Becilli, Metzler, Bracaglia et al. treated 8 children with severe/refractory autoimmune diseases (AD) with one dose of CD19 CAR T cells to reset the dysregulated immune system. CAR T cells were successfully manufactured for all patients, and promoted clearance of CD19+ cells within the first week. Furthermore, a strong and durable decrease in autoantibody titers was noted. At a median follow-up of 16.5 months, substantial improvements/resolution of AD was observed in all patients, enabling sustained discontinuation of immunosuppressive therapies, even after B cell reconstitution. Grade 1 CRS was reported in 6 patients, and ICANS were reported in 1 patient.
Contributed by Ute Burkhardt
ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy was recently proposed as a treatment for adults with B-cell-mediated autoimmune diseases (ADs) refractory to conventional immunomodulatory therapy. We present a case series of eight children with severe/refractory AD (four systemic lupus erythematosus, three dermatomyositis, one systemic sclerosis) treated at Ospedale Pediatrico Bambino Gesù, Rome, and University Hospital Erlangen with a single infusion of 1 × 106 kg-1 point-of-care manufactured autologous CD19 CAR T cells (zorpocabtagene autoleucel), in a hospital exemption (HE) program. In Europe, the HE pathway offers the opportunity to treat patients with life-threatening or seriously debilitating disorders who lack valid therapeutic options, using an advanced therapy medicinal product (ATMP) authorized on a nonroutine, single-patient basis. In contrast to the 'compassionate use' pathway, the ATMP does not necessarily need to have undergone clinical trials or marketing authorization applications. Manufacturing was successful in all patients, yielding several drug product bags. Once infused after lymphodepletion, zorpocabtagene autoleucel cells expanded in vivo, promoting prompt B cell clearance. Grade 1 cytokine release syndrome was reported in six patients, and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in one patient. Late-hematotoxicity was limited to grade 1 in two patients. All these adverse events were manageable and no severe infections occurred. With a median follow-up of 16.5 months (range = 9-24 months), all patients experienced a clinically substantial improvement/resolution of AD, as evidenced by reduction in disease activity scores and signs of reversal of organ damage. This improvement enabled sustained discontinuation of immunomodulators, even after B cell reconstitution. The activation of formal clinical trials enrolling children and adolescents is urgently needed to confirm these preliminary results and to assess the long-term safety of this approach.
Author Info: (1) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Ita
Author Info: (1) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (2) Department of Paediatrics and Adolescent Medicine, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (3) Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (4) Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (5) Department of Paediatrics and Adolescent Medicine, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (6) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (7) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (8) Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (9) Department of Paediatrics and Adolescent Medicine, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (10) Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (11) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (12) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (13) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. Department of Health Sciences, Magna Graecia University, Catanzaro, Italy. (14) Advanced Cardiothoracic and Fetal Imaging Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (15) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (16) Complex Operational Unit (UOC) Pathological Anatomy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (17) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (18) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (19) Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (20) Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Department of Internal Medicine 5-Haematology and Oncology, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (21) Transfusion Unit, Department of Laboratories, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (22) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (23) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (24) Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. (25) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (26) Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Department of Internal Medicine 5-Haematology and Oncology, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (27) Miltenyi Biomedicine, Bergisch Gladbach, Germany. (28) Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Department of Internal Medicine 5-Haematology and Oncology, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (29) Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Department of Internal Medicine 5-Haematology and Oncology, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (30) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. (31) Deutsches Zentrum Immuntherapie, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Department of Internal Medicine 3-Rheumatology and Immunology, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (32) Division of Rheumatology, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (33) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. franco.locatelli@opbg.net. Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy. franco.locatelli@opbg.net.
