cesnicabtagene autoleucel (ARI0002h) / August Pi i Sunyer Biomedical Research Institute - LARVOL DELTA

Expanding the boundaries of CAR T-cell therapy: Implementation of an outpatient-at-home (OATH) model (ASH 2025) - "Eligible patients (pts) were adults with R/R B-cell precursor acute lymphoblastic leukemia (BCP-ALL) or multiple myeloma (MM) who met predefinedclinical criteria (ECOG 0–1, no active infections, availability of a trained caregiver, and low tumor burden).Pts and caregivers received pre-enrolment education, providing symptom detection tools, including thecaregiver-performed immune effector cell encephalopathy (ICE) score and an adverse event action plan.The protocol included AH lymphodepletion with fludarabine (30 mg/m²/d) and cyclophosphamide (300mg/m²/d) for three days, followed by fractionated infusions (10%, 30%, and 60%) of one of the academicCAR-T CD19-directed (varnimcabtagene autoleucel, ARI0001, 1x10⁶ CAR T cells/kg) or BCMA-directed(cesnicabtagene autoleucel, ARI0002h, 3x10⁶ CAR T cells/kg), depending on the underlying malignancy.Infusions were administered in a day care unit, with AH follow-up post-infusion.Pts were monitored via twice-daily telephone..."

CAR T-Cell Therapy • Clinical • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • CNS Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Multiple Myeloma

Isotype-specific heavy/light chain quantification identifies prognostic biomarkers after ARI0002h BCMA-directed CAR-T cell therapy in multiple myeloma (ASH 2025) - "Recovery of uninvolved HLCs in a subset of patients suggests thathumoral immune reconstitution may progressively occur over time. Further investigation will determinehow this immunological recovery relates to CAR T-cell persistence and impacts long-term clinicaloutcomes."

Biomarker • CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma

Multi-omic analysis reveals metabolic fitness of the ARI0002h BCMA CAR T-cell infusion product as a key predictor of clinical outcomes in multiple myeloma (ASH 2025) - "These findingssuggest that assessing CAR-T metabolism prior to infusion may help predict therapeutic response andguide future product optimization. Ongoing analyses will further validate and expand these insights."

CAR T-Cell Therapy • Clinical • Clinical data • IO biomarker • Omic analysis • Hematological Malignancies • Multiple Myeloma • CD4 • CD8 • GSTM1 • S100A9 • SDHC

The point-of-care network with the BCMA-directed CART ARI0002h (Cesnicabtagene Autoleucel) in patients with relapsed/refractory multiple myeloma maintains efficacy and safety in real-world data (ASH 2025) - "Prior to infusion, lymphodepletion (LD) with cyclophosphamide and fludarabine wasadministered...Tocilizumab and steroids were administered to 80% and 39% of pts, respectively.Fourteen pts (14%) died, mainly due to disease progression (n=10) and infection (n=3).Fifty-seven (58%) pts received the booster dose at a median time of 4.3m, with none developing relevanttoxicities; 19% received a second LD according to loss of CART persistence...ARI0002h demonstrated notable efficacy and manageable toxicity in patients with RRMM, very close tothe data reported in the pivotal clinical trial. These findings support the feasibility of a PoC CAR-T networkstrategy with real-world evidence."

Clinical • IO biomarker • Real-world • Real-world evidence • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Plasmacytoma

ARI0002h (Cesnicabtagene Autoleucel), an Academic Point-of-Care B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor (CAR) T-Cell Strategy: Activity and Safety after Fractionated Initial Therapy and Booster Dose in 60 Patients with Relapsed/Refractory Multiple Myeloma (ASH 2023) - P1/2 | "Lymphodepletion (LD) with cyclophosphamide and fludarabine was used...Tocilizumab and steroids were administered in 68% (mainly for persistent grade 1 CRS) and 30% of pts, respectively... Results from 30 additional pts and a longer follow-up of the first cohort confirm the deep and durable responses obtained with ARI0002h. The booster dose may be partially responsible for the improvement of responses over time and exhaustion may play a role in relapse."

