Open Access

Hyatt Balke-Want, Philipp Gödel, Christoph Schmid, Francis Ayuketang Ayuk, Birte Friedrichs, Pearl van Heteren, Silke Holtkamp, Gregor Zadoyan, Corinne Brillant, Joana Costa, Linda Hanssens, Tatjana Holzer, Christian Wöhle, Stefanie Biedermann, Iris Bürger, Rimas J. Orentas, Toon Overstijns, Christoph Scheid, Udo Holtick, Stefan Miltenyi, Michael J. Hallek, Peter Borchmann, Nadine Kutsch

• 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 12Emerging 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.…