Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients

Abstract

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.

Review: Sustainable Clinical Development of CAR-T Cells – Switching From Viral Transduction Towards CRISPR-Cas Gene Editing

“…Optimized GMP protocols using RVs/LVs have resulted in high gene delivery efficacy, resulting a range of 25-80% CAR-positive T cells including both CD4 + CD3 + and CD8 + CD3 + CAR-T cells after transduction and expansion. Since LV gene transfer is usually robust in actively replicating T cells, manual manufacturing methods can be efficiently replaced with closed automated systems (42,43). Importantly, digitally controlled automated manufacturing systems can potentially improve the practicability and lower the costs associated with clean rooms and highly trained personnel for production of CAR-T cells for a broader patient usage (41).…”

Patient selection for CAR T or BiTE therapy in multiple myeloma: Which treatment for each patient?

“…Of the 140 patients included in a phase II trial, 12 (8.6%) patients could not receive the CAR T product because of progressive disease, patient withdrawal, manufacturing issues or a decision of the treating physician [ 61 ]. New methods to produce cells are currently being developed to shorten delay [ 99 ]. BiTE, on the other hand, has the distinct benefit of being readily available (off-the-shelf).…”

Haploidentical donor-derived memory CAR T cells: first in human experience and in vitro correlative study

“…CAR-T manufacturing according to the previously reported protocol. 15,16 Briefly, 1 × 10 8 T cells were CD4/CD8 enriched prior to CD3/CD28 stimulation, lentiviral transduction, and expansion in the presence of interleukin-7 (IL-7) and IL-15 over 7 days. Lentiviral vector encoding the second-generation CD19-4-1BBz CAR was used.…”

“…Tocilizumab was used prophylactically at 8 mg/kg, adopted from the concurrent clinical trial, and overall clinical and laboratory monitoring was performed as described. 16,17 After CAR19-Tm infusion, 2 patients developed grade 1 and 2 cytokine release syndrome and grade 1 Immune effector cellassociated neurotoxicity syndrome (Figure 1F). In one case, grade 1 GVHD (skin plus upper gastrointestinal) developed.…”

“…CAR19-Tm cells were detected after infusion by flow cytometry in 3 cases, and CAR19-Tm persistence in the peripheral blood was documented for a maximum of 60 days (Figure 1E; supplemental Table 1), compared with a persistence of 6 months in 90% of the recipients of conventional CAR T cells. 16 Leukemia response occurred in 4 cases as flow-based minimal residual disease was not detectable at day 30 in 4 cases. According to Figure 1E and supplemental Table 1, the persistence of CAR19-Tm cells was significantly shorter in comparison with conventional CAR19 T cells.…”