Allogeneic CAR-engineered cellular therapy for relapsed and refractory large B cell lymphoma: A systematic review and meta-analysis Authors

Alexander Biederstädt^1,2*Florian Bassermann^1,2,3,4Judith S Hecker^1,2,4

• ¹Department of Medicine III, Technical University of Munich (TUM), School of Medicine and Health, Munich, Bavaria, Germany
• ²TranslaTUM, Center for Translational Cancer Research, Technical University of Munich (TUM), Munich, Bavaria, Germany
• ³Deutsches Konsortium für Translationale Krebsforschung (DKTK), Heidelberg, Baden-Württemberg, Germany
• ⁴Bavarian Cancer Research Center (BZKF), Munich, Bavaria, Germany

Relapsed/refractory (r/r) large B-cell lymphoma (LBCL) remains a difficult-to-treat disease with limited treatment options, necessitating the development of new therapies with greater potency and broader applicability. While autologous chimeric antigen receptor (CAR)-T cell therapies have transformed the treatment landscape, 60–65% of patients eventually relapse, underscoring the need for improved approaches. Allogeneic CAR-T and CAR-NK cell therapies have recently emerged as promising alternatives, offering the potential to shorten manufacturing times, reduce costs, and expand access to a broader patient population. This systematic review and meta-analysis compiles the currently available clinical trial data on the efficacy and safety of these novel therapies in adult patients with r/r LBCL. The primary outcomes assessed were the best overall response rate (bORR) and best complete response rate (bCRR) at any time point. Secondary outcomes included rates of grade 1-2 and grade 3+ cytokine release syndrome (CRS), grade 1-2 and grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), grade 1-2 and grade 3+ infections and incidence of graft-versus-host disease (GvHD). Nineteen studies met the inclusion and exclusion criteria, encompassing 334 patients (155 CAR-NK; 179 CAR-T) evaluable for safety and 235 for response (77 CAR-NK; 158 CAR-T). The pooled estimates for the best overall response rate (bORR) and the best complete response rate (bCRR) were 52.5% [95% CI, 41.0-63.9] and 32.8% [95% CI, 24.2-42.0], respectively. Safety analysis revealed very low incidences of grade 3+ CRS (0.04% [95% CI 0.00-0.49]) or grade 3+ ICANS (0.64% [95% CI 0.01-2.23]) and only one GvH-like reaction across 334 infused patients, highlighting the remarkable safety profile of CAR-engineered allogeneic approaches. The overall incidence of low-grade CRS was 30% [95% CI, 14-48], while the estimated overall incidence of low-grade ICANS was 1% [95% CI, 0%-4%], markedly lower than current-generation autologous CAR-T cell products. The incidence of low-grade and severe infections was 25% [95% CI 14-36%) (n=252) and 7% [95% CI 2-14%] (n=291), respectively. Together, allogeneic CAR-T and CAR-NK cell therapies demonstrate encouraging efficacy in heavily pretreated patients with r/r LBCL. Given their favorable safety profiles, off-the-shelf allogeneic cell therapies hold great promise to broaden the reach of live cell-based treatments.