An explorable model of an adverse outcome pathway of cytokine release syndrome related to the administration of immunomodulatory biotherapeutics and cellular therapies.

Introduction: Cytokine release syndrome (CRS) is a potentially severe systemic inflammatory condition triggered by various immunomodulatory therapies, making understanding its pathogenesis critical for improving patient outcomes.

Results/methods: By combining immunotoxicology and systems biology approaches, we offer a novel and integrative conceptual model of CRS as an adverse outcome (AO), induced by five different immunomodulatory biotherapies: 1) chimeric antigen receptor (CAR) T cells, 2) checkpoint inhibitors, 3) T cell engaging bispecific modalities, 4) monoclonal antibodies targeting and activating T cell receptors, and 5) FcγR activating monoclonal antibodies. This model uniquely integrates multiple CRS-inducing therapies into a unified framework, offering a comprehensive mechanistic representation of CRS pathophysiology.

Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody.

Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers have become integral components in the treatment of relapsed/refractory multiple myeloma. We report a 63-year-old male who received ciltacabtagene autoleucel CAR T cells and the GPRC5D × CD3 bispecific talquetamab for early relapse of his multiple myeloma. Nine months after CAR T therapy, he developed a symptomatic leukemic peripheral T cell lymphoma with cutaneous and intestinal involvement.