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Med (New York, N.Y.) Jun 2024Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department...
Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department of Medicine 5 (Hematology and Oncology), University Hospital Erlangen, Germany.
Topics: Humans; Autoimmune Diseases; Immunotherapy, Adoptive; Germany; Receptors, Chimeric Antigen
PubMed: 38878762
DOI: 10.1016/j.medj.2024.04.004 -
Reviews in Medical Virology Jul 2024Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of adoptive T-cell therapy in treating cytomegalovirus infections post-haematopoietic stem cell transplantation: A systematic review and meta-analysis.
Cytomegalovirus (CMV) infection poses significant risks in allogeneic haematopoietic stem cell transplant (allo-HSCT) recipients. Despite advances in antiviral therapies, issues such as drug resistance, side effects, and inadequate immune reconstitution remain. This systematic review and meta-analysis aim to evaluate the efficacy and safety of adoptive cell therapy (ATC) in managing CMV infections in allo-HSCT recipients. Adhering to preferred reporting items for systematic reviews and meta-analyses guidelines, we conducted a comprehensive database search through July 2023. A systematic review and meta-analysis were conducted on studies involving HSCT patients with CMV infections treated with ATC. The primary outcome was the response rate to ATC, and secondary outcomes included adverse events associated with ATC. The Freeman-Tukey transformation was applied for analysis. In the meta-analysis of 40 studies involving 953 participants, ATC achieved an overall integrated response rate of 90.16%, with a complete response of 82.59% and a partial response of 22.95%. ATC source, HLA matching, steroid intake, and age group markedly influenced response rates. Donor-derived T-cell treatments exhibited a higher response rate (93.66%) compared to third-party sources (88.94%). HLA-matched patients demonstrated a response rate of 92.90%, while mismatched patients had a lower rate. Children showed a response rate of 83.40%, while adults had a notably higher rate of 98.46%. Adverse events were minimal, with graft-versus-host disease occurring in 24.32% of patients. ATC shows promising response rates in treating CMV infections post-HSCT, with an acceptable safety profile. However, to establish its efficacy conclusively and compare it with other antiviral treatments, randomised controlled trials are essential. Further research should prioritise such trials over observational and one-arm studies to provide robust evidence for clinical decision-making.
Topics: Humans; Cytomegalovirus Infections; Hematopoietic Stem Cell Transplantation; T-Lymphocytes; Treatment Outcome; Immunotherapy, Adoptive; Cytomegalovirus; Transplantation, Homologous
PubMed: 38878003
DOI: 10.1002/rmv.2558 -
Clinical and Translational Medicine Jun 2024
Topics: Neuroblastoma; Humans; Anaplastic Lymphoma Kinase; Protein Kinase Inhibitors; Immunotherapy, Adoptive
PubMed: 38877641
DOI: 10.1002/ctm2.1732 -
American Society of Clinical Oncology... Jun 2024Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in... (Review)
Review
Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell-directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.
Topics: Humans; Multiple Myeloma; Immunotherapy; Immunotherapy, Adoptive; Antibodies, Bispecific; Combined Modality Therapy; Treatment Outcome; Receptors, Chimeric Antigen
PubMed: 38875506
DOI: 10.1200/EDBK_432204 -
Scientific Reports Jun 2024Chimeric antigen receptor T-cell (CAR-T) therapies are a paradigm-shifting therapeutic in patients with hematological malignancies. However, some concerns remain that...
