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DRUG:

cesnicabtagene autoleucel (ARI0002h)

i
Other names: ARI0002h, CARTBCMA
Associations
Trials
Company:
August Pi i Sunyer Biomedical Research Institute
Drug class:
BCMA-targeted CAR-T immunotherapy
Related drugs:
Associations
Trials
1year
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)
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 • PD(L)-1 Biomarker • IO biomarker
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PD-1 (Programmed cell death 1) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2)
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PD-1 expression
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cyclophosphamide • fludarabine IV • Actemra IV (tocilizumab) • cesnicabtagene autoleucel (ARI0002h)
1year
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)
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.
Preclinical • CAR T-Cell Therapy • IO biomarker
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • IL10 (Interleukin 10) • PRDM1 (PR/SET Domain 1) • CREM (CAMP Responsive Element Modulator) • TCF7 (Transcription Factor 7)
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cesnicabtagene autoleucel (ARI0002h)
1year
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)
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
|
CD8 (cluster of differentiation 8) • GZMB (Granzyme B) • GZMK (Granzyme K) • NR4A2 (Nuclear Receptor Subfamily 4 Group A Member 2)
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cesnicabtagene autoleucel (ARI0002h)
over1year
Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study. (PubMed, Lancet Oncol)
ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach.
Journal • CAR T-Cell Therapy
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cesnicabtagene autoleucel (ARI0002h)
almost2years
BCMA AND CD229 DUAL-TARGETED CAR T CELL EFFECTIVELY CONTROLS MULTIPLE MYELOMA WITH LOSS OF BCMA EXPRESSION (EBMT 2023)
At our institution, we have developed an academic BCMA-BBζ CART product (ARI2h; NCT04309981) for relapsed/refractory MM patients with encouraging results... This is the first bispecific BCMA/CD229 CART cell that adequately controls BCMA-expressing and non-expressing myeloma cells. This approach could mitigate disease escape due to biallelic loss of BCMA.
CAR T-Cell Therapy • IO biomarker
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LY9 (Lymphocyte Antigen 9)
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LY9 expression
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cesnicabtagene autoleucel (ARI0002h)
almost2years
Molecular Mechanisms of CAR-T Cell Response in MM (EHA-EBMT-CART 2023)
CAR-T cells were FACS-isolated from infusion products (IP) as well as from bone marrow (BM) and peripheral blood (PB), at different times after cell infusion (1 and 3 months), from three MM patients enrolled in the academic clinical trial assessing ARI0002h... Overall, our data show that multiomic analysis are useful tools to characterize CAR-T cell dynamics after infusion, that presented different characteristics regarding their location (PB vs BM) and a heterogeneous behavior within the patients. Moreover, GRN analysis at single cell level offers an important tool to understand mechanisms modulating CAR-T cell response and to identify possible mechanisms of relapse.
CAR T-Cell Therapy • IO biomarker
|
CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • IL10 (Interleukin 10) • IL32 (Interleukin 32) • PRDM1 (PR/SET Domain 1) • PRF1 (Perforin 1)
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cesnicabtagene autoleucel (ARI0002h)
almost2years
Pre-clinical Validation of Co-transduced CD19/BCMA Dual-CAR-T Cells for NHL (EHA-EBMT-CART 2023)
Our In-house developed CARs targeting CD19 (ARI0001) and BCMA (ARI0002h) have proven safe and efficacious in the treatment of patients with B-cell malignancies and multiple myeloma, respectively. Here we present co-transduction as a feasible strategy to obtain dual CD19/BCMA CAR-T cells. ARI0003 responds better to lower CD19 levels than ARI0001 and presents advantages compared to the bicistronic strategy in terms of efficacy and to the pool in terms of time and cost of manufacturing. Our studies provide strong pre-clinical data to test ARI0003 dual-CAR-T cells in clinical trials to treat NHL patients.
Preclinical • CAR T-Cell Therapy • IO biomarker
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CD19 (CD19 Molecule)
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CD19 positive
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varnimcabtagene autoleucel (ARI-0001) • cesnicabtagene autoleucel (ARI0002h)
almost2years
BCMA CAR-T Cell Phenotype and Functionality Is Affected By Disease Stage of Multiple Myeloma Patients (ASH 2022)
In this work we performed phenotypic and functional characterization of CAR-T generated from healthy donors and MM patients at different disease stage.Method ology: Second generation CAR-T cells targeting BCMA and co-expressing BFP as a reporter gene (modified from ARI0002h CAR-T sequence1), were generated by lentiviral transduction of aCD3/aCD28 activated T cells, from each group of donor/patients, and expanded in the presence of IL-7/IL-15...Conclusion s : Our results would indicate that CAR-T generated from patients at later stages of the disease present a more differentiated phenotype, with reduced functionality and increased exhaustion features, that could compromise antitumor efficacy. Transcriptomic analysis allows the identification of molecular mechanisms that could be modulated for the development of improved therapies.
Clinical • CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker
|
PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • LAG3 (Lymphocyte Activating 3) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • TNFRSF9 (TNF Receptor Superfamily Member 9) • GZMA (Granzyme A) • IL15 (Interleukin 15) • IL7 (Interleukin 7)
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cesnicabtagene autoleucel (ARI0002h)
2years
Bicistronic CAR T Cell Against CD229 and BCMA Effectively Controls Multiple Myeloma (ASH 2022)
A BCMA-BBζ CAR T cell product (ARI2h; NCT04309981) has been developed at our Institution for relapsed/refractory MM patients with encouraging results (Fernández de Larrea, EHA 2022)...We have developed the first bispecific CD229/BCMA CAR T cell against MM, demonstrating that a single bicistronic vector encoding BCMA- and CD229-targeted CAR T cells effectively controls BCMA-expressing and non-expressing MM cells. This could be translated into complete mitigation of escape mediated by BCMA loss.
