death worldwide. While numerous conventional treatment modalities and cytotoxic immunotherapies are available, the intricate nature of tumor biology— driven by a multitude of genetic and cellular factors underlying tumorigenesis and metastasis—necessitates the development of advanced treatment approaches capable of acting on cellular as well as genetic fronts. Amid these advancements, Chimeric Antigen Receptor (CAR) T-cell therapy has risen as a pioneering frontier in the domain of T-cell engineering. Here, T cells obtained from the patient are engineered ex vivo to carry synthetic receptors designed to recognize tumor-associated antigens. A key feature is that these modified receptors can identify tumor antigens without requiring MHC presentation. Recently, CAR-T cell therapy has achieved significant clinical milestones, inducing remission in up to 80% of patients with hematologic malignancies, particularly those with acute lymphoblastic leukemia (ALL) and certain subtypes of non-Hodgkin lymphoma, such as large B-cell lymphoma. The anti-CD19 CAR design, UCART19, has demonstrated remarkable therapeutic potency in managing relapsed or refractory hematologic malignancies. Furthermore, other surface antigens, including CD20 and CD22, prevalent in various leukemias and lymphomas, are being actively explored as therapeutic targets, with multiple clinical trials underway. Although its application is presently concentrated on blood cancers, the integration of advanced modalities—such as bispecific CARs, tandem CARs, inhibitory CARs, multi-antigen targeting, CRISPR-based gene editing, and nanoparticle-mediated delivery—holds the promise of significantly enhancing its efficacy. These advancements may extend its utility to both hematologic and solid tumors, offering a treatment paradigm that is not only rapid and precise but also safer compared to traditional modalities. The purpose of this review is to offer an in-depth analysis of the benefits and emerging developments in CAR T-cell immunotherapy, while underscoring its rising advantage over conventional treatments like chemotherapy and radiotherapy.


The Fate(s) of CAR T-Cell Therapy: Navigating the Risks of CAR+ T-Cell Malignancy

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. 1

Abstract: Abstract The introduction of chimeric antigen receptor (CAR) T-cell therapy represents a landmark advancement in treating resistant forms of cancer such as leukemia, lymphoma, and myeloma. However, concerns about long-term safety have emerged following an FDA investigation into reports of second primary malignancies (SPM) after CAR-T cell treatment. This review offers a thorough examination of how genetically modified T cells might transform into CAR+ SPM. It explores genetic and molecular pathways leading to T-cell lymphomagenesis, the balance between CAR T-cell persistence, stemness, and oncogenic risk, and the trade-off of T-cell exhaustion, which may limit therapy efficacy but potentially reduce lymphomagenesis risk. Significance: An FDA probe into 22 cases of second primary T-cell malignancies following CAR T-cell therapy stresses the need to investigate their origins. Few may arise from preexisting genetic and epigenetic alterations and those introduced during therapeutic engineering. Technological advances, regulatory oversight, and patient monitoring are essential to mitigate potential risks.


Immune Checkpoint Inhibitors and Car-T Cell Therapy: Thrombotic and Vascular Complications

Abstract: Background: Due to the different genetic properties of malignant neoplasms and their tendency to cause the formation of blood clots, the risk of these complications is much higher than in the general population. There is even a higher risk of blood clots forming during chemotherapy or hormone therapy for cancer. Aim: This paper will summarise publications to gain a better understanding of the risks of blood clots associated with checkpoint inhibitors and CAR-T cell therapy of cancer. The review will also address potential problems and guide how to address them. Even when used on their own, checkpoint inhibitors can cause blood clots, albeit at a lower rate than chemotherapy; however, this assumption has not been definitively proven, as ICI-type agents are rarely given to cancer patients as monotherapy (or if given, these cancers baseline thrombogenicity is less active sui generis). The incidence of these problems varies depending on the type of disease, patient characteristics and somewhat on immunotherapeutic drug selection itself. It is important to inform doctors who prescribe these treatments of this fact and try to provide ideas which may help make good individual decisions. The anticoagulant prophylaxis is probably indicated in many such cases, even with monotherapy in cancer. However, still on a somewhat individual basis, as prospective, multicentre, double blind trials are not available, recommendations are based on some rather anecdotal, or retrospective data in respect of disease type, treatment and patient characteristics and the selection of an optimal anticoagulant prophylactic approach.


