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DRUG:

varnimcabtagene autoleucel (ARI-0001)

i
Other names: ARI0001, ARI 0001, IMN003A, IMN 003A, ARI-0001, PEI 19-187, CART19, adult differentiated autologous T-cells transducted with a lentivirus to express a chimeric antigen receptor with anti-CD19 specificity [A3B1] conjugated to the 4-aBB and CD3z, IMN-003A, PEI19187, PEI 19 187
Company:
August Pi i Sunyer Biomedical Research Institute, Immuneel Therap
Drug class:
CD19-targeted CAR-T immunotherapy
Related drugs:
5ms
CART19-BE-02: Study of the Infusion of ARI-0001 Cells in Patients With CD19 + Acute Lymphoid Leukemia Resistant or Refractory to Therapy (clinicaltrials.gov)
P2, N=50, Active, not recruiting, Sara V. Latorre | Trial primary completion date: Dec 2023 --> Dec 2024
Trial primary completion date
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varnimcabtagene autoleucel (ARI-0001)
12ms
Reinfusion of Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies Is Feasible with Sustained Responses (ASH 2023)
B-ALL pt received Dasatinib, Inotuzumab and CNS prophylaxis. Preparative conditioning regimen for these 4 patients were: Fludarabine-Cyclophosphamide (n=1), with Rituximab (n=2) and Rituximab with Nivolumab (n=1)... Reinfusion of varnimcabtagene autoleucel (IMN-003A) is feasible, safe and well tolerated. Preparative conditioning regimen for reinfusion needs personalization guided by CAR persistence, disease biology (CD20, PDL1 expression) and haematological reserve. After reinfusion, prolonged B cell aplasia was observed with 100% ORR at D+28 in evaluable pts.
Clinical • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • CD20 (Membrane Spanning 4-Domains A1)
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PD-L1 expression • CD19 positive
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Opdivo (nivolumab) • dasatinib • Rituxan (rituximab) • cyclophosphamide • Besponsa (inotuzumab ozogamicin) • fludarabine IV • varnimcabtagene autoleucel (ARI-0001)
12ms
Factors Associated with Refractoriness or Relapse after Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies: Phase 2 First-in-India Industry (IMAGINE) Study (ASH 2023)
In the IMAGINE study, with ORR 80. 9% at primary endpoint and median PFS not reached, relapse was seen in 37. 5% pts with median PFS of 178 days.
Clinical • P2 data • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • CD20 (Membrane Spanning 4-Domains A1) • CD8 (cluster of differentiation 8) • IL6 (Interleukin 6) • CD22 (CD22 Molecule) • CD4 (CD4 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
12ms
Modified Endothelial Activation and Stress Index (mEASIX) Score and Immune Effector Cell Associated Haematotoxicity (ICAHT) Following Varnimcabtagene Autoleucel (IMN-003A), a CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy, in the Phase-2 Study (IMAGINE) (ASH 2023)
3%) each received red cells, platelets, G-CSF and romiplostim; majority did not need supportive treatment...mEASIX score may be used as an early predictor of CRS for permissive use of Tocilizumab before onset of severe symptoms. This is the first-in-India industry study evaluating mEASIX and ICAHT in patients treated with CAR-T cell therapy. mEASIX score 1 at D+4 was mildly predictive of CRS. All patients developed ICAHT but only a small number of patients needed supportive treatment.
P2 data • CAR T-Cell Therapy • IO biomarker
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IL6 (Interleukin 6)
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LDH elevation
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Actemra IV (tocilizumab) • varnimcabtagene autoleucel (ARI-0001) • Nplate (romiplostim)
12ms
Hypogammaglobulinemia and Infection Risk in Relapsed Refractory B Cell Malignancy Patients Treated with Varnimcabtagene Autoleucel (IMN-003A), a CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy, in the Phase-2 Study (IMAGINE) (ASH 2023)
This is the first-in-India report evaluating hypogammaglobulinemia and infection risk post CAR-T cell infusion. The IVIg usage and documented infections was more in responders. The safety and efficacy outcomes of varnimcabtagene autoleucel (IMN-003A) are consistent with reported outcomes of approved CD19 directed CAR-T cell therapies.
