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

Clinical Characteristics of Pneumonia Caused by Penicillin Resistant and Sensitive Streptococcus pneumoniae in Japan

Background S. pneumoniae is the leading cause of morbidity and mortality worldwide. β-lactam antibiotics were very effective against S. pneumoniae, however resistance to this class of antibiotic has become an increasing problem. Objectives To assess the clinical differences between penicillin-sensitive and penicillin-resistant pneumococcal pneumonia. Methods The medical records of 306 patients with pneumococcal pneumonia who visited Nagasaki University Hospital or affiliated institutions between January 1997 and December 2001 were retrospectively reviewed. The Pneumonia Severity Index (PSI), sensitivity of S. pneumoniae, antibiotic choices and information on clinical outcome were evaluated. Results Penicillin sensitive and resistant organisms were responsible for 177 (57.7%) and 129 (42.0%) cases of pneumonia, respectively. The median age of patients was 65.5 years, and 72.3% (222) were males. There were no significant differences in the resistance rate between elderly (>65 years) and young patients. The median PSI score was 76. No significant association was observed between the severity of illness and sensitivities of S. pneumoniae. Previous use of beta-lactams in the last 3 months and chronic obstructive pulmonary disease were associated with penicillin resistance. The failure rate of first line antibiotics was significantly higher in the resistant group (22.5%) than in the sensitive group (9.0%). Four of 306 patients died (mortality, 1.3%). Conclusion There were no significant differences clinically between the penicillin-sensitive and penicillin-resistant groups. The failure rate of first line antibiotics was higher in the resistant than in the sensitive group. Thus, the selection of antimicrobial agents should be carefully considered in the context of the patient’s risk factors