To improve the therapeutic window of CAR T cell therapies, Manni and Del Bufalo et al. developed a humanized mouse model to study CAR T cell-related side effects, such as cytokine release syndrome (CRS), neurotoxicity, and macrophage activation syndrome. While IFNγ neutralization with clinically approved emapalumab after CAR.CD19 infusion did not affect CAR.CD19-T cell anti-lymphoma activity or impair CAR.CD19 T cell signaling, it did mitigate toxicity due to severe CRS, prevented brain damage (decreased multifocal hemorrhages), and prolonged survival, suggesting a clinical rationale for combination therapy.
Contributed by Katherine Turner
ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy may achieve long-lasting remission in patients with B-cell malignancies not responding to conventional therapies. However, potentially severe and hard-to-manage side effects, including cytokine release syndrome (CRS), neurotoxicity and macrophage activation syndrome, and the lack of pathophysiological experimental models limit the applicability and development of this form of therapy. Here we present a comprehensive humanized mouse model, by which we show that IFNγ neutralization by the clinically approved monoclonal antibody, emapalumab, mitigates severe toxicity related to CAR-T cell therapy. We demonstrate that emapalumab reduces the pro-inflammatory environment in the model, thus allowing control of severe CRS and preventing brain damage, characterized by multifocal hemorrhages. Importantly, our in vitro and in vivo experiments show that IFNγ inhibition does not affect the ability of CD19-targeting CAR-T (CAR.CD19-T) cells to eradicate CD19+ lymphoma cells. Thus, our study provides evidence that anti-IFNγ treatment might reduce immune related adverse effect without compromising therapeutic success and provides rationale for an emapalumab-CAR.CD19-T cell combination therapy in humans.
Author Info: (1) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (2) Department of Haematology-Oncology and Cell and Gene Thera
Author Info: (1) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (2) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (3) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (4) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (5) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (6) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (7) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (8) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (9) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (10) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (11) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (12) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (13) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (14) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (15) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (16) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (17) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (18) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (19) Department of Pathological Anatomy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (20) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (21) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (22) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. (23) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. biagio.deangelis@opbg.net. (24) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. franco.locatelli@opbg.net. Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy. franco.locatelli@opbg.net. (25) Department of Haematology-Oncology and Cell and Gene Therapy, Bambino Ges Children Hospital, IRCCS, Rome, Italy. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