Clinical • IO biomarker • Hematological Malignancies • Infectious Disease • Inflammation • Mood Disorders • Multiple Myeloma • Oncology • Plasmacytoma • Septic Shock • PD-1 • TIGIT

Sequential Scmultiomics of In Vivo CAR-T Cells Allows Characterization of Transcriptional Differences between Patients, and Identifies IL10 As a Potential Mechanism of Resistance to CAR-T Cells in MM (ASH 2023) - P1/2 | "To shed some light on specific transcriptomic programs activated after CAR-T cell administration, we interrogated longitudinal samples of CAR-T cells collected from patients enrolled in CARTBCMA-HCB-01 (NCT04309981) and academic clinical trial in patients with RRMM (Oliver-Caldes A, et al... Overall, our analysis combining scRNA-seq/scTCR-seq with novel machine learning models, allowed us to characterize key transcriptional differences observed between patients, infusion products and in vivo infused CAR-T, as well as between CAR-T according to their location (PB vs. BM). Importantly, our results identify IL10 as a regulatory mechanism promoting CAR-T cell dysfunction, representing a potential target to be modulated for the development of improved CAR-T therapies for MM."

CAR T-Cell Therapy • IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • CD4 • CD8 • CREM • IL10 • PRDM1 • TCF7

Longitudinal Transcriptomic Analysis of CAR-T Cells at Single-Cell Level Allows the Identification of Molecular Mechanisms Promoting Long-Term CAR-T Cell Persistence in MM (ASH 2023) - P1/2 | "To shed light on the potential mechanisms driving CAR-T cell persistence we performed longitudinal transcriptomic analysis, at single cell level, of CAR-T cells from a patient enrolled in CARTBCMA-HCB-01 clinical trial (NCT04309981) (Oliver-Caldes A, et al... Our analysis clearly showed that most CAR-T cells after administration presented expression of key markers related to T cell memory and survival without clonal expansion, suggesting that memory induction is crucial for long-term persistence. Interestingly, prior to tumor relapse, we observed reactivation of CAR-T cell with the enrichment of effector and activation signatures, and GRN analysis identified FOS and NR4A2 regulons as potential drivers involved in CAR-T cell reactivation. Overall, scRNA-seq/scTCR-seq coupled with novel machine learning models provides relevant mechanistic insights that could uncover useful targets to be modulated for the development of long-term persistent CAR-T cells."

CAR T-Cell Therapy • IO biomarker • Omic analysis • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology • Respiratory Diseases • CD8 • GZMB • GZMK • NR4A2

Outpatient Reinfusion of CAR-T Cesnicabtagene Autoleucel (ARI0002h) in Multiple Myeloma Is Feasible and Safe (ASH 2024) - "After 3 months from the initial dose, patients who remain in response, have not developed severe complications, and have an additional dose available, receive a reinfusion of 3x106 CAR-T cells/kg, with or without prior lymphodepletion (LD) (fludarabine 30 mg/m2 plus cyclophosphamide 300 mg/m2 for three days on days -6 to -4), depending on the absence or presence of circulating CAR-T cells, respectively. Only two patients experienced a relapse after 6 months of receiving the reinfusion.CONCLUSIONSOutpatient reinfusion of cesni-cel is feasible and safe, allowing patients to remain in an outpatient setting throughout the procedure and optimizing hospital resources. The insights gained from this outpatient program will enable us to expand the indications for home management of patients treated with CAR-T."

Clinical • Hematological Disorders • Hematological Malignancies • Inflammation • Multiple Myeloma • Neutropenia • Oncology

Identification and Evaluation of Novel Sdab-Based CAR-T Cells Against BCMA with Improved Therapeutic Efficacy for Multiple Myeloma (ASH 2024) - "However, despite high remission rates observed after B-Cell Maturation Antigen (BCMA) CAR-T therapy, there is a lack of long-term responses (median PFS of 13.8 months for ide-cel and 34.9 months for cilta-cel) (2), highlighting the need for improved therapeutic strategies...Interestingly, in comparison to several scFv-based CAR constructs (based on ARI0002h and a humanized version of ide-cel), our selected SdAb-based CARs presented a similar activation capacity with lower tonic signal...These findings underscore the promise of sdAb-based CAR-T cell therapy as a novel and effective treatment for BCMA-positive MM and potentially other hematological malignancies. The enhanced cytotoxicity and antitumoral efficacy observed in preclinical models pave the way for further clinical development and potential therapeutic application, offering new hope for patients with relapsed or refractory multiple myeloma."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Multiple Myeloma • Oncology • HAVCR2 • IFNG • IL15 • IL2 • IL7 • LAG3 • PD-1

Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy in Relapsed and Refractory Multiple Myeloma – a Meta-Analysis (ASH 2024) - "We included 7 trials each of Ciltacabtagene autoleucel (cilta-cel) and Idecabtagene vicleucel (ida-cel) while 21 trials used different CAR-T cell therapies including GPRC5D, HDS269B, C-CAR088, HBI0101, CART-ddBCMA, ALLO-715, ARI0002h. This analysis has limitations with significant heterogeneity among studies. There were different CAR T-cell therapies with diverse designs of studies which limit the generalization of results."

