Anbalcabtagene Autoleucel in Relapsed/Refractory CNS Lymphoma

Overview

This clinical study aims to evaluate the tolerability, safety, and efficacy of Anbal-cel in patients with recurrent or refractory PCNSL or SCNSL. Subjects who have provided written consent and meet the inclusion and exclusion criteria through screening evaluations will undergo leukapheresis (LP) for Anbal-cel manufacturing. Subjects whose collected nucleated cells are confirmed suitable for Anbal-cel production will be enrolled in the clinical study. Prior to Anbal-cel administration, lymphodepletion therapy will be performed and must be completed at least 2 days before Anbal-cel administration. Anbal-cel will be administered to subjects who meet the inclusion and exclusion criteria for Anbal-cel administration. Study subjects will be hospitalized for a minimum of 7 days to closely monitor adverse events and receive prompt necessary treatment after Anbal-cel administration. All study subjects will undergo primary visit evaluations for 12 months following Anbal-cel administration. Subjects who discontinue primary visit evaluations before the 12-month visit will undergo an end of study 1 (EOS1) visit for safety observation. For subjects whose primary visit evaluations end before the 12-month visit due to disease progression (PD), withdrawal of consent for primary visit evaluations, or subsequent anti-cancer therapy, secondary follow-up visits will be conducted from the EOS1 visit to the 12-month time point (EOS2). The timing of the first secondary follow-up visit will be determined based on when the subject's primary visit evaluation was discontinued. A separate long-term follow-up study is planned to monitor long-term safety, including delayed adverse events (AEs), in subjects who received Anbal-cel. In this long-term follow-up study, each subject will be followed for 15 years from the date of Anbal-cel administration. All specific details, including the visit schedule and examination items for the long-term follow-up study, will be described in a separate protocol.

Primary central nervous system lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) are rare and aggressive subtypes of non-Hodgkin lymphoma (NHL) with poor prognoses in relapsed or refractory cases. Existing salvage therapies provide limited clinical benefit due to low response durability and high relapse rates, underscoring the need for novel therapeutic strategies. Chimeric antigen receptor T (CAR-T) cell therapy is a form of adoptive cell transfer (ACT) that reprograms T cells to target specific tumor antigens via genetically engineered immunoreceptors. Unlike T-cell receptor (TCR)-based approaches, CAR-T cells recognize tumor-associated antigens independently of HLA presentation. Anbalcabtagene autoleucel (Anbal-cel) is an investigational autologous anti-CD19 CAR-T cell product, incorporating a CD19-specific scFv, CD8 hinge and transmembrane domains, a 4-1BB co-stimulatory domain, and a CD3-zeta signaling domain. Upon CD19 engagement, Anbal-cel forms an immunological synapse and triggers effector functions, including proliferation, cytokine secretion (e.g., IFN-γ, IL-6, TNF-α, GM-CSF), and cytotoxic activity via perforin/granzyme and death receptor pathways. Notably, Anbal-cel is engineered to minimize T-cell exhaustion by downregulating immune checkpoint molecules such as PD-1 and TIGIT, which are frequently overexpressed in B-cell lymphoma. This design is anticipated to enhance antitumor efficacy relative to conventional anti-CD19 CAR-T therapies. This single-arm, open-label pilot study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of Anbal-cel in patients with relapsed or refractory PCNSL and SCNSL. In the prior phase 1/2 study (CRC01-01, NCT04836507), patients with CNS involvement were excluded; this study represents the first clinical evaluation of Anbal-cel in this population. The study includes a safety lead-in phase involving an initial cohort of three patients receiving the recommended phase 2 dose (RP2D) of 2 × 10⁶ CAR-T cells/kg. A Safety Review Committee (SRC) will assess initial safety data before proceeding with additional enrollment. To prepare for Anbal-cel infusion, patients will receive a lymphodepletion regimen of fludarabine (30 mg/m²/day) and cyclophosphamide (500 mg/m²/day) on Days -5 to -2. This approach is supported by prior CAR-T studies (e.g., Yescarta®), which demonstrated improved expansion and persistence with acceptable safety profiles. The \*\*primary objective\*\* is to assess the overall response rate (ORR) using the International Primary CNS Lymphoma Collaborative Group criteria. * Secondary objectives\*\* include: * Complete response rate (CRR) * Time to response (TTR) * Duration of response (DOR) * Event-free survival (EFS) * Progression-free survival (PFS) * Overall survival (OS) * Safety and tolerability * Pharmacokinetics and immune profiling * Exploratory objectives\*\* include evaluating associations between Anbal-cel expansion, cytokine levels, and immune-related adverse events (e.g., CRS, ICANS), as well as biomarker analyses (e.g., CD19, PD-1, TIGIT, LAG-3, TIM-3 in tumor or CSF) to characterize immune phenotype and gene expression changes linked to response. All patients will undergo long-term follow-up for 5 years in accordance with gene therapy guidance. Additionally, subjects who provide consent will be enrolled in a separate 15-year long-term safety follow-up protocol. Dose adjustments and WBC thresholds will guide lymphodepletion decisions based on patient condition and clinical safety monitoring.