Clinical • P2 data • CAR T-Cell Therapy
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varnimcabtagene autoleucel (ARI-0001)
12ms
Cytokine Profile Following Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies in the First-in-India Industry Phase-2 Study (IMAGINE) (ASH 2023)
This is the first-in-India industry study evaluating cytokine profile at multiple timepoints before and after var-cel infusion and its correlation with clinical CRS. As per published literature, IL-6 levels were significantly associated with clinical CRS and showed association with peak var-cel expansion. There was a sharp increase in both IL-6 and IL-10 levels in serum post infusion, concurrent with clinical CRS prior to peak var-cel expansion.
Clinical • P2 data
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IFNG (Interferon, gamma) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • IL2 (Interleukin 2) • IL10 (Interleukin 10) • IL15 (Interleukin 15) • IL1B (Interleukin 1, beta) • IL7 (Interleukin 7)
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IL10 elevation
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varnimcabtagene autoleucel (ARI-0001)
12ms
The Bengaluru Score - a Prognostic Predictive Score for Clinical Efficacy Outcomes Based on Discovery Cohort of Patients Treated with Varnimcabtagene Autoleucel (IMN-003A) in the Phase-2 (IMAGINE) Study (ASH 2023)
The Bengaluru Score is probably the first predictive prognostic score for clinical efficacy outcomes and is based on multivariant statistical analysis in the discovery cohort of patients in the IMAGINE study integrating clinical, laboratory and translational data with a very high sensitivity, specificity and accuracy. The score highlights the role of overall T cell expansion in the final product for B-ALL (but not the T N+CM subsets on its own) and for B-NHL, disease burden and haematological reserve. This suggests that earlier use of varnimcabtagene autoleucel may positively influence efficacy outcome but needs to be proven in the real-world setting.
Clinical • P2 data
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CD8 (cluster of differentiation 8) • IL6 (Interleukin 6) • CD4 (CD4 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
12ms
Varnimcabtagene Autoleucel (IMN-003A): Differences in T Cell Subset Phenotype in B-ALL and B-NHL Cohorts Did Not Influence Efficacy Outcomes in the Phase-2 Study (IMAGINE) (ASH 2023)
Differences in the manufacturing outcomes (CAR % transduction, fold expansion) and T cell phenotype (naïve and effector T EMRA cell subsets) were observed in Apheresis and FP, between the B-ALL and B-NHL cohorts. A higher fraction of relatively more differentiated T cell phenotypes of effector (T EMRA) and effector memory (T EM) and a lower fraction of naïve T cells in the B-NHL cohort and within CD8 T cells, reflects a manufacturing conundrum for B-NHL patients with a higher target dose and the CD4: CD8 ratio in the final product. However, these differences in the final product did not adversely impact the clinical responses at D+90 with equivalent efficacy in both cohorts.
Clinical • P2 data
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CD8 (cluster of differentiation 8) • CCR7 (Chemokine (C-C motif) receptor 7)
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varnimcabtagene autoleucel (ARI-0001)
12ms
Varnimcabtagene Autoleucel (IMN-003A): Pharmacokinetic Profile with Predominant Naïve and Central Memory Phenotype Demonstrates Sustained In Vivo Persistence and Durable Responses in a First-in-India Industry Phase-2 Study (IMAGINE) (ASH 2023)
A fractionated infusion of 1 x 10 6 CAR+ cells (IMN-003A)/kg for B-ALL cohort and 5 x 10 6 CAR+ cells (IMN-003A)/kg for B-NHL cohort was administered over 3 days as 10%, 30% and 60% fractions after Fludarabine-Cyclophosphamide lymphodepletion regimen (LR). Varnimcabtagene autoleucel manufacturing process results in a drug product characterized by highly pure T cells, with high proportion of naïve and central memory polyfunctional cells. In this industry-led first-in-India phase-2 study, var-cel resulted in a cytokine response with sustained in vivo proliferation and persistence resulting in robust and durable responses.