CAR T-Cell Therapy • IO biomarker
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LY9 (Lymphocyte Antigen 9)
|
cesnicabtagene autoleucel (ARI0002h)
2years
CAR-T Related Cytopenia Profile in Relapsed/Refractory Multiple Myeloma: Results of Patients Treated with ARI0002h, an Academic BCMA-Directed CAR-T Cell (ASH 2022)
All pts had previous triple-exposure to bortezomib, lenalidomide and daratumumab, and 37% were penta-exposed (addition of carfilzomib and pomalidomide). ARI0002h-related neutropenia is clinically relevant and has a slower recovery profile compared to CD19-CART therapy for lymphoma, but with three differentiated phenotypes with a similar clinical behavior. CRP level and CRS duration were the only variables associated with the duration of neutropenia.
Clinical • CAR T-Cell Therapy
|
CD19 (CD19 Molecule) • CRP (C-reactive protein)
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lenalidomide • bortezomib • Darzalex (daratumumab) • carfilzomib • pomalidomide • cesnicabtagene autoleucel (ARI0002h)
2years
Genetic Disruption of Blimp-1 Drastically Augments the Persistence and Anti-Tumour Efficacy of BCMA-Targeting CAR-T Cells (ASH 2022)
Stimulated T cells transduced with ARI2h, an in-house anti-BCMA CAR that is currently being explored in a clinical trial for relapsed/refractory MM (NCT04309981), were electroporated with either Cas9 alone (WT) or Cas9 + Prdm1-targeting sgRNA (Blimp-1 KO)... Genetic disruption of Blimp-1 caused anti-BCMA CAR-T cells to maintain a memory-like phenotype that retained effector function, even following repeated challenges with tumour cells. As a result, Blimp-1 KO CAR-T cells were considerably more effective than WT CAR-T cells at treating advanced MM in a murine model. Overall, we conclude that using gene editing to restrict Blimp-1 expression represents a promising strategy to enhance the sustained efficacy of anti-BCMA CAR-T cells.
Clinical • CAR T-Cell Therapy • IO biomarker
|
IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • IL2 (Interleukin 2) • IL7R (Interleukin 7 Receptor) • CCR7 (Chemokine (C-C motif) receptor 7) • GZMB (Granzyme B) • PRDM1 (PR/SET Domain 1) • IL7 (Interleukin 7)
|
cesnicabtagene autoleucel (ARI0002h)
2years
Identification of Molecular Mechanisms Governing CAR-T Cell Response in MM Patients Using Single Cell Transcriptomics (ASH 2022)
Methodology: CAR-T cells were FACS-isolated from infusion products (IP) as well as from bone marrow (BM) and peripheral blood (PB) from three MM patients (HCB08, IBS08 and HVA02), enrolled in the academic clinical trial CARTBCMA-HCB-01 (NCT04309981) assessing ARI0002h, an autologous CAR T-cell product targeting BCMA1, at different times after cell infusion (1 and 3 months)... Overall, our data show that multiomic analysis are useful tools to characterize CAR-T cells and their dynamics after infusion, that presented different characteristics regarding their location (PB vs BM) and a heterogeneous behavior within the patients. Moreover, GRN analysis at single cell level offers an important tool to understand mechanisms modulating CAR-T cell response and to identify possible mechanisms of relapse.
Clinical • CAR T-Cell Therapy • IO biomarker
|
CD8 (cluster of differentiation 8) • LAG3 (Lymphocyte Activating 3) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • CD4 (CD4 Molecule) • TNFRSF9 (TNF Receptor Superfamily Member 9) • IL10 (Interleukin 10) • FOXP1 (Forkhead Box P1) • GZMB (Granzyme B) • HLA-DRA (Major Histocompatibility Complex, Class II, DR Alpha) • GZMA (Granzyme A) • IL32 (Interleukin 32) • PRDM1 (PR/SET Domain 1) • PRF1 (Perforin 1)
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LAG3 expression
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cesnicabtagene autoleucel (ARI0002h)
2years
Co-Transduced CD19/BCMA Dual-Targeting CAR-T Cells for the Treatment of Non-Hodgkin Lymphoma (ASH 2022)
CAR constructs targeting CD19 (ARI0001) or BCMA (ARI0002h) were engineered in our institution and both have demonstrated safety and efficacy for treating patients with B-cell lymphoid neoplasms and multiple myeloma, respectively. Co-transduction is advantageous with respect to the pool since it only requires one manufacturing process, decreasing the cost of the therapy and increasing patients' access to these novel therapies. Our studies provide a strong rational to test CD19/BCMA dual-CAR-T cells in clinical trials for the treatment of NHL patients.
CAR T-Cell Therapy • IO biomarker
|
CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001) • cesnicabtagene autoleucel (ARI0002h)
3years
Correlative Biological Studies Related to the Response, Peak and Persistence of ARI0002h, an Academic BCMA-Directed CAR-T Cell, with Fractionated Initial Infusion and Booster Dose for Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) (ASH 2021)
ARI0002h production is fast and feasible. The peak of CART expansion occurs after 14d of infusion and also in some pts after reinfusion, regardless of LR, which suggests that LR may not be mandatory to allow further expansion after booster dose. Responses obtained are deep and construct immunogenicity seems to be low.
Clinical • CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • LAG3 (Lymphocyte Activating 3) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • CD4 (CD4 Molecule)
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LAG3 expression
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cesnicabtagene autoleucel (ARI0002h)