Johnson & Johnson’s Dual-Targeting CAR T-Cell Therapy Shows Encouraging First Clinical Results in Large B-Cell Lymphoma
Johnson & Johnson recently presented promising first-in-human data from its ongoing Phase 1b study evaluating JNJ-90014496 (JNJ-4496) — an investigational, dual-targeting, autologous chimeric antigen receptor (CAR) T-cell therapy — in patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) who have not previously received a CAR T-cell therapy. The data were presented during the 2025 European Hematology Association (EHA) Congress (Abstract #S239).
Relapsed or refractory large B-cell lymphoma, or R/R LBCL, comprises a group of aggressive hematologic malignancies stemming from B-cells — a key component of the adaptive immune system. The most frequently encountered form within this group is diffuse large B-cell lymphoma (DLBCL). Currently, treatment options for patients with relapsed or refractory disease remain limited, and prognosis is poor. Standard single-target CD19-directed CAR T-cell therapies typically enable long-term remissions in roughly 40% of patients, emphasizing a significant unmet need for new and more effective treatment strategies.
JNJ-4496, previously called C-CAR039, is a novel anti-CD19/anti-CD20 bispecific autologous CAR T-cell therapy designed to enable dual binding to both CD19 and CD20 — two surface proteins frequently present on malignant B-cells. This dual-target approach, alongside a 4-1BB costimulatory domain incorporated into its construct, is meant to aid in strengthening binding activity and persistence while reducing the likelihood of resistance mechanisms that can emerge following treatment with CD19-directed therapy alone.
Phase 1b Study Design and Efficacy Findings
The ongoing Phase 1b dose confirmation study (NCT05421663) is evaluating JNJ-4496 in patients with relapsed or refractory large B-cell lymphoma who have not previously undergone treatment with a CD19-directed CAR T-cell therapy. The study used a recommended Phase 2 dose (RP2D) of 75 million CAR+ T-cells, a dosage determined to provide a strong balance of safety and activity.
At a median follow-up of 4 months, data from 22 patients at the RP2D who were evaluated for efficacy revealed impressive responses. Among those who had received one prior line of therapy (n = 10), the objective response rate (ORR) was 100% (with a complete response rate [CRR] of 80%). Among patients who had previously undergone two or more lines of therapy (n = 12), the ORR was 92% and the CRR was 75%. The 95% confidence interval for ORR in this group fell between 62% and 100%. These results highlight the strong activity and depth of response for JNJ-4496 in a patient population that typically shows resistance to standard treatments.
Clinical Benefit and Investor Comments
“There is a pressing need to continue advancing new treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma. Currently, only about 40% of patients achieve long-term remissions with CD19-directed CAR T-cell therapy alone, reflecting a significant opportunity for further improvement in patient outcomes,” said Krish Patel, M.D., Director of Lymphoma Research at Sarah Cannon Research Institute and principal study investigator for the trial. “The data presented today show encouraging clinical activity and a strong safety profile for JNJ-4496 — representing a step forward in delivering a potential new treatment option to patients battling the most aggressive forms of B-cell lymphoma.”
Safety Profile and Adverse Events
Safety signals were closely evaluated in the study population, which predominantly consisted of heavy-pretreated patients — 52% (n = 13) had received two or more lines of therapy, and 56% (n = 14) had undergone bridging therapy before infusion. Importantly, there were no cases of Grade 3 or 4 cytokine release syndrome (CRS) — a potentially severe side effect frequently associated with CAR T-cell therapy.
Two cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed — one Grade 1 and another Grade 3, with the Grade 3 event occurring in a patient with central nervous system (CNS) lymphoma. Overall, 84% (n = 21) of patients experienced Grade 3 or 4 treatment-emergent adverse events (TEAEs), and 28% (n = 7) had serious TEAEs. The most frequently observed Grade 3 or 4 TEAE was neutropenia, affecting 72% of patients (n = 18), reflecting a drop in white blood cells — a well-understood side effect in this context. Additionally, one patient experienced a Grade 3 infection.
Commitment to Innovation in B-Cell Malignancies
“Our team is excited to share these first results for our dual-targeting, CD19 and CD20-directed CAR T-cell therapy in relapsed or refractory large B-cell lymphoma, reflecting our ongoing, more than a decade-long commitment to developing novel treatments for patients with hard-to-treat hematologic malignancies,” said Jeffrey Infante, M.D., Vice President of Early Clinical Development and Translational Research at Johnson & Johnson Innovative Medicine. “As we pursue the full potential of this new generation of cellular therapies, these data further reinforce the promise that JNJ-4496 might improve outcomes for many patients who otherwise have limited treatment options.”
Continuing Clinical Development
JNJ-4496 forms a key component of Johnson & Johnson’s growing pipeline of cellular therapies for B-cell malignancies and is a product of its ongoing collaboration with AbelZeta Inc. (formerly Cellular Biomedicine Group, Inc.). This collaboration, initially forged in 2023, aims to bring forward next-generation CAR T-cell therapies for patients in need, with the exception of the Greater China market, where separate rights apply. An initial Phase 1 study for C-CAR039 was previously conducted in China in patients with B-cell non-Hodgkin lymphoma — predominantly large B-cell lymphoma — adding depth to the growing body of data.
Additionally, Johnson & Johnson is evaluating the safety and efficacy of JNJ-4496 in a separate study involving a global patient population outside of Greater China. This trial aims to further validate the promise of the therapy in patients with relapsed or refractory large B-cell lymphoma. Furthermore, additional data from these ongoing trials will be presented at the 2025 International Conference on Malignant Lymphoma, which is scheduled to take place from June 17–21.
