A four-domain framework for secondary immunodeficiency after CAR T-cell and T-cell-engaging antibody therapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapies and T-cell-engaging antibodies have transformed the treatment of hematologic malignancies but can induce prolonged, overlapping, and dynamically evolving immune deficits that are not adequately captured by hypogammaglobulinemia alone. Infection susceptibility reflects the interplay among the underlying disease and prior treatment, the immune-effector modality and therapeutic target, the predominant immune-deficit phenotype, and its evolution over time. We therefore propose a four-domain framework—Disease substrate, Drug and target, Deficit profile, and Dynamics—as a pragmatic structure for longitudinal characterization of secondary immunodeficiency after CAR T-cell and T-cell-engaging antibody therapy. The framework integrates myeloid, humoral, cellular, combined, and mucosal or epithelial barrier deficits with treatment-specific exposures and patterns of immune recovery, linking them to phenotype- and phase-adapted monitoring and prevention. We synthesize evidence on infection epidemiology, immune reconstitution, vaccination, antimicrobial prophylaxis, and immunoglobulin replacement while distinguishing established recommendations from practices supported mainly by observational data or expert consensus. A dynamic, phenotype-guided approach may improve targeting of preventive interventions while limiting avoidable prophylactic exposure. Priority research needs include standardized immune and infection end points, prospective longitudinal immune phenotyping, externally validated dynamic risk models, and comparative-effectiveness studies of immunoglobulin replacement, response-adapted extension of dosing intervals for T-cell-engaging antibodies, and antimicrobial prophylaxis.