Novel CAR T-Cell Therapy Yields Responses in Relapsed/Refractory Lymphoma

“These results support KITE-363 as a promising therapeutic approach for patients with relapsed/refractory B-cell lymphoma, including those with highly refractory LBCL,” according to lead study author Saurabh Dahiya, MD, FACP.

High responses and manageable safety were reported in patients who received treatment with KITE-363 for relapsed/refractory B-cell lymphoma, according to data from a first-in-human phase 1 trial (NCT04989803) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Safety data indicated that no dose-limiting toxicities (DLTs) were reported in phase 1a. Grade 3 or higher adverse effects (AEs) were experienced by 2 patients who received the agent at dose level 1 (DL1; n = 3), which was 0.5 x 10⁶ CAR T cells/kg. Grade 3 or higher AEs were reported in 6 patients who received dose level 2 (DL2; n = 8), which was 1 x 10⁶ CAR T cells/kg. In those who received dose level 3 (DL3; n = 26), which was 2 x 10⁶ CAR T cells/kg, the most common grade 3 or higher AEs included decreased white blood cell (WBC) count (n = 11), neutropenia (n = 8), and decreased neutrophil count (n = 11).

Moreover, 1 grade 3 case of cytokine release syndrome (CRS) was reported in a patient with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL); the duration of the event was 1 day. Three grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) events were observed: 1 in the DL2 group, which had a duration of 4 days, and 2 in the DL3 group, which had durations of 1 and 2 days, respectively. Notably, no grade 3 or higher CRS or ICANS events were observed in those with primary refractory large B-cell lymphoma (LBCL) who received the CAR T-cell therapy at DL3 (n = 15).

In patients without prior exposure to CAR T-cell therapy who received KITE-363 at DL3 (n = 23), the objective response rate (ORR) was 87%, and this was comprised of a complete response (CR) rate of 78% and a partial response (PR) rate of 9%; 4% of patients had stable disease (SD) and 9% of patients had progressive disease (PD). Within this group, those with LBCL who had previously received at least 2 lines of therapy (n = 7) experienced an ORR and CR rate of 100% each. Those with primary refractory LBCL (n = 15) experienced an ORR of 80% and a CR rate of 67%. Of the 3 patients who had prior CAR T exposure and received DL3, 1 achieved a CR.

Among those who received KITE-363 at DL1 and DL2 (n = 11), the ORR was 64%, with a CR rate of 36% and a PR rate of 27%; 9% experienced SD, and 27% had PD.

“These results support KITE-363 as a promising therapeutic approach for patients with relapsed/refractory B-cell lymphoma, including those with highly refractory LBCL,” Saurabh Dahiya, MD, FACP, an associate professor of medicine at Stanford University School of Medicine in Stanford, California, said in a presentation of the data.

Keeping Up With KITE-363 and Its Evaluation in R/R B-Cell Lymphoma

The bicistronic, lentiviral-encoded autologous CAR T-cell therapy, KITE-363, is dual targeted. The anti-CD19 and anti-CD20 CAR possess a CD28 costimulatory domain and a 4-1BB costimulatory domain, respectively. “Dual targeting has the potential to address tumor heterogeneity and improve the durability of responses by preventing CD19-negative relapses,” Dahiya noted.

The open-label, multicenter, phase 1 study utilized a 3+3 study design; it was comprised of a phase 1a dose-escalation portion and a phase 1b dose-expansion portion. For phase 1a, patients had histologically confirmed relapsed/refractory B-cell lymphoma by World Health Organization criteria following more than 2 lines of therapy or second-line primary refractory disease. Phase 1b only enrolled patients with relapsed/refractory LBCL, which included those with second-line primary refractory disease. All patients were at least 18 years of age and had an ECOG performance status of 0 or 1.

They were excluded if they had Richter transformation, central nervous system (CNS) involvement of lymphoma, active infection, or a CNS disorder of clinical significance. Those with clinically significant autoimmune or cardiac disease were also excluded.

The primary end points for phase 1a and phase 1b were incidence of DLTs and ORR, respectively. Secondary end points included CR rate, duration of response (DOR), progression-free survival, time to next treatment, overall survival, safety, and levels of CAR T cells and cytokines in the blood.

After screening, patients were enrolled and underwent leukapheresis; this was followed by optional bridging therapy, which was comprised of corticosteroids with or without local radiation therapy per investigator discretion. From day –5 to –3, patients received lymphodepleting chemotherapy comprised of cyclophosphamide at 300 mg/m² daily and fludarabine at 30 mg/m² daily for 3 days. On day 0, patients were infused with KITE-363 at one of the 3 dose levels. For DL3, the median time from leukapheresis to infusion with the CAR T-cell therapy was 27 days (range, 21-56). The first post-infusion response assessment was conducted on day 28.

A total of 41 patients were enrolled and underwent leukapheresis; 3 of these patients were not treated, and the remaining 38 went on to receive lymphodepleting chemotherapy. Because 1 patient did not meet protocol-required eligibility to receive KITE-363, a total of 37 patients received the CAR T-cell therapy.

