In Vivo CD19/CD20 CAR T-Cell Therapy for Relapsed/Refractory B-Cell Lymphoma

This Phase 1, open-label, single-arm, dose-escalation study is designed to evaluate the safety and tolerability of SL1617 Injection in patients with relapsed or refractory B-cell lymphoma. SL1617 Injection is an investigational in vivo CAR T-cell immunotherapy targeting CD19 and CD20, based on an engineered lentiviral vector system. The vector is designed to specifically target and transduce T cells and NK cells in vivo, enabling in situ generation of functional CAR-expressing immune cells following a single intravenous infusion SL1617 Injection will be administered as a single intravenous infusion. Dose escalation will follow a traditional 3+3 design. The planned starting dose is 1.0 × 10^9 transducing units (TU), followed sequentially by dose levels of 3.0 × 10^9 TU and 6.0 × 10^9 TU.

At each dose level, three participants will initially be enrolled. If none of the first three participants experiences a dose-limiting toxicity (DLT), enrollment may proceed to the next dose level. If two or more of the first three participants experience a DLT, further dose escalation will be stopped.

If one of the first three participants experiences a DLT, three additional participants will be enrolled at the same dose level. Dose escalation may proceed if none of the three additional participants experiences a DLT. Dose escalation will be stopped if at least one of the three additional participants experiences a DLT, resulting in DLTs in at least two of six participants at that dose level.

If the maximum tolerated dose (MTD) is not reached after completion of the DLT observation period for the 6.0 × 10^9 TU dose cohort, the investigators may explore higher dose levels based on cumulative safety data and pharmacodynamic evidence.

The primary objective is to evaluate the safety of SL1617 Injection, including the incidence and severity of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, hematologic toxicity, organ toxicity, and other treatment-related adverse events. Secondary objectives include assessment of preliminary antitumor activity using objective response rate, complete response rate, partial response rate, overall survival, progression-free survival, and event-free survival. Exploratory objectives include characterization of in vivo CAR-T cell kinetics (CAR copy number, Cmax, Tmax, and AUC28d) and clonal evolution.

Inclusion criteria

• 1. The subject voluntarily agrees to participate in the study, has signed the informed consent form, and is willing and able to comply with the scheduled visits, study treatment, laboratory tests, and other study procedures.

• Patients with B-cell lymphoma confirmed by cytological or histopathological examination according to the 2022 World Health Organization classification, meeting all of the following criteria:
• Lymphoma cells are confirmed to express CD19 and/or CD20 antigens by immunophenotyping or immunohistochemical examination.
• Eligible B-cell lymphomas include:

• Aggressive B-cell lymphomas, including large B-cell lymphoma (LBCL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL);
• Indolent B-cell lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), and hairy cell leukemia (HCL).
• Relapsed or refractory B-cell lymphoma, defined as follows:

• Relapse: The patient has received adequate prior therapy and previously achieved a complete response (CR) or partial response (PR) after first-line systemic therapy (which must include an anti-CD20 monoclonal antibody and an anthracycline-containing chemotherapy regimen), second-line or subsequent systemic therapy, or autologous hematopoietic stem cell transplantation (ASCT), but relapsed after the completion of treatment, with disease progression confirmed by cytology or histology;
• Refractory: The patient failed to achieve CR or PR after first-line systemic therapy, or had no response to the most recent second-line or subsequent systemic therapy regimen, with progressive disease (PD) or stable disease (SD) as a best response of treatment.
• The patient must have at least one measurable lesion. If salvage therapy was administered after ASCT, the patient must have no response to the most recent salvage therapy or must have relapsed after the most recent salvage therapy. Patients with relapsed indolent lymphoma may be enrolled only if clinical indications for treatment are present, such as symptomatic mass lesions, organ compression, cytopenias, or B symptoms.

• Male or female subjects aged 18-75 years, inclusive. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 5. Estimated life expectancy of more than 3 months from the date of signing the informed consent form.

• Absolute neutrophil count≥1×10^9/L, platelet count≥75×10^9/L, hemoglobin≥60g/L.

• Adequate renal, hepatic, cardiac, and pulmonary function, defined as follows:
• Creatinine clearance (estimated by the Cockcroft-Gault formula) ≥60 mL/min;
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×upper limit of normal (ULN), total bilirubin≤1.5×ULN;
• Cardiac ejection fraction≥50%, no pericardial effusion on echocardiography, and no significant abnormalities on electrocardiogram (ECG);
• No clinically significant pleural effusion, and oxygen saturation >92% on room air at baseline.

• Subjects agree to use effective contraception from the time of signing the informed consent form until 1 year after cell infusion.

Exclusion criteria

• 1. The patient has severe cardiac dysfunction, or left ventricular ejection fraction (LVEF) <50%, or a history within the 12 months prior to enrollment of myocardial infarction, coronary angioplasty or coronary stent implantation, unstable angina, clinically significant arrhythmia, or other severe cardiovascular diseases.

• A history of severe pulmonary dysfunction or severe pulmonary disease associated with impaired lung function.

• The patient has a history of malignancies other than B-cell lymphoma, and is ineligible unless they have been disease-free and have not received any form of antineoplastic therapy for at least 3 consecutive years.

• Severe active infection that cannot be effectively controlled. 5. The patient has severe autoimmune disease, congenital immunodeficiency or active autoimmune disease requiring ongoing treatment, or is currently within the washout period after having received medications that may affect CAR-T cell immunotherapy, or is anticipated to require medications during the study period that may affect CAR-T cell immunotherapy treatment.

• The patient has tuberculosis infection, active hepatitis B virus (HBV) infection, active hepatitis C virus (HCV) infection, or human immunodeficiency virus (HIV) infection; has received a live vaccine within 4 weeks, or is anticipated to require a live vaccine during the study period.

• The patient has previously undergone allogeneic hematopoietic stem cell transplantation, solid organ allogeneic transplantation, or allogeneic cell therapy.

• A history of severe allergic reactions to biological products, including antibiotics.

• The patient has other significant uncontrolled comorbidities that may affect protocol compliance or interpretation of results.

• The investigator judges that the patient is unlikely to complete all visits and procedures required by the study protocol (including medium- and long-term follow-up visits), such as insufficient willingness of the patient and their family members to participate in the study, refusal to participate, inability of the patient to fully cooperate with the study arrangements, or inadequate compliance on the part of the patient and their family members.

• Any other severe physical or psychiatric disorder or clinically significant laboratory abnormality that may increase the risk associated with study participation, interfere with the interpretation of study results, or, in the investigator's judgment, make the patient unsuitable for participation in the study.