Chimeric Antigen Receptor Research Articles

Quantitative pharmacology of dual-targeted bicistronic CAR-T-cell therapy using multiscale mechanistic modeling.

Despite the initial success of single-targeted chimeric-antigen receptor (CAR) T-cell therapy in hematological malignancies, its long-term effectiveness is often hindered by antigen heterogeneity and escape. As a result, there is a growing interest in cell therapies targeting multiple antigens (≥2). However, the dose-exposure-response relationship and specific factors influencing the pharmacology of dual-targeted CAR-T-cell therapy remain unclear. In this study, we have developed a multiscale cellular kinetic-pharmacodynamic (CK-PD) model using case studies from CD19/CD22 and GPRC5D/BCMA autologous CAR-Ts. Initially, an invitro tumor-killing model characterized the impact of individual binder affinities and their contribution to overall potency across varying (1) effector: target (ET) ratios and (2) tumor-associated antigen (TAA) expressing cell lines. Subsequently, an integrated CK-PD model was developed in pediatric acute lymphoblastic leukemia (ALL) patients, which accounted for CAR-T-cell product composition and relative antigen abundance in patients' tumor burden to characterize patient-level multiphasic cellular kinetics using multiple bioanalytical assays (e.g., flow and qPCR-based readouts). Global sensitivity analysis highlighted relative antigen expression, maximum killing rate constant, and CAR-T expansion rate constant as major determinants for observed exposure of dual-targeted CAR-T-cell therapy. This modeling framework could facilitate dose-optimization and construct refinement for dual-targeted bicistronic CAR-T-cell therapies, serving as a valuable tool for both forward and reverse translation in drug development.

To BE or to PE: Prime editors provide more choices for epitope-editing-based immunotherapy

Epitope editing is a promising strategy for protecting hematopoietic cells from eradication by immunotherapies. Recently, in Cell Stem Cell, Ji etal. applied both base editing (BE) and prime editing (PE) to alter the epitope of CD123 in hematopoietic stem cells for CAR-T therapy against acute myeloid leukemia.1.

CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges

Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers worldwide, highlighting the urgent need for improved diagnostic and therapeutic methodologies. The standard treatment regimen generally involves surgical intervention followed by systemic therapies; however, the median survival rates for patients remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a pivotal advancement in cancer treatment. Both clinical and preclinical studies emphasize the notable efficacy of CAR T cells in targeting HCC. Various molecules, such as GPC3, c-Met, and NKG2D, show significant promise as potential immunotherapeutic targets in liver cancer. Despite this, employing CAR T cells to treat solid tumors like HCC poses considerable challenges within the discipline. Numerous innovations have significant potential to enhance the efficacy of CAR T-cell therapy for HCC, including improvements in T cell trafficking, strategies to counteract the immunosuppressive tumor microenvironment, and enhanced safety protocols. Ongoing efforts to discover therapeutic targets for CAR T cells highlight the need for the development of more practical manufacturing strategies for CAR-modified cells. This review synthesizes recent findings and clinical advancements in the use of CAR T-cell therapies for HCC treatment. We elucidate the therapeutic benefits of CAR T cells in HCC and identify the primary barriers to their broader application. Our analysis aims to provide a comprehensive overview of the current status and future prospects of CAR T-cell immunotherapy for HCC.

Acute kidney injury in hematological patients treated with CAR-T cells: risk factors, clinical presentation and impact on outcomes.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, yet it carries significant risks, including acute kidney injury (AKI). In this study, we investigated the risk factors and clinical impact of AKI in patients undergoing CAR-T cell therapy. This retrospective study involved hematologic patients treated with CAR-T therapy. Clinical and laboratory data were collected, and clinical outcomes were monitored during follow-up after CAR-T infusion. AKI was defined according to KDIGO criteria. The outcome measures included early mortality, overall survival (OS), and disease-free survival (DFS). Among the 48 patients analyzed, 14 (29%) developed AKI, with a mean onset of 6 days after CAR-T infusion. The risk of AKI was associated with baseline performance status (OR 8.65, IC95% 6.2-12, p = 0.032) and the development of severe cytokine release syndrome post-therapy (OR 16.4 95%CI 1.9-138.5, p = 0.01). Patients with AKI more frequently required intensive care. Furthermore, severe AKI was independently associated with worse clinical outcomes, including reduced OS and DFS (HR 18.2, 95%CI 2.6-27.3, p = 0.003). Additionally, patients who developed AKI post-CAR-T therapy were more likely to progress to chronic kidney disease during follow-up. In conclusion, frail patients undergoing CAR-T therapy are at an increased risk of developing AKI, which can significantly affect both short- and long-term outcomes. Preventive strategies and early recognition of AKI are essential in these patients.