A Protease-Mediated Regulatory Chimeric Antigen Receptor (CAR): "Double Arm" CAR System Improves Tumor-Cell-Specificity of CAR-T Cell Therapy

Satoru Aoyama, Shunichiro Yasuda, Daisuke Watanabe, Hiroki Akiyama, Yoshihiro Umezawa, Ayako Nogami, Osamu Miura, Norihiko Kawamata

Department of Immunotherapy for Hematopoietic Disorders, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

Abstract: 【 Introduction 】 CAR-T cell therapy has shown excellent therapeutic effects against some malignancies including refractory B cell lymphoma or leukemia. This adoptive T cell transfer therapy is an attractive methodology; however, there are several disadvantages to be overcome. Current CAR-T cell therapy targets single cell-surface molecule, which leads to damage of normal cells expressing the target protein. Such "On-target / off-tumor" effect is one of the major adverse effects. Improvement of target-cell-specificity is needed to avoid this serious adverse effect and to expand target diseases of this therapy. Here, we show the protease-mediated "Double-Arm" CAR-T cell system, which improved the specificity of CAR-T cell therapy by recognizing two distinct cell-surface proteins. We designed two types of CARs: "Effector CAR" and "Scissors CAR". The "Effector CAR" is constituted of a single chain Fv fragment (scFv) targeting a cell-surface protein (protein X) on tumor cells, Human Immunodeficiency Virus protease (HIVPR) recognition polypeptide sequence, and a functional domain of CD3-zeta. The "scissors CAR" is constituted of a recognition portion targeting another protein (protein Y) and HIVPR. The HIVPR induces cleavage of the recognition polypeptide sequence in the effector CAR leading to inactivation of the effector CAR when the CAR-T cells contact with cells expressing both proteins X and Y. 【 Material and Methods 】 For proof of principle, we first constructed "anti-CD19 mCherry CAR" harboring mCherry fluorescence protein in the cytoplasmic region under the HIVPR recognition polypeptide sequence. Also, we constructed "anti-CD19 scissors CAR", low affinity "anti-HER2 (4D5-3) scissors CAR" and high affinity "anti-HER2 (4D5-8) scissors CAR". To analyze the target-cell-dependent cleavage of mCherry CAR, 293T cells expressing these CARs were co-cultured with target cells, including K562 (CD19-, HER2-), Raji (CD19+, HER2+), or SK-BR-3 (CD19-, HER2+). To obtain target cells expressing both CD19 and HER2, Raji and SK-BR-3 cells were molecularly manipulated. (1) To evaluate efficiency of this system, after co-cultivation of CAR-transduced 293T and the target cells (K562, Raji, SK-BR-3), the localization of mCherry was examined under the microscopy and Western blotting. (2) To assess the T cell activation, we constructed "anti-CD19 effector CAR" and established Jurkat cells expressing both the "effector CAR" and the "anti-HER2 scissors CAR". These cells were co-cultured with wild type or engineered Raji or SK-BR-3 cells. T cell activation was analyzed with flowcytometric analysis. (3) To assess the CAR activity of this system, we transduced these CARs to primary T cells from healthy donors. After co-cultivation with the target cells, we measured target-specific cytotoxic activity. 【 Results 】 (1) Transduced "anti-CD19 mCherry CAR" was detected as a membrane-bound protein in 293T cells. Co-cultivation of 293T cells expressing both the "anti-CD19 mCherry CAR" and "anti-HER2 scissors CAR" with engineered Raji cells expressing both CD19 and HER2 induced cleavage of the recognition site and translocation of the mCherry from the membrane to the cytoplasm. These results suggested that this system would regulate activities of CAR-T cell through HIVPR-mediated cleavage of the "effector CAR" in vitro. (2) Jurkat cells expressing "anti-CD19 effector CAR" were activated through a target-cell-dependent manner. Furthermore, "anti-HER2 scissors CAR" attenuated T cell activation driven by "anti-CD19 effector CAR" when Jurkat cells expressing both the "anti-CD19 effector CAR" and the "anti-HER2 scissors CAR" contacted with target-cells expressing both CD19 and HER2. In addition, high affinity 4D5-8 scissors CAR showed more potent attenuation than the low affinity 4D5-3 scissors CAR. (3) Primary human T cells expressing "anti-CD19 effector CAR" showed CD19-expressing target-cell-specific cytotoxic activity. We also demonstrated that "Double Arm" primary human CAR-T cells showed tumor-cell-specificity as seen in cell-line models described above. 【Discussion】 Our "Double-Arm" CAR-T cell system has improved tumor-cell-specificity even in primary human T-cells as we expected. This system would attenuate the adverse effects of clinical CAR-T cell therapies. Disclosures No relevant conflicts of interest to declare.