CAR T-Cell Therapy • Retrospective data • Anemia • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

Enhanced Antitumoral Efficacy of ARI0002h CAR-T with CD28-TMD in Normal and Low BCMA Expressing Myeloma Cells (ASH 2024) - "CONCLUSION : The incorporation of a CD28-TMD into the ARI0002h CAR enhances its potency against MM tumor cell lines with both normal and reduced BCMA expression, demonstrating superior in vitro and in vivo efficacy. This modification enables better control of higher tumor burdens and offers improved long-term disease management compared to CARs with CD8α-TMD."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD8 • LAG3 • PD-1 • TIGIT

Macrophage activation syndrome-like in multiple myeloma patients treated with the academic CAR-T against BCMA ARI0002h. (PubMed, Front Immunol) - "MAS-like is associated with poorer responses, reduced PFS and OS, especially in patients meeting all UCSF criteria. High tumour burden, including elevated monoclonal component, high ISS and extramedullary disease, seems to contribute to MAS-like development."

Journal • Retrospective data • Dyslipidemia • Hematological Disorders • Hematological Malignancies • Hypertriglyceridemia • Multiple Myeloma • Oncology

Macrophage Activation Syndrome-Like in Multiple Myeloma Patients Treated with the Academic Bcma-Directed Car-T Ari0002h: Genomic Insights and Clinical Implications (IMS 2025) - "MAS-like is associated with poorer responses and reduced PFS and OS, especially in patients meeting all three UCSF criteria: elevated ferritin, hypofibrinogenemia and increased LDH. High tumour burden, including elevated monoclonal component, high ISS and extramedullary disease, seems to contribute to MAS-like development."

Clinical • IO biomarker • Dyslipidemia • Hematological Disorders • Hematological Malignancies • Hypertriglyceridemia • Multiple Myeloma • PRF1 • UNC13D

Optimizing CAR-T Therapy in Multiple Myeloma: Outpatient Reinfusion of Cesnicabtagene Autoleucel (ARI0002h) (IMS 2025) - "Before first CART infusion, bridging therapy was used in 77.2%, mainly cyclophosphamide-based regimens (41.1%). Outpatient second administration of ARI0002h within a structured AH care model is safe, feasible, and effective in RRMM. This approach enables outpatient care while optimizing hospital resources. Second infusions enhanced depth of response and maintained CAR-T activity, providing a promising strategy to optimize long-term disease control in RRMM."

Clinical • Amyloidosis • CNS Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma

TIGIT blockade in the context of BCMA-CART cell therapy does not augment efficacy in a multiple myeloma mouse model. (PubMed, Oncoimmunology) - "However, this improvement was not significant compared to ARI0002h (p = 0.07). This study failed to demonstrate a significant benefit of TIGIT-blockade on ARI0002h cells despite using three different approaches, suggesting that targeting a single immune checkpoint may be insufficient."

IO biomarker • Journal • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • TIGIT

Microbiota shape metabolic and immune determinants of CAR-T therapy and correlate with outcomes in myeloma. (PubMed, Blood Cancer Discov) - "This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized BCMA-directed CAR-T therapy, ARI0002h...These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by day 100 and 180 post-infusion. These findings suggest that metabolites and gut microbiota correlate with CAR-T cell therapy responses and can be a valuable tool for risk assessment."

Biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • CD4

EXPANDING CAR T-CELL THERAPY BOUNDARIES: DEVELOPING A MIXED OUTPATIENT-AT HOME MODEL (EBMT 2025) - "Eligible patients and their caregivers underwent pre-enrolment education, providing symptom detection tools, including the caregiver-administered ICE score and an adverse event action plan.The protocol involved AH lymphodepletion with fludarabine (30 mg/m²/d i.v.) and cyclophosphamide (300 mg/m²/d i.v.) for three days, followed by fractionated infusions (10%, 30%, and 60%) of academic CD19-directed (varnimcabtagene autoleucel, ARI0001, 1x10⁶ CAR T cells/kg) or BCMA-directed (cesnicabtagene autoleucel, ARI0002h, 3x10⁶ CAR T cells/kg) based on the haematologic malignancy...The median age was 38 years (range 33–71), with 60% female, receiving a median of three prior therapies (range 2-4), including inotuzumab (20%), autologous stem cell transplantation (20%) and allogeneic stem cell transplantation (allo-SCT) (40%).The median follow-up in the home care unit was 21 days (range 12–30)...CRS was managed with a single dose of tocilizumab and dexamethasone in one..."