Predictive value of pre-treatment circulating tumor DNA genomic landscape in patients with relapsed/refractory multiple myeloma undergoing anti-BCMA CAR-T therapy: Insights from tumor cells and T cells.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy yield remarkable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in the distribution and genetic variations in R/RMM. Herein, the ctDNA of 108 peripheral blood plasma samples from patients with R/RMM was thoroughly investigated before administration of anti-BCMA CAR-T therapy to establish its predictive potential. Flow cytometry is used primarily to detect subgroups of T cells or CAR-T cells. In this study, several tumor and T cell effector-mediated factors were considered to be related to treatment failure by an integrat analysis, including higher percentages of multiple myeloma (MM) cells in the bone marrow (P=0.013), lower percentages of CAR-T cells in the peripheral blood at peak (P=0.037), and higher percentages of CD8+ T cells (P=0.034). Furthermore, there is a substantial correlation between high ctDNA level (>143ng/mL) and shorter progression-free survival (PFS) (P=0.007). Multivariate Cox regression analysis showed that high levels of ctDNA (>143ng/mL), MM-driven high-risk mutations (including IGLL5 [P=0.004], IRF4 [P=0.024], and CREBBP [P=0.041]), number of multisite mutations, and resistance-related mutation (ERBB4, P=0.040) were independent risk factors for PFS. Finally, a ctDNA-based risk model was built based on the above independent risk factors, which serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy. Chinese Clinical Trial Registry (ChiCTR2100046474) and National Clinical Trial (NCT04670055, NCT05430945).

Folate Receptor Alpha—A Secret Weapon in Ovarian Cancer Treatment?

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Due to its nonspecific symptoms and unreliable screening tools, EOC is not diagnosed at an early stage in most cases. Unfortunately, despite achieving initial remission after debulking surgery and platinum-based chemotherapy, most patients experience the recurrence of the disease. The limited therapy approaches have encouraged scientists to search for new detection and therapeutic strategies. In this review, we discuss the role of folate receptor alpha (FRα) in EOC development and its potential application as a biomarker and molecular target in designing new EOC screening and treatment methods. We summarize the mechanisms of the action of various therapeutic strategies based on FRα, including MABs (monoclonal antibodies), ADCs (antibody–drug conjugates), FDCs (folate–drug conjugates), SMDCs (small molecule–drug conjugates), vaccines, and CAR-T (chimeric antigen receptor T) cells, and present the most significant clinical trials of some FRα-based drugs. Furthermore, we discuss the pros and cons of different FR-based therapies, highlighting mirvetuximab soravtansine (MIRV) as the currently most promising EOC-targeting drug.

A Conversation with ChatGPT about Systemic Lupus Erythematosus and Chimeric Antigen Receptor (CAR)-T Cell Therapy

A Conversation with ChatGPT about Systemic Lupus Erythematosus and Chimeric Antigen Receptor (CAR)-T Cell Therapy

An assessment model for the efficacy of autologous CD19 chimeric antigen receptor T-cell therapy and relapse or refractory diffuse large B-cell lymphoma risk.

An assessment model for the efficacy of autologous CD19 chimeric antigen receptor T-cell therapy and relapse or refractory diffuse large B-cell lymphoma risk.

Paediatric Acute Lymphoblastic Leukaemia: A Narrative Review of Current Knowledge and Advancements.

This review aims to provide an update on current knowledge regarding paediatric acute lymphoblastic leukaemia (ALL), focusing on recent advancements in diagnosis and treatment, as well as future directions in the field. ALL is the most frequently diagnosed paediatric malignancy, with advances leading to a 90% survival rate. The heterogeneity of childhood ALL requires a precise diagnostic algorithm incorporating morphological, immunophenotypic, and cytogenetic analyses. Research is exploring next-generation sequencing and artificial intelligence-aided techniques for future diagnostic approaches. Despite these advancements, global disparities in healthcare access hinder prompt diagnosis and management. The pathophysiology of ALL involves chromosomal and genetic alterations which disrupt cell-cycle regulation and result in uncontrolled lymphoblast proliferation. Environmental factors also contribute to leukaemogenesis. Risk-stratification based on genetic subtypes has significant implications for risk-based therapy. Chemotherapy is administered in three phases: induction, consolidation, and maintenance, with prophylactic intrathecal chemotherapy considered essential. For high-risk, refractory, or relapsed ALL, haematopoietic stem cell transplantation and novel therapies such as tyrosine kinase inhibitors, chimeric antigen receptor T-cell therapy, and blinatumomab immunotherapy, have improved outcomes. Ongoing clinical trials aim to further improve treatment efficacy, reduce toxicity, and increase survival. Although prevention strategies for ALL exist at three levels, the supporting evidence remains limited, highlighting a need for further research. Continued research and clinical trials are essential to addressing the gaps treatment efficacy and prevention strategies. Efforts to improve global healthcare access and integrate novel diagnostic and therapeutic approaches are crucial for advancing outcomes for paediatric patients with ALL.