In vivo CAR therapy: quo vadis?

Executive advisor, NewCo, Beverly Hills, CA, USA

Abstract: In vivo CAR therapies are rapidly emerging as a strategy to address the scalability, access, and toxicity limitations associated with conventional ex vivo CAR-T cell products. This article reviews viral and LNP–RNA platform technologies, emerging clinical evidence, and key safety and regulatory considerations relative to established CAR-T and immune cell engager approaches. While early progress is encouraging, careful translational evaluation is essential to determine whether in vivo CAR strategies can ultimately meet or surpass current standards of care across oncology, autoimmunity, and other indications.


A Novel Protease-Mediated Chimeric Antigen Receptor (CAR): "Double-Arm" CAR-T Cell System Improves Target Specificity of CAR-T Cell Therapy

Abstract: 【 Introduction 】 CAR-T cell therapy is an attractive methodology in the field of cancer immunotherapy. Anti-CD19 CAR is used for treating refractory B cell malignancies and shows excellent therapeutic effects. However, there are several disadvantages to be overcome in this therapy. "On-target / off-tumor" effect is one of such adverse effects. Current CAR-T cell therapy targets single cell-surface molecule, which leads to damage of normal cells expressing the target protein. Improvement of target-cell-specificity is one of important issues in CAR-T cell therapy to avoid this serious adverse effect. Here, we show the protease-mediated "Double-Arm" CAR-T cell system (Figure), which improved the specificity of CAR-T cell therapy by recognizing two distinct cell-surface proteins. We designed two types of CAR: "Effector CAR" and "Scissors CAR" (Figure, left panel). The "effector CAR" is constituted of a single chain Fv fragment (scFv) targeting a cell-surface protein (protein X) on tumor cells, Human Immunodeficiency Virus protease (HIVPR) recognition polypeptide sequence, and a functional domain of CD3-zeta. The "scissors CAR" is constituted of a recognition portion targeting another protein (protein Y) and HIVPR. The HIVPR induces cleavage of the recognition polypeptide sequence in the effector CAR leading to inactivation of the effector CAR when the CAR-T cells contact with cells expressing both protein X and Y (Figure, right panel). 【 Material and Methods 】 For proof of principle, we first constructed "anti-CD19 mCherry CAR" harboring mCherry fluorescence protein in the cytoplasmic region under the HIVPR recognition polypeptide sequence. Also, we constructed "anti-CD19 scissors CAR" and "anti-HER2 scissors CAR". To analyze the target-cell-dependent cleavage of mCherry CAR, 293T cells expressing these CARs were co-cultured with target cells, including K562 (CD19-, HER2-), Raji (CD19+, HER2+), or SK-BR-3 (CD19-, HER2+). To obtain target cells expressing both CD19 and HER2, Raji and SK-BR-3 cells were molecularly manipulated. (1) To evaluate efficiency of this system, after co-cultivation of CAR-transduced 