Chimeric antigen receptor T-cell (CAR-T) therapies are a paradigm-shifting therapeutic in patients with hematological malignancies. However, some concerns remain that they may cause serious cardiovascular adverse events (AEs), for which data are scarce. In this study, gradient boosting machine algorithm-based model was fitted to identify safety signals of serious cardiovascular AEs reported for tisagenlecleucel in the World Health Organization Vigibase up until February 2024. Input dataset, comprised of positive and negative controls of tisagenlecleucel based on its labeling information and literature search, was used to train the model. Then, we implemented the model to calculate the predicted probability of serious cardiovascular AEs defined by preferred terms included in the important medical event list from European Medicine Agency. There were 467 distinct AEs from 3,280 safety cases reports for tisagenlecleucel, of which 363 (77.7%) were classified as positive controls, 66 (14.2%) as negative controls, and 37 (7.9%) as unknown AEs. The prediction model had area under the receiver operating characteristic curve of 0.76 in the test dataset application. Of the unknown AEs, six cardiovascular AEs were predicted as the safety signals: bradycardia (predicted probability 0.99), pleural effusion (0.98), pulseless electrical activity (0.89), cardiotoxicity (0.83), cardio-respiratory arrest (0.69), and acute myocardial infarction (0.58). Our findings underscore vigilant monitoring of acute cardiotoxicities with tisagenlecleucel therapy.
Topics: Humans; Pharmacovigilance; Machine Learning; Female; Male; Middle Aged; Cardiovascular Diseases; Aged; Adult; Immunotherapy, Adoptive; Adolescent; Young Adult; Child; Receptors, Antigen, T-Cell; Hematologic Neoplasms; Child, Preschool
PubMed: 38871843
DOI: 10.1038/s41598-024-64466-x -
Frontiers in Immunology 2024Chimeric antigen receptor-expressing T cells (CAR T cells) have revolutionized cancer treatment, particularly in B cell malignancies. However, the use of autologous T...
INTRODUCTION
Chimeric antigen receptor-expressing T cells (CAR T cells) have revolutionized cancer treatment, particularly in B cell malignancies. However, the use of autologous T cells for CAR T therapy presents several limitations, including high costs, variable efficacy, and adverse effects linked to cell phenotype.
METHODS
To overcome these challenges, we developed a strategy to generate universal and safe anti-CD19 CAR T cells with a defined memory phenotype. Our approach utilizes CRISPR/Cas9 technology to target and eliminate the and genes, reducing graft-versus-host and host-versus-graft responses. Additionally, we selected less differentiated T cells to improve the stability and persistence of the universal CAR T cells. The safety of this method was assessed using our CRISPRroots transcriptome analysis pipeline, which ensures successful gene knockout and the absence of unintended off-target effects on gene expression or transcriptome sequence.
RESULTS
experiments demonstrated the successful generation of functional universal CAR T cells. These cells exhibited potent lytic activity against tumor cells and a reduced cytokine secretion profile. The CRISPRroots analysis confirmed effective gene knockout and no unintended off-target effects, validating it as a pioneering tool for on/off-target and transcriptome analysis in genome editing experiments.
DISCUSSION
Our findings establish a robust pipeline for manufacturing safe, universal CAR T cells with a favorable memory phenotype. This approach has the potential to address the current limitations of autologous CAR T cell therapy, offering a more stable and persistent treatment option with reduced adverse effects. The use of CRISPRroots enhances the reliability and safety of gene editing in the development of CAR T cell therapies.
CONCLUSION
We have developed a potent and reliable method for producing universal CAR T cells with a defined memory phenotype, demonstrating both efficacy and safety . This innovative approach could significantly improve the therapeutic landscape for patients with B cell malignancies.
Topics: Humans; CRISPR-Cas Systems; Immunotherapy, Adoptive; Antigens, CD19; Gene Editing; Transcriptome; Receptors, Chimeric Antigen; Immunologic Memory; T-Lymphocytes; Phenotype; Cell Line, Tumor
PubMed: 38868778
DOI: 10.3389/fimmu.2024.1401683 -
Nature Medicine Jun 2024Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have...
Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Middle Aged; Antigens, Neoplasm; Immunotherapy, Adoptive; GPI-Linked Proteins; Neoplasm Proteins; Receptors, Chimeric Antigen; Neoplasm Metastasis; T-Lymphocytes; Prostate-Specific Antigen
PubMed: 38867077
DOI: 10.1038/s41591-024-02979-8 -
Journal For Immunotherapy of Cancer Jun 2024Adoptive cancer immunotherapy, using engineered T-cells, expressing chimeric antigen receptor or autologous tumor infiltrating lymphocytes became, in recent years, a...