P2 data • PK/PD data • Preclinical • IO biomarker
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CD8 (cluster of differentiation 8) • IL6 (Interleukin 6) • CD4 (CD4 Molecule) • CCR7 (Chemokine (C-C motif) receptor 7)
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cyclophosphamide • fludarabine IV • varnimcabtagene autoleucel (ARI-0001)
1year
Varnimcabtagene Autoleucel (ARI-0001) for Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) and Richter Transformation (RT) (ASH 2023)
Patients received lymphodepletion with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2) followed by 0.1-1 (CLL) and 0.5-5 (RT) x10e6 CART19 cells/kg in single or fractionated administration (10%, 30% and 60%) in a single institution...At screening patients had a median age of 58 years (44-74), 47% were females, with a median of 4 prior lines of therapy (2-9) including ibrutinib (89%), venetoclax (53%), R-CHOP (58%) and allo-HCT (21%)...Tocilizumab and corticosteroids were administered in 44% and 17% of patients, respectively... Administration of the CART19 var-cel (ARI-0001) was feasible in 95% of CLL/RT patients, with robust and durable var-cel engraftment in 89% of treated patients, and durable complete responses observed in 61% of patients. These initial outcomes or var-cel in this population contrasts with the overall findings of CART19 therapy in CLL/RT and encourages to further develop var-cel on this high-risk population.
IO biomarker
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TP53 (Tumor protein P53) • IGH (Immunoglobulin Heavy Locus)
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LDH elevation • LDH-L
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • cyclophosphamide • fludarabine IV • Actemra IV (tocilizumab) • varnimcabtagene autoleucel (ARI-0001)
1year
Trial completion
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TP53 (Tumor protein P53)
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TP53 mutation
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varnimcabtagene autoleucel (ARI-0001)
over1year
RITUXIMAB BASED LYMPHODEPLETION MAY INCREASE ENGRAFTMENT AND EFFICACY OF SECOND INFUSIONS OF CART19 CELLS IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA. (EHA 2023)
At 1st infusion patients had a median of 4 prior treatment lines (3-6), including inotuzumab 67% (8/12), and alloHCT 92% (11/12)...All patients received LD with fludarabine (90 mg/m 2 ) and cyclophosphamide (900 mg/m 2 ), but all 2nd infusions (except 1) also included rituximab on day -6 (375 mg/m 2 )... Second ARI-0001 CART19 infusions with prior rituximab based lymphodepletion was able to achieve long term remissions in a subset of patients. Adding rituximab may lead to partial protection to humoral-mediated rejection of second CART19 administrations. CAR-T, ALL, Rituximab
Clinical
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Rituxan (rituximab) • cyclophosphamide • Besponsa (inotuzumab ozogamicin) • fludarabine IV • varnimcabtagene autoleucel (ARI-0001)
over1year
CD19/BCMA Dual-Targeting CAR-T Cells Generated by Co-Transduction for the Treatment of Non-Hodgkin Lymphoma (ASGCT 2023)
Our in-house developed CARs targeting CD19 (ARI0001) and BCMA (ARI0002) have proven safe and efficacious in the treatment of patients with B-cell malignancies and multiple myeloma, respectively... In summary, we propose the co-transduction as an efficient strategy to obtain highly effective CD19/BCMA dual CAR-T cells. We are currently preparing the required documentation to get approval from the regulatory agencies to initiate clinical trials to treat NHL patients with this therapy.
