CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Age ≥ 18 years, regardless of gender.
* Histologically confirmed large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL, not otherwise specified) or high-grade B-cell lymphoma.
* Received prior CD19-targeted chimeric antigen receptor (CAR) T-cell therapy.
* Confirmed stable disease (SD) or progressive disease (PD) at the most recent imaging assessment (according to Lugano 2014 criteria) following CAR-T therapy.
* Able to provide a formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (fresh biopsy or archival specimen obtained before CAR-T therapy or after recent progression) with sufficient quantity and quality for immunohistochemistry (IHC) testing.
* Confirmed CD20-positive tumor cells by central laboratory IHC testing.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2.
* Adequate organ function (including bone marrow, liver, kidney, and heart).
* Women of childbearing potential must agree to use highly effective contraception during the study and for a specified period after the last dose of study drug; male patients must agree to use effective contraception during the study and for a specified period after the last dose.
* Voluntarily agreed to participate in the study, signed the written informed consent form, and willing to comply with the study visit schedule and other protocol requirements.

Exclusion Criteria:

* Prior treatment with glofitamab resulting in disease progression.
* Known severe allergic reactions to any components of the study drugs.
* Active central nervous system (CNS) lymphoma involvement.
* Presence of a severe, uncontrolled active infection.
* Presence of severe cardiovascular or cerebrovascular diseases, uncontrolled diabetes, or uncontrolled hypertension that, in the investigator's judgment, makes the patient unsuitable for study participation.
* History of or current other malignancies (exceptions: adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, etc.).
* Pregnant or breastfeeding women.
* Positive for human immunodeficiency virus (HIV) antibody, or active hepatitis B virus (HBV) infection (HBsAg positive with HBV-DNA \> 1x10\^3 copies/mL), or active hepatitis C virus (HCV) infection (HCV antibody positive and HCV-RNA positive).
* Any medical or psychiatric condition that might interfere with study execution or result interpretation, or place the patient at unacceptable risk.
* Received other anti-tumor therapies (including chemotherapy, radiotherapy, immunotherapy, etc.) within 2 weeks prior to study enrollment, or have not recovered from toxicities of prior therapies to ≤ Grade 1 or baseline levels (excluding alopecia or other irreversible but non-clinically significant toxicities).

主要终点：Progression-Free Survival (PFS) · PFS is defined as the time from the date of randomization to the date of first documented disease progression (PD) or death from any cause, whichever occurs first. Disease response and progression will be assessed by a Blinded Independent Central Review (BICR) according to the Lugano 2014 classification criteria for lymphoma. · From the date of randomization until the first documented disease progression or death from any cause, whichever occurs first, assessed up to approximately 24 months.
次要终点：Objective Response Rate (ORR)；Complete Response Rate (CRR)；Duration of Response (DOR)；Overall Survival (OS)；Incidence and Severity of Adverse Events (AEs)

• Experimental: LME-Guided Combination Therapy · EXPERIMENTAL · Participants receive a tailored combination therapy based on their baseline Lymphoma Microenvironment (LME) subtype identified via immunohistochemistry (IHC). The specific regimens are: GC Type: Glofitamab combined with a BCL-2 inhibitor. IN Type: Glofitamab combined with a PD-1 inhibitor and lenalidomide. ME Type: Glofitamab combined with local radiotherapy and a BTK inhibitor. DE Type: Glofitamab combined with chidamide (an HDAC inhibitor).
• Active Comparator: Glofitamab Monotherapy · ACTIVE_COMPARATOR · All participants in this control arm receive single-agent therapy with the CD3xCD20 bispecific antibody glofitamab. The drug will be administered according to the approved product label and standard clinical practice.

This study evaluates a personalized treatment strategy for patients with large B-cell lymphoma (LBCL) whose disease has relapsed or not responded after CD19 CAR-T cell therapy. Researchers believe that the area surrounding the tumor, called the lymphoma microenvironment (LME), plays a major role in why treatments fail. In this study, researchers will classify patients into four different LME subtypes (GC, IN, ME, or DE) using a standard lab test on their tumor samples. Patients will then be randomly assigned to one of two groups. The control group will receive a standard single-drug therapy (glofitamab). The experimental group will receive a tailored combination therapy based specifically on their tumor's LME subtype. The main hypothesis of this study is that customizing the treatment based on the tumor's microenvironment will significantly improve how long patients live without their disease getting worse (progression-free survival) compared to the standard single-drug approach.