firicabtagene autoleucel (CRG-022)

Myeloablative conditioning with cyclophosphamide and total body irradiation precede infusion of investigational Orca-T, which consists of infusions of HSPCs and Tregs on Day 0 and an infusion of T conventional (Tcon) cells on Day 2. Here, we report very promising initial feasibility, safety and efficacy of the combination of allogeneic CD19/CD22-CAR T cells with Orca-T in patients with high-risk B-ALL. This paradigm shifting combination of allogeneic CAR T and allo-HCT resulted in 100% MRD- CR with full donor chimerism but without GVHD or severe CAR-mediated toxicity. These data, which demonstrate antigen-specific anti-tumor benefit of allogeneic CAR T cells in combination with GVHD prophylaxis mediated by Tregs and tacrolimus, have potential implications that could benefit patients with other hematologic diseases.

P1, N=20, Recruiting, Stanford University | Not yet recruiting --> Recruiting

P1, N=20, Not yet recruiting, Stanford University

Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

P1, N=52, Active, not recruiting, Stanford University | Trial completion date: Dec 2024 --> Dec 2037

P1, N=10, Active, not recruiting, Stanford University | Suspended --> Active, not recruiting | N=52 --> 10 | Trial completion date: Aug 2035 --> Sep 2036 | Trial primary completion date: Aug 2025 --> Oct 2023

P1, N=52, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=92 --> 52 | Trial completion date: Sep 2034 --> Dec 2024 | Trial primary completion date: Apr 2023 --> Dec 2024

P1, N=52, Suspended, Stanford University

Conclusion While different expansion patterns were observed, CD22 CAR T-cells manufactured in the Prodigy were as safe and effective as those made by bag culture. As commercial CAR T-cells move to automated manufacture, CAR T-cell phenotype, expansion, and functionality especially in patients with EMD may require further study.

P2, N=123, Recruiting, CARGO Therapeutics | Not yet recruiting --> Recruiting

Patients most commonly received high-dose glucocorticoids, tocilizumab and anakinra. Additional agents for grade 4 IEC-HS included anti-thymoglobulin, dasatanib and emapalumab...The observed IFN-γ cytokine signature is consistent with myeloid cell activation and Th1 T-cell skewing that likely contributes to IEC-HS pathogenesis. These cytokines may be amenable to therapeutic intervention and further study of approaches targeting JAK/STAT and IFN-γ are warranted.

With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted.

After lymphodepletion (LD) with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 days from Day -5 to -3, patients were infused with cryopreserved CAR T-cells after a 7- to 12-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). CAR22 is a highly effective and safe salvage therapy for patients with CAR19-refractory LBCL. A multicenter phase 2 clinical trial is planned to open in 2023. CAR-T, Cellular therapy, DLBCL

P1, N=92, Recruiting, Stanford University | Trial primary completion date: Sep 2022 --> Apr 2023

After lymphodepletion (LD) with fludarabine and cyclophosphamide, patients were infused with cryopreserved CAR T-cells after a 7- to 12-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). CAR22 is a highly effective and safe salvage therapy for CAR19-refractory LBCL and recently granted FDA-Breakthrough Designation. A multicenter phase 2 clinical trial is planned to open in 2023.

The CAR was manufactured using an automated CliniMACS Prodigy (Miltenyi Biotec, Bergisch Gladbach, Germany) lentiviral transduction system2 that has been previously used to successfully create single and dual-targeted CARs.3,4 Sixteen patients received lymphodepletion with fludarabine (30 mg/m2/day IV on Days -5, -4, and -3) and cyclophosphamide (500mg/m2/day on Days -5, -4, and -3) followed by fresh or cryopreserved CAR T cell infusion after a 7-9 day production time...Four patients (22%) had also received inotuzumab... The results of our Phase Ib trial recapitulate previous findings with CD22 CARs and demonstrate that this CAR maintains its safety and feasibility profile in adults and children with heavily pre-treated ALL. The CD22 CAR resulted in high rates of CR and MRD-negativity independent of prior CD19 CAR and/or blinatumomab exposure. CRS was common but reversible, and the incidence and grades of CRS, ICANS and car-HLH were consistent with long-term follow up data from CD22 CAR studies in pediatric populations.6 CD22 CARs thus present a promising option for both pediatric and adult patients with r/r ALL.

P1, N=52, Suspended, Stanford University | Enrolling by invitation --> Suspended

P1, N=18, Not yet recruiting, Stanford University

P1, N=52, Enrolling by invitation, Stanford University | Recruiting --> Enrolling by invitation

After lymphodepletion (LD) with fludarabine and cyclophosphamide, patients are infused with cryopreserved CAR T-cells after a 7- to 11-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). Infusion of CAR22 in R/R LBCL is safe and well tolerated at DL1. Manufacturing of CAR22 was uniformly successful. With a mean follow-up of 7.3 months, the ORR and CR rates are 18/21 (86%) and 14/21 (67%), respectively.