293T cell and target cells (K562, Raji, SK-BR-3), the localization of mCherry was examined under the microscopy and Western blotting. (2) To assess the T cell activation, we constructed "anti-CD19 effector CAR" and established Jurkat cells expressing both the "effector CAR" and the "anti-HER2 scissors CAR". These cells were co-cultured with wild type or engineered Raji or SK-BR-3 cells. T cell activation was analyzed with flowcytometric analysis and IL-2 mRNA expression measured with qRT-PCR. 【 Results 】 (1) Transduced "anti-CD19 mCherry CAR" was detected as a membrane-bound protein in 293T cell. Co-cultivation of 293T cell expressing both the "anti-CD19 mCherry CAR" and "anti-HER2 scissors CAR" with engineered Raji cells expressing both CD19 and HER2 induced cleavage of the recognition site and translocation of the mCherry from the membrane to cytoplasm. In addition, the cleavage was inhibited by a HIVPR inhibitor, Saquinavir. These results suggested that this novel system would regulate CAR-T cell activities through HIVPR-mediated cleavage of the "effector CAR" in vitro. (2) Jurkat cells expressing "anti-CD19 effector CAR" were activated through the target-cell-dependent manner. In addition, "anti-HER2 scissors CAR" attenuated T cell activation driven by "anti-CD19 effector CAR" when Jurkat cells expressing both the "anti-CD19 effector CAR" and the "anti-HER2 scissors CAR" contacted with the target cells expressing both CD19 and HER2. 【Discussion】 This is a novel protease-mediated controllable CAR system. The "scissors CAR" regulated activity of CAR-T cells depending on expression pattern of target molecules on the target cells. Our "Double-Arm" CAR-T cell system (Figure) would improve target specificity. It would attenuate the adverse effects and contribute to expansion in application of CAR-T cell therapy other than B cell malignancies. Figure Disclosures No relevant conflicts of interest to declare.


Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

Canadian Journal of Health Technologies, CADTH

Abstract: What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy. The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS. Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management. Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy. What Did We Do? We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines. Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes. The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1. We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual. We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS. What Does This Mean? Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality. To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.


Transplantation in combination with CAR T-cell therapy for refractory/relapsed aggressive B-cell lymphoma after failure of CD19 CAR-T cell therapy

Fan Yang, Rui Liu, Yuelu Guo, Lixia Ma, Miaomiao Cao, Biping Deng, Haifeng Wu, Alex H. Zhang, Xiaoyan Ke, Kai Hu

