T cells isolated from G-CSF-treated multiple myeloma patients are suitable for the generation of BCMA-directed CAR-T cells

Autologous cell immunotherapy using B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells is an effective novel treatment for multiple myeloma (MM). This therapy has only been used for relapsed and refractory patients, at which stage the endogenous T cells used to produce the CAR-T cells are affected by the immunosuppressive nature of advanced MM and/or side effects of previous therapies. An alternative pool of fitter T cells is found in leukocytoapheresis products that are routinely collected to obtain hematopoietic progenitor cells for autologous stem cell transplantation (ASCT) early in the treatment of MM. However, to mobilize the progenitor cells, patients are dosed with granulocyte colony-stimulating factor (G-CSF), which is reported to adversely affect T cell proliferation, function, and differentiation. Here, we aimed to first establish whether G-CSF treatment negatively influences T cell phenotype and to ascertain whether previous exposure of T cells to G-CSF is deleterious for anti-BCMA CAR-T cells. We observed that G-CSF had a minimal impact on T cell phenotype when added in vitro or administered to patients. Moreover, we found that CAR-T cell fitness and anti-tumor activity were unaffected when generated from G-CSF-exposed T cells. Overall, we showed that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture

Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Tisagenlecleucel (tisa-cel) is a second-generation autologous CD19-targeted chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa-cel in the standard-of-care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa-cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa-cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non-relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow-up of 14.1 months from CAR T-cell infusion, median progression-free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa-cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses

Supplementary Figure S1 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma [Dataset]

B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2–37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5–100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5–22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.Instituto de Salud Carlos III (ISCIII) 'la Caixa' Foundation ('la Caixa') Fundación Científica Asociación Española Contra el Cáncer (AECC)Peer reviewe

Efficacy of CAR T-Cell Therapy is Not Impaired by Previous Bispecific Antibody Treatment in Large B-Cell Lymphoma.

International audienceIn this retrospective study, CAR T-cells remained effective in relapsed/refractory LBCL patients after prior exposure to bispecific antibodies (BsAbs) targeting different antigens. These results are relevant to clinical practice, particularly given the increasing use of BsAbs in earlier treatment lines