Unique loop-structured CD19/CD22 bispecific CAR-T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma: an observational study

Early Clinical Experience of CD19 x CD22 Dual Specific CAR T Cells for Enhanced Anti-Leukemic Targeting of Acute Lymphoblastic Leukemia

Outcomes of Aggressive B Cell Lymphoma Patients with No Evidence of Measurable Disease at the Time of CD19 Chimeric Antigen Receptor T Cell Therapy: The Experience from the CAR T Cell Consortium

Modulation of CD22 Antigen Density Improves Efficacy of CD22 Chimeric Antigen Receptor (CAR) T Cells Against CD22lo B-Lineage Leukemia and Lymphoma

Phase 1/2 Study of AUTO3 the First Bicistronic Chimeric Antigen Receptor (CAR) Targeting CD19 and CD22 Followed By an Anti-PD1 in Patients with Relapsed/Refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL): Results of Cohort 1 and 2 of the Alexander Study

A Feasibility and Safety Study of CD19 and CD22 Chimeric Antigen Receptors-Modified T Cell Cocktail for Therapy of B Cell Acute Lymphoblastic Leukemia

Safety and Feasibility of Intrathecal Infusion of CD19 and/or CD22 CAR T Cells in r/r B-ALL Patients with CNSL or High-Risk CNS Relapse

CD22 CAR Optimization for Improved in-Human Activity Following Inadequate CD22 CAR Activity in Phase 1 Clinical Trial PLAT-04

Updated Follow-up of a Phase 1 Trial of Bispecific CART19/20 Cells for Relapsed or Refractory Non-Hodgkin Lymphoma

e19002 Background : The management of relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is associated with high morbidity and mortality. Chimeric antigen receptor (CAR) T-cell therapy against CD19 has emerged as a revolutionary treatment for r/r DLBCL. There are currently three FDA-approved CAR T-cell therapy products with two different co-stimulatory domains (CSD): axicabtagene ciloleucel (CD-28 CSD), tisagenlecleucel (4-1BB CSD), and lisocabtagene maraleucel (4-1BB CSD). CSDs mediate CAR-T anti-tumor effects while also influencing treatment-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Here, we report our real-world experience of CAR-T-cell products (CD28 vs. 4-1BB) in r/r DLBCL. Methods: We conducted a retrospective analysis of patients diagnosed with r/r DLBCL at our institute who received CAR-T therapy with 2 years of post-therapy follow-up. We collected data on baseline demographics, bridging therapy, lymphodepletion (LD) regimen, and specific CAR-T product used. Differences in clinical outcomes were determined between patients treated with CD28 vs. 4-1BB CAR-T cell products. Clinical endpoints included incidence and severity of CRS/ICANS, response rate, progression-free survival (PFS), and overall survival (OS). Survival functions were estimated using Kaplan-Meier estimators. Results: A total of 111 patients with r/r B-cell malignancies received CAR-T therapy at our institute between 2018 and 2023, of which 95 patients had r/r DLBCL diagnosis. The median age was 64 years. CRS occurred in 59 out of 95 patients (62.1%), with severe CRS (Grade 3 or 4) occurring in eight patients (13%). Fifty-four patients (57%) achieved a complete response (CR) after CAR-T therapy. Among the 54 patients who achieved CR, 22 died from treatment-related toxicities, including 7 deaths associated with COVID-19 infection. Moreover, 41 patients (43%) experienced disease progression post CAR-T therapy, and 95% of them (39 patients) died from r/r DLBCL. The median OS for the entire cohort was 14.8 months. Patients who experienced disease progression had a significantly shorter median OS of 5 months. No statistically significant differences were observed in PFS or OS based on time from apheresis to treatment, LD regimen used, or the CAR-T product (CD28 vs. 4-1BB). Conclusions: In our real-world experience, CAR-T cell therapy can cure approximately 30% of r/r DLBCL patients regardless of the cellular therapy product subtype utilized. Patients who progressed after CAR T-cell therapy prior to the availability of Bispecific T-cell engagers (BiTEs) had a dismal outcome, with most of them dying from lymphoma. In the absence of clinical trials or access to BiTEs-based therapy, early goals-of-care discussions and hospice should be considered for patients who progress after CAR T-cell therapy.

CD229 CAR T Cell Therapy for the Treatment of Relapsed B Cell Lymphoma

Repeat Infusion of CD19-Specific Chimeric Antigen Receptor T-Cell Could Improve the Efficacy with Consistent Safety in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

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 >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.

Mitigating the Risk of Cytokine Release Syndrome (CRS): Preliminary Results from a DLBCL Cohort of Epcore NHL-1

Early Response Data for Pediatric Patients with Non-Hodgkin Lymphoma Treated with CD19 Chimeric Antigen Receptor (CAR) T-Cells

Immunotherapy in lymphoma.