1Department of Lymphoma and Myeloma Research Center, Beijing, China

Abstract: Abstract Background: The prognosis for patients with refractory/relapsed aggressive B-cell lymphoma (R/R B-NHL) who have failed CD19 CAR-T cell therapy is exceptionally poor. Aims: This study conducted a retrospective analysis of the treatment efficacy and survival of the patients who underwent autologous transplantation combined with another targeted CAR-T therapy(auto-HSCT+CAR-T) and allogeneic transplantation with donor-derived CAR-T therapy (allo-HSCT+donor CAR-T) after failing CD19 CAR-T therapy. Methods: From May 2020 to March 2024, 24 patients were included (Table 1). The median age was 39 years (range: 16-54). Diagnoses included DLBCL NOS (n=12), HGBL (n=9), PMBL (n=2), and MCL (n=1). The median IPI score was 3 (range: 2-5). Fourteen patients (58.3%) presented with extranodal lesions, and 8 (33.3%) had bulky disease (&gt;7cm).After bridging therapy (BT), 7 of the 24 patients (29.2%) exhibited disease progression before transplantation. Twelve patients (50%) were selected for auto-HSCT+CAR-T and the other 12 (50%) for allo-HSCT+donor CAR-T, at a median of 8 months (range: 2-48) post-CD19 CAR-T infusion. Prior to the study, CD20/CD22 antigen expression in tumor tissue was confirmed by pathology, with the target selected based on antigen expression. The conditioning regimen for the auto-HSCT+CAR-T group was BEAM, while that for the allo-HSCT+donor CAR-T group consisted of a busulfan-fludarabine-based regimen. In the allo-HSCT+donor CAR-T group, there was 1 MSD, 1 MUD, and 10 HID. Tacrolimus,MMF, short-term MTX, and ATG were employed for GVHD prophylaxis. Results: The median number of CAR-T cells infused was 2.2×10^6/kg (range: 0.3-4.48×10^6/kg). The expansion of CAR-T cells was monitored in all patients, with the median time for both auto and donor CAR-T cells being 7 days post-infusion. The incidence of grade 3 CRS was 25% (6/24). Grade 1-2 neurotoxicity occurred in 4.2% (1/24) of patients. Nineteen patients experienced infections, with 16 (66.7%) suffering from grade 3 or higher severity. Among the patients who underwent allo-HSCT+donor CAR-T, 3 of 12 (25%) developed aGVHD(Table 2). The median follow-up period was 28.6 months (95% CI: 25.2-52.2). The ORR was 91.7%, with a CR of 83.3% and a PR of 8.3%. The median OS was 14.56 months (95% CI: 8.9-45.6), and the median PFS was 9.21 months (95% CI: 5.12-12.9). Among the 12 patients treated with autoHSCT+CAR-T therapy, 11 (91.7%) achieved CR, while 7 (63.6%) survived disease-free. In this cohort, 4 patients (33.3%) relapsed and died, while 1 patient (8.3%) died from an infection. In the alloHSCT+donor CAR-T group, 9 (75%) achieved CR and 2 (16.7%) achieved PR, with 4 (36.4%) surviving disease-free. In this group, 3 patients (25%) relapsed and died, while 5 (41.7%) died due to infections. Conclusion: Transplantation combined with CAR-T therapy presents an effective option for R/R B-cell lymphoma following the failure of CD19 CAR-T. Effective BT prior to transplantation significantly enhances survival rates.


Management of Infections and Vaccination in CAR-T Cell Therapy

Journal of Bone Marrow Transplantation and Cellular Therapy

JOURNAL OF BONE MARROW TRANSPLANTATION AND CELLULAR THERAPY

Abstract: Candidates for CAR-T cell therapy are at increased risk of infections due to the high degree of pre-existing immunosuppression. In addittion, the currently approved CAR-T cell therapy products have severe toxicities, including cytokine release syndrome (CRS) and immune-effector cell associated neurological syndrome (ICANS), which treatments may result in deep and long-term immunological deficits, as the CAR-T cells can persist for years. Approximately 18% to 34% of patients develop infections within the first 2 months after CAR-T therapy despite antimicrobial prophylaxis. The goals of the present manuscript are: 1) Describe the procedures necessary for the clinical and epidemiological evaluation of the chimeric antigen receptor T-cell therapy (CAR-T cell therapy) candidate, classify the infectious risk, define the criteria for the implementation of prophylactic, empirical and preemptive antimicrobial strategies and guide laboratory and clinical monitoring of the infectious events; 2) Define the indications and contraindications of inactivated and attenuated vaccines and propose a vaccination schedule before and after CAR-T therapy.


