varnimcabtagene autoleucel (ARI-0001)

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.

P2, N=50, Active, not recruiting, Sara V. Latorre | Trial primary completion date: Dec 2023 --> Dec 2024

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.

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.

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.

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.

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.

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.

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.

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.

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.

P1, N=50, Completed, Sara V. Latorre | Active, not recruiting --> Completed

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

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.

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.

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.

P2, N=300, Recruiting, University Medical Center Groningen

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.

P1, N=50, Active, not recruiting, Sara V. Latorre | Trial completion date: Sep 2022 --> Dec 2022

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.

P2, N=38, Recruiting, Sara V. Latorre | Trial completion date: Mar 2024 --> Oct 2024 | Trial primary completion date: Jun 2022 --> Oct 2022

P1, N=50, Active, not recruiting, Sara V. Latorre | Trial completion date: May 2022 --> Sep 2022 | Trial primary completion date: May 2022 --> Sep 2022

No abstract available

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.

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.

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.

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.

P1, N=50, Active, not recruiting, Sara V. Latorre | Trial completion date: May 2021 --> May 2022 | Trial primary completion date: May 2021 --> May 2022

P2, N=38, Recruiting, Sara V. Latorre | Not yet recruiting --> Recruiting

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.

P2, N=38, Not yet recruiting, Sara V. Latorre