TOPLINE

Anbalcabtagene autoleucel (anbal-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy with dual PD-1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) knockdown was associated with high response rates in patients with relapsed or refractory large B-cell lymphoma (LBCL) in a phase 1/2 study. Among 73 evaluable patients, the complete response rate was 67.1%, and those who maintained complete response for at least 6 months had 18-month progression-free survival (PFS) and overall survival (OS) rates of 79.4% and 83.9%, respectively. 

METHODOLOGY

• CAR T-cell therapy has transformed the treatment of B-cell cancers, achieving complete response rates above 50% for approved products. Some patients still do not respond or relapse because of CAR T-cell exhaustion and other factors. Anbal-cel switches off two exhaustion-related proteins, PD-1 and TIGIT, to improve durability.
• Researchers conducted a multicenter, single-arm phase 1/2 study to evaluate the performance of anbal-cel in patients with relapsed or refractory LBCL (after at least two prior lines of chemotherapy or after autologous stem cell transplant failed to produce adequate response), including diffuse LBCL-not otherwise specified, follicular lymphoma grade 3B, high-grade B-cell lymphoma, or primary mediastinal LBCL.
• Phase 1 (n = 11) tested three dose levels to assess tolerability of anbal-cel and identify the recommended phase 2 dose; no dose-limiting toxicities were detected. In phase 2, 79 patients (median age, 65 years) received the recommended dose of 2 × 10⁶ cells/kg; 73 patients were included in the efficacy analysis set and all 79 in the safety analysis set.
• The primary endpoint in phase 2 was objective response rate (combined complete and partial response rates), assessed by an independent review committee. The secondary endpoints were PFS, OS, and adverse events. The survival analysis drew on phase 2 data, with a median follow-up duration of 8.5 months.
• Lymphodepletion involved the administration of cyclophosphamide 500 mg/m2 per day and fludarabine 30 mg/m2 per day for three consecutive days before anbal-cel infusion; bridging therapy was permitted and used in 64.6% of patients in phase 2. Response assessments were performed as per the Lugano criteria on day 28, in month 3, and then every 3 months until month 18.

TAKEAWAY

• The objective response rate was 75.3%, comprising a complete response rate of 67.1% and a partial response rate of 8.2%, as assessed by an independent review committee.
• PFS rates were 50.9% at 6 months, 41.1% at 12 months, and 35.2% at 18 months. The median OS was not reached by the data cutoff point; the OS rates were 66.6% at 12 months and 57.3% at 18 months.
• Patients with a complete response lasting at least 6 months (long-term response group) had ″lower PD-1 and TIGIT expression levels″ on CAR+ T cells (vs the non-long-term response group), and their 18-month PFS rate was 79.4% and OS rate was 83.9%. Based on pharmacokinetics, CAR T cells expanded more in responders than in nonresponders (median peak CAR T-cell expansion level: 20,403 vs 8580 copies/μg; median area under the curve through day 28: 192,452 vs 62,529 day × copies/μg).
• Nearly all patients (97.5%) had a grade 3 or higher adverse event, most often low neutrophil counts (93.7%), low platelet counts (41.8%), and anemia (30.4%). Cytokine release syndrome (CRS) developed in 57.0% of patients and neurologic events in 13.9%. Grade 3 CRS was observed in 8.9% of patients, and none had grade 4 CRS. Neurologic events of grade 2 occurred in 3.8%. Serious infections (grade 3 or higher) were seen in 25.3% of patients, and three of these infections were fatal (grade 5).

IN PRACTICE

"Our findings provide supportive evidence that dual PD-1 and TIGIT knockdown is associated with high response rates after CAR T-cell therapy. Immunophenotypic analyses further demonstrated that durable remissions were associated with lower PD-1 and TIGIT expression on CAR T cells. Moreover, the favorable safety profile observed in this study, particularly the low incidence of neurotoxicity, may contribute to improving the accessibility of CAR T-cell therapy for patients with LBCL," the authors of the study concluded.

SOURCE

The study, led by Won Seog Kim, Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Republic of Korea, was published online in Blood.

LIMITATIONS

Because the trial had a single-arm design, the authors could not determine whether PD-1 and TIGIT knockdown directly contributed to the high complete response rate. Cross-trial comparisons may have been affected by differences in the eligibility criteria and patient characteristics between this study and earlier CAR T-cell trials. In addition, as several analyses were exploratory in nature and conducted post hoc, those findings need to be interpreted carefully.

DISCLOSURES

The study was supported by research funding from Curocell Inc and the Korea Drug Development Fund. Two authors declared being employees of Curocell and holding stock in the company. One author reported receiving grants or research support from Sanofi, BeiGene, Boryong, Roche, Kyowa-Kirin, and Dong-A Pharma. Full author disclosures are reported in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.