Vaccine Boosting CAR-T Cell Therapy: Current and Future Strategies

Emmanuel Owusu Ansah, Andy Baah, Emmanuel Boateng Agyenim

Department of Gene Therapy, Thrivus Institute for Biomedical Science and Technology, Accra, Ghana

Abstract: Immunotherapy for cancer treatment is growing at an unprecedented rate since the inception of chimeric antigen receptor T (CAR-T) cells. However, the efficacy of CAR-T cells against solid tumors is hampered by various issues, including “on-target, off-tumor toxicities,” T cell exhaustion, and immunosuppressive tumor microenvironment. To overcome these limitations, recent advances focus on optimizing CAR-T cells using vaccines to develop more effective cell immunotherapies. Here, we summarize the most recent studies on how vaccine-based CAR-T therapies are advancing the response of cancer immunotherapy as well as the current state of their clinical and preclinical development. Finally, we share perspectives on how future studies can incorporate other strategies to augment the antitumor response of vaccine-assisted CAR-T cell therapy.


CAR T-cell Therapy for Solid Tumors?

Abstract: Abstract Scientists have identified a wide variety of challenges preventing the development of effective CAR T-cell therapies for solid tumors, but they are investigating just as many potential solutions. Progress has been slow, but many researchers remain optimistic that successful CAR T-cell therapies, either alone or in combination with other treatments, will eventually be developed.


The Role of Physical Therapy Following CAR T-Cell Therapy: A Case Report

Ovid Technologies (Wolters Kluwer Health)

Helaine Firestein, PT, DPT, CLTMemorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (USA)..

Abstract: Background: Diffuse large B-cell lymphoma (DLBCL) affects 7 out of 100 000 people in the United States every year. Chimeric antigen receptor (CAR) T-cell therapy is approved by the Food and Drug Administration to treat patients with relapsed/refractory DLBCL who have not responded to 2 prior lines of therapy. CAR T-cell therapy can lead to debilitating side effects necessitating rehabilitation intervention. Case Description: This case report details a 38-year-old woman with refractory DLBCL who received CAR T-cell therapy. The patient experienced grade 2 cytokine release syndrome and grade 4 immune effector cell-associated neurotoxicity syndrome, which resulted in, among other symptoms, lower extremity paraplegia. Upon medical stabilization, the patient was referred to physical therapy. Outcomes: The patient participated in acute care rehabilitation for 8 weeks and progressed significantly toward her prior level of function before being discharged to an inpatient rehabilitation facility. Upon discharge, the patient was able to ambulate with a rolling walker, a knee orthosis, and supervision for safety and had initiated stair training. Discussion/Conclusion: Physical therapists need to understand and recognize the range of side effects that can occur following CAR T-cell therapy. As more patients receive CAR T-cell therapy to treat malignancies, acute care oncology units will undoubtedly be challenged with patients exhibiting severe side effects. Physical therapists are well trained to address physical impairments resulting from CAR T-cell therapy's side effects and will play a vital role in these patients' interdisciplinary care.


FDA Approves Second CAR T-cell Therapy

Abstract: Abstract The FDA approved the chimeric antigen receptor T-cell therapy axicabtagene ciloleucel, making it the second such treatment for blood cancers in the United States. The therapy is indicated for adults with certain non-Hodgkin lymphomas who have tried at least two other treatments.


CAR-T Cell Therapy

International Journal of Molecular Sciences

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA

Abstract: CAR-T therapy has revolutionized the treatment of select hematological malignancies, namely, acute lymphoblastic leukemia and large B-cell lymphomas [...]


CAR T-cell Therapy: Defining Response Characteristics

Abstract: Abstract Findings from a phase I study suggest that the durability of patients' response to CAR T-cell therapy, and their long-term survival, are influenced by whether they have minimal residual or morphologic disease prior to treatment. The former fared better overall, and also experienced less-severe side effects from this form of immunotherapy.


Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors


Organometal Halide Perovskites as Visible-Light Sensitizers for Photovoltaic Cells

Journal of the American Chemical Society

Akihiro Kojima, Kenjiro Teshima, Yasuo Shirai, Tsutomu Miyasaka

Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan, Graduate School of Engineering, Toin University of Yokohama, and Peccell Technologies, Inc., 1614 Kurogane-cho, Aoba, Yokohama, Kanagawa 225-8502, Japan, and Graduate School of Engineering, Tokyo Polytechnic University, 1583 Iiyama, Atsugi, Kanagawa 243-0297, Japan


Phylogenetic identification and in situ detection of individual microbial cells without cultivation

Lehrstuhl für Mikrobiologie, Technische Universität München, Germany.

