Abstract CT023: Phase 1 trial of CD19/CD20 bispecific chimeric antigen receptor-engineered naïve/memory T cells for relapsed or refractory non-Hodgkin lymphoma
Authors: Puliafito Benjamin R. , Walthers Christopher , Ji Brenda , Ghafouri Sanaz N. , Naparstek Jacob , Trent Jacqueline , Chen Jia M. , Roshandell Mobina , Harris Caitlin , Khericha Mobina , Schweppe Thomas , Berent-Maoz Beata , Gosliner Stanley B. , Almaktari Amr , Ceja Melanie Ayala , Allen-Auerbach Martin S. , Said Jonathan , Nawaly Karla , Mead Monica , de Vos Sven , Young Patricia A. , Oliai Caspian , Schiller Gary J. , Timmerman John M. , Ribas Antoni , Chen Yvonne Y. , Larson Sarah M. 
Published: April 2023

Abstract
Despite excellent responses to anti-CD19 chimeric antigen receptor (CAR)-T cell therapy in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), more than half of patients will relapse due to poor CAR-T persistence or CD19 antigen escape. Engineering naïve/memory T (TN/MEM) cells with a bispecific anti-CD19/CD20 CAR could improve outcomes by mitigating these limitations. Here we report an update of the first-in-human phase 1 clinical trial with TN/MEM cells expressing a bispecific anti-CD19/CD20 CAR (CART19/20) for patients with R/R NHL (NCT04007029). Eligible patients were ≥18 years old with R/R diffuse large B-cell lymphoma (DLBCL) or primary mediastinal B-cell lymphoma (PMBCL) after ≥2 prior lines of therapy, or with mantle-cell lymphoma (MCL), follicular lymphoma (FL), or CLL/SLL after ≥3 prior lines of therapy. Prior CAR-T cell therapy was excluded, but other forms of CD19- or CD20-targeted therapies were allowed. Autologous leukocytes were obtained by leukapheresis and sorted for CD14-/CD25-/CD62L+ TN/MEM cells, followed by lentiviral transduction of the bispecific CD19/CD20 CAR. Bridging therapy after leukapheresis was allowed. Lymphodepletion chemotherapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day was administered for 3 days from Day −5 to Day −3 prior to CAR-T cell infusion. The primary endpoint was safety and the secondary endpoints were ORR, progression free survival (PFS), overall survival (OS), and CART19/20 transgene persistence. As of December 19, 2022, 11 patients have been treated with CART19/20 cells (7 DLBCL, including 4 transformed FL and 1 PMBCL; 3 FL; and 1 MCL). Patients were enrolled at two dose levels, including 50 × 106 CAR+ cells (8 patients) and 200 × 106 CAR+ cells (3 patients). The median age was 58 (range: 34 to 70). All patients had stage IV disease and 9 of 11 patients received bridging therapy. Six patients had grade-1 cytokine release syndrome (CRS), without any occurrence of higher-grade CRS. Neurotoxicity was not observed. Ten of the 11 patients achieved an objective response (91% ORR), with 8 patients (73%) achieving complete response (CR). One patient with FL relapsed at 18 months, received a second CART19/20 cell infusion (112 × 106 CAR+ cells), and re-achieved a CR that has persisted for &gt;6 months at last follow-up. With a median follow-up of 20.9 months (range: 3.4 - 37 months), 7 patients remain in CR with a median PFS of 18.2 months (95% CI 3.4 months - not estimable) and the median OS was not reached. This phase 1 study demonstrates robust safety and tolerability of CART19/20 T-cells in patients with R/R NHL, without occurrence of severe CRS or neurotoxicity. CART19/20 cells, utilizing a bispecific CAR and TN/MEM cells, may be an effective strategy to overcome the challenges of poor CAR T-cell persistence and antigen escape.
Citation Format: Benjamin R. Puliafito, Christopher Walthers, Brenda Ji, Sanaz N. Ghafouri, Jacob Naparstek, Jacqueline Trent, Jia M. Chen, Mobina Roshandell, Caitlin Harris, Mobina Khericha, Thomas Schweppe, Beata Berent-Maoz, Stanley B. Gosliner, Amr Almaktari, Melanie Ayala Ceja, Martin S. Allen-Auerbach, Jonathan Said, Karla Nawaly, Monica Mead, Sven de Vos, Patricia A. Young, Caspian Oliai, Gary J. Schiller, John M. Timmerman, Antoni Ribas, Yvonne Y. Chen, Sarah M. Larson. Phase 1 trial of CD19/CD20 bispecific chimeric antigen receptor-engineered naïve/memory T cells for relapsed or refractory non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT023.