Anbalcabtagene Autoleucel in Relapsed/Refractory CNS Lymphoma

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.