BACKGROUND
Adoptive cancer immunotherapy, using engineered T-cells, expressing chimeric antigen receptor or autologous tumor infiltrating lymphocytes became, in recent years, a major therapeutic approach for diverse types of cancer. However, despite the transformative potential of adoptive cancer immunotherapy, this field still faces major challenges, manifested by the apparent decline of the cytotoxic capacity of effector CD8 T cells upon their expansion. To address these challenges, we have developed an ex vivo "synthetic immune niche" (SIN), composed of immobilized CCL21 and ICAM1, which synergistically induce an efficient expansion of antigen-specific CD8 T cells while retaining, and even enhancing their cytotoxic potency.
METHODS
To explore the molecular mechanisms through which a CCL21+ICAM1-based SIN modulates the interplay between the proliferation and cytotoxic potency of antigen-activated and CD3/CD28-activated effector CD8 T cells, we performed integrated analysis of specific differentiation markers via flow cytometry, together with gene expression profiling.
RESULTS
On day 3, the transcriptomic effect induced by the SIN was largely similar for both dendritic cell (DC)/ovalbumin (OVA)-activated and anti-CD3/CD28-activated cells. Cell proliferation increased and the cells exhibited high killing capacity. On day 4 and on, the proliferation/cytotoxicity phenotypes became radically "activation-specific"; The DC/OVA-activated cells lost their cytotoxic activity, which, in turn, was rescued by the SIN treatment. On longer incubation, the cytotoxic activity further declined, and on day7, could not be rescued by the SIN. SIN stimulation following activation with anti-CD3/CD28 beads induced a major increase in the proliferative phenotype while transiently suppressing their cytotoxicity for 2-3 days and fully regaining their killing activity on day 7. Potential molecular regulatory pathways of the SIN effects were identified, based on transcriptomic and multispectral imaging profiling.
CONCLUSIONS
These data indicate that cell proliferation and cytotoxicity are negatively correlated, and the interplay between them is differentially regulated by the mode of initial activation. The SIN stimulation greatly enhances the cell expansion, following both activation modes, while displaying high survival and cytotoxic potency at specific time points following stimulation, suggesting that it could effectively reinforce adoptive cancer immunotherapy.
Topics: Cell Proliferation; Humans; Intercellular Adhesion Molecule-1; Chemokine CCL21; Lymphocyte Activation; Immunotherapy, Adoptive; CD8-Positive T-Lymphocytes; Cytotoxicity, Immunologic
PubMed: 38866588
DOI: 10.1136/jitc-2024-009011 -
The New England Journal of Medicine Jun 2024
Topics: Female; Humans; Male; Middle Aged; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Lymphoma, T-Cell
PubMed: 38865665
DOI: 10.1056/NEJMe2405538 -
The New England Journal of Medicine Jun 2024Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received...
Indolent CD4+ cytotoxic chimeric antigen receptor (CAR) T-cell lymphoma involving the small intestine was diagnosed in a patient who had previously received ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy for treatment of myeloma. Targeted messenger RNA sequencing revealed the presence of CAR gene product in tumor cells. Whole-genome sequencing of samples of tumor and peripheral blood identified a single lentiviral insertion site within the second intron of the gene. In addition, numerous genetic alterations that may have contributed to malignant transformation were identified in the tumor sample. (Funded by MedStar Georgetown University Hospital.).
Topics: Humans; Male; Middle Aged; Biological Products; CD4-Positive T-Lymphocytes; Immunotherapy, Adoptive; Lymphoma, T-Cell; Multiple Myeloma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Antineoplastic Agents, Immunological
PubMed: 38865661
DOI: 10.1056/NEJMoa2401530