Central nervous system lymphoma (CNSL) includes primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL), with diffuse large B-cell lymphoma as the predominant pathological type. Disease progression is often rapid and the relapse rate is high. Current standard treatment is centered on CNS-directed regimens based on high-dose methotrexate (HD-MTX), but salvage options for relapsed or refractory disease remain limited. In addition, the blood-brain barrier restricts effective exposure of many drugs within the central nervous system, making deep remission and durable disease control difficult to achieve. This study evaluates autologous CD19-CD20-NKG2D-nsBicephali CAR-T in patients with relapsed or refractory PCNSL or SCNSL. By engineering the patient's T cells into effector cells capable of recognizing both CD19 and CD20, this approach is intended to address tumor antigen heterogeneity and reduce immune escape associated with downregulation or loss of a single target. CAR-T cells may also migrate into cerebrospinal fluid and brain parenchyma, expand within the CNS compartment, and directly eliminate CD19/CD20-positive lymphoma cells. The study is designed to systematically evaluate the safety and preliminary efficacy of this investigational CAR-T therapy in relapsed or refractory CNSL.
This is a single-center, open-label exploratory clinical study to evaluate the safety, tolerability, and efficacy of autologous CD19-CD20-NKG2D-nsBicephali CAR-T in relapsed/refractory central nervous system lymphoma. The study has two stages. The first stage is a dose-escalation stage with two planned dose groups: a low-dose group of 1×10\^6 CAR-positive T cells/kg and a high-dose group of 2×10\^6 CAR-positive T cells/kg. A 3+3 design will be used for dose escalation. After enrollment and completion of the DLT observation period in each dose group, available safety and pharmacokinetic data will be reviewed to determine subsequent enrollment and treatment decisions, including whether additional dose groups should be added. The second stage is a dose-expansion stage. Once a given dose group is confirmed to be safe, that dose group and any lower confirmed dose groups may be expanded concurrently. Participants will be followed for safety and efficacy for 24 months after cell infusion. After completion of the main study, participants will be re-consented for long-term safety follow-up until 15 years after cell infusion.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Autologous CD19-CD20-NKG2D-nsBicephali CAR-T is an autologous cell product derived from the participant's own cells. Peripheral blood mononuclear cells are collected by leukapheresis, T cells are isolated, and viral transduction is used ex vivo to generate autologous CAR-T cells for reinfusion. The product name stated in the protocol is Autologous CD19-CD20-NKG2D-nsBicephali CAR-T Cell Injection. Package specification is approximately 10-40 mL per dose. Transport condition is 2-8°C. Storage condition is sealed, protected from light, and maintained in liquid nitrogen conditions.
Beijing GoBroad Boren Hospital
Beijing, Fengtai District, China
Proportion of participants with dose-limiting toxicity (DLT) within 28 days after infusion; determination of MTD or RP2D.
Time frame: Within 28 days after infusion.
Grade and frequency of adverse events (AEs), serious adverse events (SAEs), laboratory abnormalities, and adverse events of special interest (AESIs, including CRS and ICANS).
Time frame: From signing of informed consent through 24 months after infusion or the end-of-study visit, whichever occurs first.
Proportion of participants achieving objective response
Time frame: at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24.
Proportion of participants achieving complete response (CR)
Time frame: Month 3 (3 months ±14 days)
Response categories (CR/CRu/PR/SD/PD)
Time frame: Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24
Best overall response (BOR)
Time frame: From Day 0 (CAR-T infusion) until disease progression, initiation of new anti-tumor therapy, death, or Month 24 after infusion, whichever occurs first; response is assessed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24.
Time to response (TTR)
Time frame: From Day 0 to the first documented PR or CR/CRu, assessed through Month 24 after infusion; tumor assessments are performed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24.
Duration of response (DOR)
Time frame: From the date of first documented CR/CRu/PR until first documented PD or death, whichever occurs first, assessed through Month 24 after infusion.
Progression-free survival (PFS)
Time frame: From Day 0 until first documented disease progression or death, whichever occurs first, assessed through Month 24 after infusion.
Overall survival (OS)
Time frame: From Day 0 until death from any cause, assessed through Month 24 after infusion.
CNS response components
Time frame: Assessed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24 after infusion.
In baseline CSF-positive participants only: CSF conversion to negative, CSF MRD conversion to negative if MRD is performed, and duration of CSF MRD negativity
Time frame: Assessed at Day 28 and Months 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24 after infusion; duration of CSF MRD negativity is assessed through Month 24.
Cmax
Time frame: Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.
Tmax
Time frame: Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.
AUC0h-28d
Time frame: Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.
AUC0-last
Time frame: Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.
PD parameters, including changes in peripheral blood CD19-CD20-NKG2D-positive cells and serum cytokines such as TNF-alpha and IFN-gamma before and after infusion
Time frame: Assessed from Day 0 through Month 24 after infusion on Days 0, 1, 3, 5, 7, 9, 11, 14, 21, and 28; Months 2, 3, 6, 9, 12, 15, 18, and 24; and through study completion or early withdrawal, up to 24 months.
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