CAR T-Cell Therapy • IO biomarker
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CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
almost2years
Mathematical Optimization of Personalized CAR-T Cell Products (EHA-EBMT-CART 2023)
The prediction model will be externally validated.Figure 1.Methodology to develop a prediction model Data for the learning set were shared by Clinic Foundation for Biomedical Research (FCRB) from the CART19-BE-01 (ARI-0001) and ARI-0002h study (N=171)... The paper presents a new AI method to predict which CAR-T cell products will be most effective for individual patients. Personalized medicine requires harmonization and sharing of clinical data. These combined medical and mathematical procedures promise to improve personalized CAR-T cell treatment.
CAR T-Cell Therapy
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
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
New P2 trial • CAR T-Cell Therapy • Head-to-Head
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BCL2 (B-cell CLL/lymphoma 2) • BCL6 (B-cell CLL/lymphoma 6)
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BCL6 rearrangement • BCL2 rearrangement
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Yescarta (axicabtagene ciloleucel) • varnimcabtagene autoleucel (ARI-0001)
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
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CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001) • cesnicabtagene autoleucel (ARI0002h)
2years
CART19-BE-01: Pilot Study on the Infusion of ARI-0001 Cells in Patients With CD19+ Leukemia or Lymphoma Refractory to Therapy (clinicaltrials.gov)
P1, N=50, Active, not recruiting, Sara V. Latorre | Trial completion date: Sep 2022 --> Dec 2022
Trial completion date
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TP53 (Tumor protein P53) • CD19 (CD19 Molecule)
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TP53 mutation
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varnimcabtagene autoleucel (ARI-0001)
2years
Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. (PubMed, Front Immunol)
In summary, we showed here that, although there are still some risks of genotoxicity due to genome editing, disruption of the TCR is a feasible strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We propose to further validate this protocol for the treatment of patients that do not fit the requirements for standard autologous CAR-T cells administration.
Journal • CAR T-Cell Therapy
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CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
over2years
CART19-BE-02: Study of the Infusion of ARI-0001 Cells in Patients With CD19 + Acute Lymphoid Leukemia Resistant or Refractory to Therapy (clinicaltrials.gov)
P2, N=38, Recruiting, Sara V. Latorre | Trial completion date: Mar 2024 --> Oct 2024 | Trial primary completion date: Jun 2022 --> Oct 2022
Trial completion date • Trial primary completion date
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CD19 (CD19 Molecule)
|
varnimcabtagene autoleucel (ARI-0001)
over2years
CART19-BE-01: Pilot Study on the Infusion of ARI-0001 Cells in Patients With CD19+ Leukemia or Lymphoma Refractory to Therapy (clinicaltrials.gov)
P1, N=50, Active, not recruiting, Sara V. Latorre | Trial completion date: May 2022 --> Sep 2022 | Trial primary completion date: May 2022 --> Sep 2022
Trial completion date • Trial primary completion date
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TP53 (Tumor protein P53) • CD19 (CD19 Molecule)
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TP53 mutation
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varnimcabtagene autoleucel (ARI-0001)
over2years
Clinical • Clinical data • Journal
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CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
over2years
Results of ARI-0001 CART19 cell therapy in patients with relapsed/refractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease. (PubMed, Am J Hematol)
Patients received cyclophosphamide and fludarabine followed by 1 x10 ARI-0001 cells/kg, initially as a single dose (first patient) and later split into 3 fractions (10%, 30%, and 60%)...Tocilizumab was used in 6% of patients (1/18)...Progression-free and overall survival were 49% (95% CI: 30-79%) and 61% (95% CI: 40-92%) at 2?years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.
Journal
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CD19 (CD19 Molecule)
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CD19 positive
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cyclophosphamide • fludarabine IV • Actemra IV (tocilizumab) • varnimcabtagene autoleucel (ARI-0001)
over2years
Results of ARI-0001 CART19 Cells in Patients With Chronic Lymphocytic Leukemia and Richter's Transformation. (PubMed, Front Oncol)
With a median follow-up of 5.6 months, two patients with RT experienced a CD19-negative relapse. In conclusion, ARI-0001 cell therapy was feasible, safe, and effective in patients with high-risk CLL or RT.