Abstract: The frequent discrepancy between direct microscopic counts and numbers of culturable bacteria from environmental samples is just one of several indications that we currently know only a minor part of the diversity of microorganisms in nature. A combination of direct retrieval of rRNA sequences and whole-cell oligonucleotide probing can be used to detect specific rRNA sequences of uncultured bacteria in natural samples and to microscopically identify individual cells. Studies have been performed with microbial assemblages of various complexities ranging from simple two-component bacterial endosymbiotic associations to multispecies enrichments containing magnetotactic bacteria to highly complex marine and soil communities. Phylogenetic analysis of the retrieved rRNA sequence of an uncultured microorganism reveals its closest culturable relatives and may, together with information on the physicochemical conditions of its natural habitat, facilitate more directed cultivation attempts. For the analysis of complex communities such as multispecies biofilms and activated-sludge flocs, a different approach has proven advantageous. Sets of probes specific to different taxonomic levels are applied consecutively beginning with the more general and ending with the more specific (a hierarchical top-to-bottom approach), thereby generating increasingly precise information on the structure of the community. Not only do rRNA-targeted whole-cell hybridizations yield data on cell morphology, specific cell counts, and in situ distributions of defined phylogenetic groups, but also the strength of the hybridization signal reflects the cellular rRNA content of individual cells. From the signal strength conferred by a specific probe, in situ growth rates and activities of individual cells might be estimated for known species. In many ecosystems, low cellular rRNA content and/or limited cell permeability, combined with background fluorescence, hinders in situ identification of autochthonous populations. Approaches to circumvent these problems are discussed in detail.


Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

Kazutoshi Takahashi, Koji Tanabe, Mari Ohnuki, Megumi Narita, Tomoko Ichisaka, Kiichiro Tomoda, Shinya Yamanaka


Multilineage Potential of Adult Human Mesenchymal Stem Cells

Mark F. Pittenger, Alastair M. Mackay, Stephen C. Beck, Rama K. Jaiswal, Robin Douglas, Joseph D. Mosca, Mark A. Moorman, Donald W. Simonetti, Stewart Craig, Daniel R. Marshak

Osiris Therapeutics, 2001 Aliceanna Street, Baltimore, MD 21231–3043, USA.

Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.


A simple salting out procedure for extracting DNA from human nucleated cells


Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement

M. Dominici, K. Le Blanc, I. Mueller, I. Slaper-Cortenbach, F.C Marini, D.S. Krause, R.J. Deans, A. Keating, D.J. Prockop, E.M. Horwitz


Continuous cultures of fused cells secreting antibody of predefined specificity


Photoelectrochemical cells


Detailed Balance Limit of Efficiency of<i>p-n</i>Junction Solar Cells

Shockley Transistor, Unit of Clevite Transistor, Palo Alto, California

Abstract: In order to find an upper theoretical limit for the efficiency of p-n junction solar energy converters, a limiting efficiency, called the detailed balance limit of efficiency, has been calculated for an ideal case in which the only recombination mechanism of hole-electron pairs is radiative as required by the principle of detailed balance. The efficiency is also calculated for the case in which radiative recombination is only a fixed fraction fc of the total recombination, the rest being nonradiative. Efficiencies at the matched loads have been calculated with band gap and fc as parameters, the sun and cell being assumed to be blackbodies with temperatures of 6000°K and 300°K, respectively. The maximum efficiency is found to be 30% for an energy gap of 1.1 ev and fc = 1. Actual junctions do not obey the predicted current-voltage relationship, and reasons for the difference and its relevance to efficiency are discussed.


