作者
Michael Maschan,Paolo Caimi,Jane Reese-Koc,Gabriela Sanchez,Ashish Sharma,Olga Molostova,Larisa Shelikhova,Dmitry Pershin,Alexey Stepanov,Yakov Muzalevskii,Vinicius G. Suzart,Folashade Otegbeye,David J. Wald,Ying Xiong,Darong Wu,Adam C. Knight,Ibe Oparaocha,Beatrix Ferencz,André Roy,Andrew Worden,Winfried Kruger,Michael Kadan,Dina Schneider,Rimas J. Orentas,Rafick Pierre Sekaly,Marcos de Lima,Boro Dropulic
摘要
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.