Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

CAR-T細胞製造を成功させるためのレシピ --アフェレーシス前の下ごしらえでの工夫--. 京都大学プレスリリース. 2023-04-27.For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients

Central nervous system infection following allogeneic hematopoietic stem cell transplantation

Objective/background: Here, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years. Methods: Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection. Results: A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10–1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n = 6), enterococcus (n = 2), staphylococcus (n = 2), streptococcus (n = 2), varicella zoster virus (n = 1), cytomegalovirus (n = 1), John Cunningham virus (n = 1), adenovirus (n = 1), and Toxoplasma gondii (n = 1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. Conclusion: Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p = .02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p = .04). Keywords: Allogeneic hematopoietic stem cell transplantation, Central nervous system infections, Human herpesvirus

Supplementary Figure S3 from Dual CAR-T Cells Targeting CD19 and CD37 Are Effective in Target Antigen Loss B-cell Tumor Models

Supplemental Figure S3. Analysis of differentiation markers of CAR-T cells. Each CAR-T cells and tEGFR-T cells were stimulated with CD19/CD37 positive Raji cells at a 1:5 ratio every 7 days and stained for CD62L, CD45RA, CCR7, CD27 and CD28. A, B, Summary data of the percentage of CD45RA-/CD62L+ central memory T (TCM) cell fraction (A) and CD45RA-/CD62L- effecter memory T (TEM) cell fraction (B). C–E, Summary data of the percentage of CCR7-/CD27+/CD28+ early TEM cell fraction (C), CCR7-/CD27+/CD28- late TEM cell fraction (D) and CCR7-/CD27-/CD28- effecter T cell fraction (E). Data represent mean ± SEM from five different donors (two-way ANOVA, *p < 0.05, **p < 0.01, ***p < 0.001).</p