At the data cutoff date of March 18, 2025, the median follow-up in those who received treatment (n = 37) was 12.4 months (range, 6.0-39.2). The median follow-up for those who were in the DL3 group was 11.1 months (range, 6.0-22.0).

The median age for all treated patients was 62 years (range, 25-83), with 46% aged 65 years or older and 11% aged 75 years or older. In the DL3 group, the median age was 60.5 years (range, 25-82), with 42% of patients aged 65 years or older and 12% aged 75 years or older. More than half of patients were male (65%), most were White (78%), most were not Hispanic or Latino (86%), and had an ECOG performance status of 1 (60%). Moreover, 73% of all treated patients had stage III or IV disease at study entry, as did 65% of those in the DL3 group.

In all treated patients, the most common histologic subtype was LBCL (92%), followed by indolent non-Hodgkin lymphoma (5%), and NLPHL (3%). In the DL3 group, the most common histologic subtype was also LBCL (96%), followed by NLPHL (4%). Nineteen percent of all treated patients and 15% of those in the DL3 group had bulky disease, which was defined as at least 7.5 cm. Dahiya noted that patients had tumors that were positive for CD19 and/or CD20, with most patients (78%) having tumors that were positive for both. Thirteen percent of patients had tumors that were positive for 1 antigen.

In all treated patients, 46% were primary refractory, and 54% had received 2 or more prior regimens. Nineteen percent received prior CD19-targeted CAR T-cell therapy, 14% previously underwent autologous stem cell transplant (ASCT), and 57% had received bridging therapy. In the DL3 group, 58% were primary refractory, and 42% had received at least 2 prior lines of treatment. In the 15 patients who were primary refractory, 4 experienced PRs as best response to frontline treatment, and 11 experienced PD. Prior CD19-targeted CAR T-cell therapy and prior ASCT were received by 12% and 15% of patients, respectively. Fifty-eight percent of patients in this group received bridging therapy.

Additional Efficacy Data

The median duration of complete response (DOCR), defined as DOR of all patients who achieved a CR as best response, was not reached (95% CI, 5.2-not evaluable). The DOCR rate at 6 months was 71.4% (95% CI, 44.3%-87.0%). “Data beyond 6 months is heavily impacted by censoring,” Dahiya noted. “Longer follow-up is needed.” Nine of the 37 patients who received treatment died; 8 of these patients died due to PD.

Safety Spotlight

Among those who received the CAR T-cell therapy at DL3, all patients experienced any-grade AEs; 81% of these effects were grade 3 or higher. Any-grade and grade 3 or higher serious AEs were reported in 54% and 38% of patients, respectively. Any-grade cardiac disorders were experienced by 35% of patients; 4% of these cases were grade 3 or higher. Any-grade infections occurred in 42% of patients; they were grade 3 or higher for 15% of patients. Hematologic toxicities included neutropenia (any grade, 38%; grade ≥3, 31%), thrombocytopenia (8%; 4%), and anemia (31%; 15%). Hypogammaglobulinemia occurred in 15% of patients.

In those who received KITE-363 at DL1 or DL2, grade 1 or 2 CRS occurred in 64% of patients, and grade 3 ICANS occurred in 9% of patients. The median time to onset of CRS was 6 days (range, 2-8) and the median duration of the event was 3 days (range, 1-10). The median time to onset of ICANS was also 6 days (range, 6-6) and median duration was 6 days (range, 6-6). CRS was managed with tocilizumab (Actemra) in 45% of patients and corticosteroids in 27% of patients. ICANS was managed by corticosteroids in 9% of patients and anakinra (Kineret) in 9% of patients.

In those who received the agent at DL3, grade 1/2 CRS occurred in 88% of patients and grade 3 CRS occurred in 4% of patients. The median time to onset was 3.5 days (range, 2-9) and the median duration was 5.0 days (range, 2-11). Most events were managed with tocilizumab (88%), followed by corticosteroids (65%) and anakinra (4%). Grade 1/2 ICANS was experienced by 38% of patients; this effect was grade 3 for 8% of patients. The median time to onset was 6.0 days (range, 2-13) and the median duration was 4.5 days (range, 1-13). These effects were largely managed with corticosteroids (38%) followed by anakinra (15%).

Additional Revelations and Take-Home Message

“KITE-363 cell expansion was dose dependent, with markedly robust expansion observed in DL3, appearing greater than 3- to 5-fold higher than with axicabtagene ciloleucel [Yescarta],” Dahiya said. Post-infusion peak levels of serum analytes were also linked with KITE-363 pharmacokinetics and reduced toxicity.

Due to these early results, the robust CAR T-cell expansion and the acceptable toxicity profile, the agent is also under development for patients with autoimmune disease, Dahiya concluded.

Disclosures: Dahiya serves in a consulting or advisory role for Adaptive Biotechnologies, Bristol Myers Squibb, and Kite/Gilead.

Reference

Dahiya S, Ulrickson M, Topp MS, et al. A phase 1 study of KITE-363 anti-CD19/CD20 Chimeric Antigen Receptor T-cell therapy in patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2025;43(suppl 16):7003. doi:10.1200/JCO.2025.43.16_suppl.7003