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

Abstract

Summary 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.

High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach

“…The approval process for new drugs often entails rigorous and prolonged evaluation to ensure compliance with regulatory requirements. Moreover, the marketing of novel drugs necessitates a period of usage and surveillance to ascertain their effectiveness and safety [ 46 ]. It is noteworthy that the utilization of novel drugs may incur exorbitant costs that exceed the financial capabilities of ordinary households [ 45 , 47 ].…”

Early predictive factors of failure in autologous CAR T-cell manufacturing and/or efficacy in hematologic malignancies

“…More recently, Jo et al identified the use of bendamustine with ≥3 cycles and washout period <3 months as a high-risk factor of tisa-cel production failure. 19 …”

“… 38 It is worth noting that CD4:CD8 ratio <1:3 was identified as a risk factor of tisa-cel production failure. 19 This ratio may be affected by high quantities of monocytes, erythrocytes, or neutrophils in the apheresis product. Elavia et al showed that the contamination of cellular starting material by myeloid or erythroid cells were associated with higher quantities of CD4 + T cells, whereas CD8 + T cells were increased with neutrophils.…”

CAR-T cell manufacturing: Major process parameters and next-generation strategies

“…Even in the absence of medical complications during the vein-to-vein time, 4–7% of patients are unable to receive their CAR-T cell products as a result of manufacturing failures ( Bhaskar et al, 2021 ; St Martin et al, 2023 ), with risk factors including reduced fitness of patient T cells following multiple lines of treatment and the lengthy manufacturing process itself ( Jo et al, 2023 ). Therapeutic options following unsuccessful product manufacturing include repeating apheresis or transitioning to alternative therapies, though survival outcomes are poor in both cases ( Jagannath et al, 2021 ; Jo et al, 2023 ; Mateos et al, 2023 ). Altogether, the multiple sources of delays leading to loss of life underscore the criticality of timely access to CAR-T cell products ( Chen et al, 2022 ).…”