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

• Published in: Nature communications Vol. 12; no. 1; p. 7200
• Main Authors: Maschan, Michael, Caimi, Paolo F, Reese-Koc, Jane, Sanchez, Gabriela Pacheco, Sharma, Ashish A, Molostova, Olga, Shelikhova, Larisa, Pershin, Dmitriy, Stepanov, Alexey, Muzalevskii, Yakov, Suzart, Vinicius G, Otegbeye, Folashade, Wald, David, Xiong, Ying, Wu, Darong, Knight, Adam, Oparaocha, Ibe, Ferencz, Beatrix, Roy, Andre, Worden, Andrew, Kruger, Winfried, Kadan, Michael, Schneider, Dina, Orentas, Rimas, Sekaly, Rafick-Pierre, de Lima, Marcos, Dropulić, Boro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.12.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adolescent; Adult; Aged; Animals; Anticancer properties; Antigens; Antigens, CD19 - immunology; B-cell lymphoma; B-Lymphocytes - immunology; CD19 antigen; Child; Child, Preschool; Chimeric antigen receptors; Clinical trials; Cyclic GMP; Failure rates; Female; Humans; Infant; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma, B-Cell - immunology; Male; Malignancy; Manufacturing; Mice; Mice, Inbred NOD; Middle Aged; Neoplasm, Residual; Patients; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Progression-Free Survival; Receptors; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen - immunology; Receptors, Tumor Necrosis Factor - chemistry; Remission; Russia; Survival; T-Lymphocytes - immunology; Transmembrane domains; Tumors; United States; Xenografts; Xenotransplantation; Young Adult; United States; Russia
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27312-6

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.