CAR T-Cell Therapy • Clinical • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Multiple Myeloma • Oncology

EXPANDING CAR T-CELL THERAPY BOUNDARIES: DEVELOPING A MIXED OUTPATIENT-AT HOME MODEL (EBMT 2025) - "Eligible patients and their caregivers underwent pre-enrolment education, providing symptom detection tools, including the caregiver-administered ICE score and an adverse event action plan.The protocol involved AH lymphodepletion with fludarabine (30 mg/m²/d i.v.) and cyclophosphamide (300 mg/m²/d i.v.) for three days, followed by fractionated infusions (10%, 30%, and 60%) of academic CD19-directed (varnimcabtagene autoleucel, ARI0001, 1x10⁶ CAR T cells/kg) or BCMA-directed (cesnicabtagene autoleucel, ARI0002h, 3x10⁶ CAR T cells/kg) based on the haematologic malignancy...The median age was 38 years (range 33–71), with 60% female, receiving a median of three prior therapies (range 2-4), including inotuzumab (20%), autologous stem cell transplantation (20%) and allogeneic stem cell transplantation (allo-SCT) (40%).The median follow-up in the home care unit was 21 days (range 12–30)...CRS was managed with a single dose of tocilizumab and dexamethasone in one..."

CAR T-Cell Therapy • Clinical • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Multiple Myeloma • Oncology

Academic model for CAR T development in multiple myeloma: clinical results with ARI0002h and future plans (EBMT 2025) - "Sponsored by MILTENYI BIOTEC."

Clinical • Hematological Malignancies • Multiple Myeloma • Oncology

GEM-PLASMACAR: Study to Evaluate the Safety and Efficacy of ARI0002h, for the Initial Treatment of Patients With Primary Plasma Cell Leukaemia (clinicaltrials.gov) - P2 | N=25 | Not yet recruiting | Sponsor: Fundacion Clinic per a la Recerca Biomédica

New P2 trial • Hematological Malignancies • Leukemia • Oncology

Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin's lymphoma and characterization of the loss of the target antigen. (PubMed, J Immunother Cancer) - "Based on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL."

IO biomarker • Journal • Preclinical • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CD20 • CD22 • CD79B

Catalonia treats the first multiple myeloma patient with CAR-T cells outside a clinical trial [Google translation] (Ara) - "The Catalan Institute of Oncology (ICO) has treated the first multiple myeloma patient in Catalonia with CAR-T cells funded by the Public Health System. Until now, this type of treatment could only be done within clinical trials to test its effectiveness....The immunotherapy is called Ari-0002h."

Clinical • Multiple Myeloma

Rheumatic Complications Post-CAR-T Cell Therapy. Experience of a Single Center (ACR Convergence 2024) - "Patients treated with anti-CD19 CAR-T therapy (ARI-0001, (A3B1)4-1BB/CD3ζ ) and anti–BCMA CAR-T (ARI0002h) were included...Systemic and localized reactions were observed during the first weeks (mean 3.0 weeks), and inflammatory arthritis appeared after a mean time of 2 months.Five patients had CRS (all mild), treated with tocilizumab in 5 cases and anakinra in one. Rheumatological complications related to CAR-T therapy are infrequent (< 2%) and usually manifest as early inflammatory complications (within the first month) or later as inflammatory arthritis (after the second month). Given the increased use of this therapy, rheumatologists need to be aware of these previously unknown complications."

CAR T-Cell Therapy • Clinical • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Inflammatory Arthritis • Leukemia • Lupus • Lymphoma • Multiple Myeloma • Myositis • Oncology • Rare Diseases • Rheumatology • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis

Clinical impact of [18F]FDG-PET/CT in ARI0002h treatment, a CAR-T against BCMA for relapsed/refractory multiple myeloma. (PubMed, Blood Adv) - P1/2 | "These results highlight the importance of EMD evaluation by [18F]FDG-PET/CT before and after CAR T-cell infusion. NCT04309981, and EudraCT, 2019-001472-11."

FDG PET • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma

ARI0003: Co-transduced CD19/BCMA Dual-targeting CAR-T Cells for the Treatment of Non-Hodgkin Lymphoma. (PubMed, Mol Ther) - P1 | "We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase I clinical trial (CARTD-BG-01, NCT06097455) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL."

CAR T-Cell Therapy • IO biomarker • Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD19 • CD22