Zamtocabtagene autoleucel

Emerging long-term data indicates relapse rates of over 50% after CD19 redirected chimeric antigen receptor (CAR) T cell therapy in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen we conducted a first-in-human phase I clinical trial of zamtocabtagene autoleucel (zamto-cel) - a non-cryopreserved tandem CD20-CD19-directed CAR-T cell therapy. Two predefined dose levels (DL1=1x106 and DL2=2.5x106 CAR+ T cells/kg body) were applied. The primary endpoint (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events (AEs), best overall response (BOR) and biomarker assessments. A total of 12 patients, 6 per dose level were treated. No DLT and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75% with 5/12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with higher mean Cmax and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ TCM cells in patients with CR, thus facilitating persistence and improved outcomes in r/r B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal Phase II clinical trials for patients with r/r aggressive B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT03870945.

Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary approach in immunotherapy that has shown remarkable success in the treatment of blood cancers. Many preclinical studies are currently underway worldwide to extend the CAR-T-cell therapy benefits to a broad spectrum of cancers, using rodent models. Alternative in vivo platforms are essential for overcoming the drawbacks associated with rodent models, including immunodeficiency in humanized models, ethical concerns, extended time requirements, and cost. In this work, we used the chicken chorioallantoic membrane (CAM) assay to evaluate the in vivo efficacy of cluster-of-differentiation 19 (CD19)-targeting CAR-T cells expressing a second-generation CAR construct against human lymphoma derived from the Raji cell line. Our results confirm the efficacy of selected CAR-T cells on tumor growth, metastasis, and angiogenesis. Further, the chicken embryo has an intrinsic active immune system. Therefore, the dialog between CAR-T cells and endogenous immune cells, as well as their participation in the tumor challenge, has also been studied. In conclusion, our study demonstrates that the chicken CAM assay provides a relevant in vivo, 3Rs (Replacement, Reduction and Refinement)-compliant new approach methodology (NAM), which is well-suited for the current needs of preclinical research on CAR-T-cell therapy.