CheckM: assessing the quality of microbial genomes recovered from isolates, single cells, and metagenomes

Donovan H. Parks, Michael Imelfort, Connor T. Skennerton, Philip Hugenholtz, Gene W. Tyson

Natural Sciences and Engineering Research Council of Canada, Great Barrier Reef Foundation, Australian Research Council, Discovery Outstanding Researcher Award, Australian Research Council, Australian Research Council

Abstract: Large-scale recovery of genomes from isolates, single cells, and metagenomic data has been made possible by advances in computational methods and substantial reductions in sequencing costs. Although this increasing breadth of draft genomes is providing key information regarding the evolutionary and functional diversity of microbial life, it has become impractical to finish all available reference genomes. Making robust biological inferences from draft genomes requires accurate estimates of their completeness and contamination. Current methods for assessing genome quality are ad hoc and generally make use of a limited number of “marker” genes conserved across all bacterial or archaeal genomes. Here we introduce CheckM, an automated method for assessing the quality of a genome using a broader set of marker genes specific to the position of a genome within a reference genome tree and information about the collocation of these genes. We demonstrate the effectiveness of CheckM using synthetic data and a wide range of isolate-, single-cell-, and metagenome-derived genomes. CheckM is shown to provide accurate estimates of genome completeness and contamination and to outperform existing approaches. Using CheckM, we identify a diverse range of errors currently impacting publicly available isolate genomes and demonstrate that genomes obtained from single cells and metagenomic data vary substantially in quality. In order to facilitate the use of draft genomes, we propose an objective measure of genome quality that can be used to select genomes suitable for specific gene- and genome-centric analyses of microbial communities.


On the Origin of Cancer Cells

Director of the Max Planck Institute for Cell Physiology, Berlin-Dahlem, Germany


Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells

Hadi Valadi, Karin Ekström, Apostolos Bossios, Margareta Sjöstrand, James J Lee, Jan O Lötvall


Dendritic cells and the control of immunity


Efficient Hybrid Solar Cells Based on Meso-Superstructured Organometal Halide Perovskites

Michael M. Lee, Joël Teuscher, Tsutomu Miyasaka, Takurou N. Murakami, Henry J. Snaith

Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.

Abstract: Perovskite Photovoltaics For many types of low-cost solar cells, including those using dye-sensitized titania, performance is limited by low open-circuit voltages. Lee et al. (p. 643 , published online 4 October; see the Perspective by Norris and Aydil ) have developed a solid-state cell in which structured films of titania or alumina nanoparticles are solution coated with a lead-halide perovskite layer that acts as the absorber and n-type photoactive layer. These particles are coated with a spirobifluorene organic-hole conductor in a solar cell with transparent oxide and metal contacts. For the alumina particles, power conversion efficiencies of up to 10.9% were obtained.


Electron-Hole Diffusion Lengths Exceeding 1 Micrometer in an Organometal Trihalide Perovskite Absorber

Samuel D. Stranks, Giles E. Eperon, Giulia Grancini, Christopher Menelaou, Marcelo J. P. Alcocer, Tomas Leijtens, Laura M. Herz, Annamaria Petrozza, Henry J. Snaith

University of Oxford, Clarendon Laboratory, Parks Road, Oxford OX1 3PU, UK.

Abstract: Unrestricted Travel in Solar Cells In the past 2 years, organolead halide perovskites have emerged as a promising class of light-harvesting media in experimental solar cells, but the physical basis for their efficiency has been unclear (see the Perspective by Hodes ). Two studies now show, using a variety of time-resolved absorption and emission spectroscopic techniques, that these materials manifest relatively long diffusion paths for charge carriers energized by light absorption. Xing et al. (p. 344 ) independently assessed (negative) electron and (positive) hole diffusion lengths and found them well-matched to one another to the ~100-nanometer optical absorption depth. Stranks et al. (p. 341 ) uncovered a 10-fold greater diffusion length in a chloride-doped material, which correlates with the material's particularly efficient overall performance. Both studies highlight effective carrier diffusion as a fruitful parameter for further optimization.