Immunological consequences of CAR T-cell therapy: an analysis of infectious complications and immune reconstitution

Abstract

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 1-year follow-up analysis of 52 patients (42 with R/R DLBCL and 10 with R/R MM) treated with anti-CD19- and B-cell maturation antigen-targeted CAR T cells, focusing on immune reconstitution and infectious complications. Our findings reveal that CAR T-cell therapy leads to profound depletion of B and T cells. CD4+ T cells and CD19+ B cells exhibited impaired regeneration after 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 patients with DLBCL and 4.6 in patients with MM, with bacterial infections predominating in this early period after CAR T-cell infusion. In addition, we observed a shift to viral infections in the long-term follow-up, alongside with a decline in infection density to 0.1 in patients with DLBCL and 0.4 infections per 100 days at risk in patients with MM, respectively. Severe cytokine release syndrome was associated with a higher risk of late-onset infections. These findings highlight the importance of close monitoring and prophylactic measures in patients undergoing CAR T-cell therapy to reduce infection risks and enhance immune recovery.

Graphical abstract

Figure 1.

Early-onset pathogens and foci following CAR T-cell therapy. (A) Early-onset infections and (B) infection foci after (i) anti-BCMA CAR T-cell therapy (n = 10), (ii) anti-CD19 CAR T-cell therapy (n = 42), and (iii) overall cohort receiving either CAR T-cell therapy (n = 52).

Figure 2.

Late-onset pathogens and foci following CAR T-cell therapy. (A) Late-onset infections and (B) long-term foci after (i) anti-BCMA CAR T-cell therapy, (ii) anti-CD19 CAR T-cell therapy, and (iii) overall cohort receiving either CAR T-cell therapy. Respiratory infections increase in the long-term follow-up, whereas urogenital and abdominal foci were observed less frequently. A switch from bacterial infections in the short-term follow-up to mostly viral infections from day 30 to day 360 was observed.

Figure 3.

Risk factors for early- and late-onset infectious complications after CAR T-cell therapy. (A) ORs (univariate analysis) for early- and late-onset infectious complications for (i) the overall cohort receiving either CAR T-cell therapy and (ii) the anti-CD19 CAR T-cell cohort. Whiskers indicate 5th to 95th percentile. (Bi) CAR expansion at day 30 in the MM and DLBCL cohort (t test; mean, 3.53 vs 11.97; P = .009). Whiskers indicate 5th to 95th percentile. (Bii) CAR expansion in patients with DLBCL depending on infectious events within the first 30 days (t test; mean, 3.73 vs 12.58; P = .02).

Figure 4.

Cellular and humoral reconstitution within the first year after CAR T-cell treatment. Reconstitution of the hematopoiesis after CAR T-cell therapy for (Ai) MM and (Bi) DLBCL (whiskers indicate SD). A deficiency of CD4⁺, CD8⁺, and CD19⁺ cells was observed in the first year in patients treated with (Aii) anti-BCMA and (Bii) anti-CD19 CAR T cells. Course of immunoglobulin reconstitution after CAR T-cell therapy (whiskers indicate SD) for (Aiii) MM and (Biii) DLBCL. Patients were included in the analysis until progressive disease or reaching the end point of 1 year after CAR T-cell therapy. All data were included in the analysis, containing patients who received G-CSF or IVIG. IVIG, IV immunoglobulin.

Figure 5.

Prognostic factors of cellular reconstituion after CAR T-cell treatment. Reconstitution of (A) ANC, (B) lymphocytes, and (C) CD4⁺ T cells depending on (i) CRS grading, (ii) ICANS grading, and (iii) HEMATOTOX risk in patients with DLBCL. Squares indicate mean values and whiskers indicate standard deviation. Data were analyzed with a mixed effects model. ICANS grading >1 is associated with lower lymphocyte and CD4⁺ T-cell counts (column factor, P = .02 and P = .01, respectively). Low HEMATOTOX grading was associated with lower lymphocyte and CD4⁺ counts in the long-term follow-up (time × column factor, P = .03 and P = .01, respectively).