Journal
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CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
almost3years
OUTCOME AFTER RELAPSE POST CD19 CAR T-CELLS IN CHILDREN AND YOUNG ADULTS WITH RELAPSED/REFRACTORY B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (R/R B-ALL) (EBMT 2022)
Clinical Trial Registry: CTL019: EudraCT 2013-003205-25 / EudraCT 2016-001991-31 and approved tisagenlecleucel; ARI-0001 cells EudraCT 2016-002972-29 Background: CAR-T therapy has improved the outcome of pediatric patients with R/R B-ALL.  The outcome of patients who relapse after CART19 therapy is very poor and therapeutic options are scarce. Although CR can be achieved in some patients with inotuzumab or blinatumomab (CD22+ and CD19+ disease, respectively) consolidation with HSCT treatment is needed and long-term remission is very rare.
Clinical • CAR T-Cell Therapy
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CD19 (CD19 Molecule) • CD22 (CD22 Molecule)
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Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin) • Kymriah (tisagenlecleucel-T) • varnimcabtagene autoleucel (ARI-0001)
3years
Is Hospital Exemption an alternative or a bridge to EMA for developing Academic CAR-T in Europe? Our experience with ARI0001. (PubMed, Hum Gene Ther)
This authorization was a first step in the development of, and access to, academic CAR T-cell products in the EU. The fact that HE is limited to a specific country and hospital, the need of continuous evaluation by the NCA, and the potential future overlap with other centrally approved ATMPs, suggest that the HE could be used as an intermediate step before obtaining a centralized MA by the European Medicines Agency.
Clinical • Journal
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CD19 (CD19 Molecule)
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varnimcabtagene autoleucel (ARI-0001)
3years
CART19-BE-01: Pilot Study on the Infusion of ARI-0001 Cells in Patients With CD19+ Leukemia or Lymphoma Refractory to Therapy (clinicaltrials.gov)
P1, N=50, Active, not recruiting, Sara V. Latorre | Trial completion date: May 2021 --> May 2022 | Trial primary completion date: May 2021 --> May 2022
Clinical • Trial completion date • Trial primary completion date
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TP53 (Tumor protein P53) • CD19 (CD19 Molecule)
|
TP53 mutation
|
varnimcabtagene autoleucel (ARI-0001)
over3years
Clinical • Enrollment open
|
CD19 (CD19 Molecule)
|
varnimcabtagene autoleucel (ARI-0001)
over3years
[VIRTUAL] FACTORS ASSOCIATED WITH PROGRESSION-FREE SURVIVAL (PFS) OF ADULT AND PEDIATRIC PATIENTS WITH RELAPSED / REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH ARI-0001 CART19 THERAPY. (EHA 2021)
Lymphodepletion was performed with fludarabine (90 mg/m2) and cyclophosphamide (900 mg/m2), followed by the infusion of 0.1-5 x106 ARI-0001 cells/kg in a single or fractionated manner...Patients had a median of 4 prior treatment lines (2-8), including blinatumomab 23% (12/53), inotuzumab 53% (28/53) and alloHCT 79% (42/53)...Conclusion ARI-0001 therapy was able to achieve long term remissions in this population of R/R B-ALL patients across all patient subgroups. Nevertheless, patients referred for ARI-0001 cell therapy with 5% or more of bone marrow blasts and those who lost B-cell aplasia after ARI-0001 cell therapy had a shorter PFS.
Clinical
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CD19 (CD19 Molecule)
|
Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin) • fludarabine IV • varnimcabtagene autoleucel (ARI-0001)
over3years
Clinical • New P2 trial
|
CD19 (CD19 Molecule)
|
varnimcabtagene autoleucel (ARI-0001)