Immunological Consequences of CAR T-Cell Therapy - Analysis of Infectious Complications and Immune Reconstitution

• CAR T-cells induce a cellular and humoral immunodeficiency resulting in an initial susceptibility for bacterial and later viral infections

• Severe CRS harbors a relevant risk for late-onset infectious complications

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in treating relapsed and refractory (R/R) B-cell neoplasms, such as diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Despite its success, the long-term effects and sequelae of CAR T cells on the immune system remain underexplored. This study presents a one-year follow-up analysis of 52 patients (42 with R/R DLBCL and 10 with R/R MM) treated with anti-CD19- and BCMA-targeted CAR T-cells, focusing on immune reconstitution and infectious complications. Our findings show that CAR T-cell therapy leads to profound depletion of B- and T-cells. In particular, CD4+ T-cells and CD19+ B-cells exhibited impaired regeneration post-treatment. Infections were more frequent during the first 30 days. In the short-term follow up, density of infections within 100 days at risk was 1.8 in DLBCL patients and 4.6 in MM patients, with bacterial infections predominating in this early period after CAR-T infusion. Additionally, we observed a shift to viral infections in the long-term follow-up, alongside with a decline in infection density to 0.1 in DLBCL patients and 0.4 infections per 100 days at risk in MM patients, respectively. Severe cytokine release syndrome (CRS) was associated with a higher risk of late-onset infections. These findings highlight the importance of close monitoring and prophylactic measures in CAR T-cell therapy patients to reduce infection risks and enhance immune recovery.