Inhibition of K+ Channels Affects the Target Cell Killing Potential of CAR T Cells

Ion channels of T cells (Kv1.3, KCa3.1, and CRAC) participate in the regulation of activation and effector functions via modulation of the Ca2+-dependent pathway. T cells expressing chimeric antigen receptors (CAR T cells) showed a remarkable role in anti-tumor therapy, especially in the treatment of chemotherapy-resistant liquid cancers. Nevertheless, many challenges remain to be overcome to improve the treatment for solid tumors. In this study, we assessed the expression and role of ion channels in CAR T cells. We found that HER2-specific CAR T cells had higher KCa3.1 conductance compared to the non-transduced (NT, control) cells, which was more prominent in the CD8+ population (CD4+ cell also showed elevation). Conversely, the Kv1.3 expression level was the same for all cell types (CD4+, CD8+, CAR, and NT). Single-cell Ca2+ imaging revealed that thapsigargin-induced SOCE via CRAC is suppressed in CD8+ CAR T cells, unlike for CD4+ and CD8+ NT cells. To dissect the functional role of Kv1.3 and KCa3.1, we used specific antagonists (Kv1.3: Vm24; KCa3.1: TRAM-34): the target cell elimination capacity of the CD8+ CAR T cells was improved either by blocking KCa3.1 or Kv1.3. These results imply that ion channels could be a target in CAR T cell immunotherapy elaboration.

Clinical Application and Risk Assessment of CAR-T Cell Technology in Cancer Immunotherapy

As a cutting-edge personalized treatment method, CAR-T cell technology transforms patients' own T cells through genetic engineering, making them have the ability to specifically identify and kill tumor cells. The aim of this paper is to thoroughly organize the foundational principles and clinical utility of CAR-T cell technology, highlighting its recent advancements in treating both hematological and solid tumors. Through a comprehensive assessment of CAR-T cell technology's efficacy and risks, this study aims to inform clinical decision-making. Initially, the paper outlines the basic mechanisms of CAR-T cell technology, followed by an analysis of its notable therapeutic outcomes in hematological tumors. Additionally, it addresses the challenges posed by solid tumor treatment, including antigen expression complexity and tumor microenvironment impact. Emphasis is placed on the crucial role of regulatory bodies in enhancing oversight and developing risk management strategies to safeguard patient safety.

Optimizing CAR-T cell therapy for solid tumors: current challenges and potential strategies.

Chimeric antigen receptor (CAR)-T cell therapy demonstrates substantial efficacy in various hematological malignancies. However, its application in solid tumors is still limited. Clinical studies report suboptimal outcomes such as reduced cytotoxicity of CAR-T cells and tumor evasion, underscoring the need to address the challenges of sliding cytotoxicity in CAR-T cells. Despite improvements from fourth and next-generation CAR-T cells, new challenges include systemic toxicity from continuously secreted proteins, low productivity, and elevated costs. Recent research targets genetic modifications to boost killing potential, metabolic interventions to hinder tumor progression, and diverse combination strategies to enhance CAR-T cell therapy. Efforts to reduce the duration and cost of CAR-T cell therapy include developing allogenic and in-vivo approaches, promising significant future advancements. Concurrently, innovative technologies and platforms enhance the potential of CAR-T cell therapy to overcome limitations in treating solid tumors. This review explores strategies to optimize CAR-T cell therapies for solid tumors, focusing on enhancing cytotoxicity and overcoming application restrictions. We summarize recent advances in T cell subset selection, CAR-T structural modifications, infiltration enhancement, genetic and metabolic interventions, production optimization, and the integration of novel technologies, presenting therapeutic approaches that could improve CAR-T cell therapy's efficacy and applicability in solid tumors.

Human herpesvirus 6 (HHV-6) encephalitis secondary to chimeric antigen receptor (CAR)-T cell therapy.

Human herpesvirus (HHV)-6 encephalitis secondary to chimeric antigen receptor (CAR)-T cell therapyis relatively rare in clinical practice and needs to be differentiated from immune effector cell-associatedneurotoxicity syndrome (ICANS). We retrospectively reported a case of HHV-6 encephalitis secondary to CAR-T cell therapy. A male patient from China with diffuse large B-cell lymphoma underwent chimeric CAR-T cell therapy anddeveloped a generalized rash on the 8th day, followed by cognitive changes, memory loss, and disorientation onthe 14th day after CAR-T cell therapy. Initially, ICANS was suspected. A lumbar puncture was performed on the 18th day. The cerebrospinal fluid (CSF) analysis revealed slightly elevated protein levels and a high presence of HHV-6B sequences by mNGS. Brain MRI showed bilateral hippocampal abnormalities. The patient was ultimatelydiagnosed with HHV-6 encephalitis and treated with ganciclovir and dexamethasone. After one week of treatment,follow-up CSF analysis showed a reduction in HHV-6B sequences. The patient was discharged with improvedmemory and orientation. HHV-6 encephalitis secondary to CAR-T cell therapy may be easily confused with ICANS. Timely andaggressive diagnostic procedures, such as mNGS of CSF and cranial imaging, along with prompt antiviral therapy,are crucial for improving patient outcomes.

