KITE-363, an investigational dual CD19/CD20-targeted chimeric antigen receptor (CAR) T-cell therapy, demonstrated remarkable efficacy in patients with relapsed/refractory large B-cell lymphoma (LBCL), achieving an 87% objective response rate in a phase 1 study presented at the 2025 ASCO Annual Meeting.
The first-in-human study (NCT04989803) enrolled 37 patients across three dose levels, with the highest dose of 2 x 10⁶ CAR T cells per kg selected as the recommended phase 2 dose (RP2D). Among 23 CAR T-cell naive patients treated at this dose level, the therapy achieved a complete response (CR) rate of 78% and an objective response rate (ORR) of 87%.
Breakthrough Results in Treatment-Resistant Disease
The therapy showed particularly promising results in challenging patient populations. In patients with LBCL who had received two or more prior lines of therapy, the CR rate reached 100% at the RP2D. Among the 15 patients with primary refractory LBCL—a population with historically poor outcomes—the ORR was 80% with a CR rate of 67%.
"The response appeared durable with an immediate duration of complete response that has not been reached," said lead investigator Saurabh Dahiya, MD, from Stanford University School of Medicine. At six months, 71.4% of patients who experienced a complete response continued to respond to treatment, with the median duration of response not yet reached.
Enhanced CAR-T Cell Expansion
KITE-363 demonstrated markedly robust CAR-T cell expansion compared to existing therapies. In the DL3 group, the median CAR-T cell expansion peak was 132.3 cells per μL with a median time to peak of 9 days. This represents a 3-5 fold higher expansion than axicabtagene ciloleucel (Yescarta), which showed peak expansions of 52.9 cells/μL in ZUMA-1 and 25.8 cells/μL in ZUMA-7 trials.
"The robust expansion in this particular study is likely a function of synergistic activity of the dual CARs that are expressed on T cells," Dahiya explained. The bicistronic, lentiviral-encoded therapy features anti-CD19 CAR with a CD28 costimulatory domain and anti-CD20 CAR with a 4-1BB costimulatory domain.
Improved Safety Profile
The therapy demonstrated a notably improved safety profile compared to current FDA-approved CAR-T therapies. At the RP2D, no grade 3 or 4 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed among patients with primary refractory LBCL.
Across all dose levels, only one case of grade 3 CRS was reported in a patient with nodular lymphocyte-predominant Hodgkin lymphoma, lasting one day. Three patients experienced grade 3 ICANS events with durations ranging from 1-4 days. At the RP2D, grade 1/2 CRS occurred in 88% of patients with a median onset of 3.5 days and duration of 5 days, while grade 1/2 ICANS was seen in 38% of patients.
The lymphodepleting regimen used was notably less intense than standard protocols, consisting of cyclophosphamide at 300 mg/m²/day and fludarabine at 30 mg/m²/day for three days. Management of adverse events followed established protocols, with 88% of patients receiving tocilizumab and 65% receiving corticosteroids for CRS management.
Study Design and Patient Characteristics
The multicenter, open-label phase 1 study utilized a 3+3 dose escalation design across three dose levels: 0.5 x 10⁶, 1 x 10⁶, and 2 x 10⁶ CAR T cells per kg. The median age of enrolled patients was 62 years, with 11% being 75 years or older. Most patients (73%) had stage III/IV disease, and 54% had received two or more prior lines of therapy.
Manufacturing took a mean of 27 days from apheresis to infusion. The study enrolled patients with various B-cell lymphoma subtypes, with 92% having LBCL histology. Notably, 19% of patients had received prior CD19-targeted CAR-T therapy, and most patients (78%) had tumors positive for both CD19 and CD20 antigens.
Future Development
Based on these encouraging results, including the robust CAR-T cell expansion and acceptable toxicity profile, KITE-363 is also under development for patients with autoimmune diseases. The dual-targeting approach addresses tumor heterogeneity and has the potential to improve response durability by preventing CD19-negative relapses, a common mechanism of resistance with single-targeted therapies.