Identification of clonally expanded γδ T-cell populations during CAR-Tcell therapy.

Anti-CD19 Chimeric Antigen Receptor (CAR)-Tcell therapies have shown promise for treating B cell malignancies, but the clinical outcome is influenced by both the CAR-T product and the patient's immune system. The role of γδ Tcells in the context of CAR-T cell therapy remains poorly understood. This study investigates the transcriptional heterogeneity, clonal expansion and dynamics of γδ Tcells in patients undergoing anti-CD19 CAR-T cell therapy. Longitudinal single cell multi-omics analysis was performed on γδ Tcells from four patients receiving anti-CD19 CAR-T cell therapy. Single cell RNA-seq, antibody-based protein profiling (AbSeq) and full-length TCRγδ sequences revealed clonally expanded populations displaying plasticity in Tcell differentiation, and temporal dynamics of large clones, suggesting ongoing expansion and differentiation. Clonally expanded γδ Tcells had heterogeneous gene expression profiles, occupying seven transcriptionally distinct clusters. Analysis of chemokine markers indicated cluster-specific homing tendencies of circulating γδ Tcells to peripheral tissues. We found unexpectedly high frequencies of Vδ1 and Vδ3 cells in the blood with distinct gene and protein expression profiles. This analysis provides insights into the dynamic and heterogeneous nature of γδ Tcells following anti-CD19 CAR-T cell therapy, contributing valuable information for optimizing CAR-T cell therapies in B cell malignancies.

Engineering and targeting potential of CAR NK cells in colorectal cancer.

Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promise, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.

Recommendations for the timing, dosage, and usage of corticosteroids during cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR)-T cell therapy for hematologic malignancies.

Recommendations for the timing, dosage, and usage of corticosteroids during cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR)-T cell therapy for hematologic malignancies.

Chimeric antigen receptor T cells targeting CD312 as a therapy for acute myeloid leukemia.

Chimeric antigen receptor T cells targeting CD312 as a therapy for acute myeloid leukemia.

Emerging strategies to overcome ovarian cancer: advances in immunotherapy

Ovarian cancer is the second most common malignant neoplasm of gynecological origin and the leading cause of death from cancer in the female reproductive system worldwide. This scenario is largely due to late diagnoses, often in advanced stages, and the development of chemoresistance by cancer cells. These challenges highlight the need for alternative treatments, with immunotherapy being a promising option. Cancer immunotherapy involves triggering an anti-tumor immune response and developing immunological memory to eliminate malignant cells, prevent recurrence, and inhibit metastasis. Some ongoing research investigate potentially immunological advancements in the field of cancer vaccines, immune checkpoint blockade, CAR-T cell, and other strategies.

Fluctuation of physical function during chimeric antigen receptor T‐cell therapy during rehabilitation intervention: Real‐world data and risk factor analyses

AbstractIntroductionPatients undergoing chimeric antigen receptor (CAR) T‐cell therapy face prolonged treatment timelines and are prone to cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) after infusion. Disabilities in physical function and the importance of rehabilitation during CAR‐T‐cell therapy to maintain physical function have been poorly documented.MethodWe performed a retrospective cohort study to assess changes in exercise tolerance via differences in a 6‐min‐walking distance (Δ6MWD) and factors influencing it.ResultsA total of 77 patients who underwent rehabilitation during CAR‐T‐cell therapy were enrolled, and their 6MWD was 450 m (median, range 180–705 m) before and 450.5 m (107.0–735.0 m) 30 days after CAR‐T treatment. No significant alteration in Δ6MWD was observed overall (11.0 m, 95% confidence interval, −56.1 to 88.2 m). Multiple regression analyses indicated that age (over vs. under 65 years) revealed no notable differences in Δ6MWD (20 vs. 10 m), while ΔHb (β = 0.24, p = 0.03), moderate/severe CRS (grade 1 with continuous fever or grade ≥2; β = −0.25, p = 0.03), and ICANS (any grade; β = −0.22, p = 0.04) were significantly associated with lower Δ6MWD.ConclusionThis real‐world study indicated that CAR‐T‐cell therapy is less likely to reduce physical function even in older patients if rehabilitation is properly performed, whereas CRS and ICANS can be risk factors to deprive exercise tolerance.

Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.