Safety and Efficacy Study of Anti-PD1 Armored CD19 CAR-T Cells in Adult Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

A Prospective, Open-label and Single-arm Study of Anti-PD1 Armored CD19 CAR-T Cells in Adult Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

The purpose of this study is to investigate the safety and tolerability of anti-PD1 armored CD19 CAR-T Cells in adult subjects with relapsed or refractory diffuse large B-cell lymphoma.

This is a prospective, open-label, single-arm clinical study to evaluate the safety, tolerability of anti-PD1 armored CD19 CAR-T Cells in adult subjects with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).The study plans to explore across three dose levels (1.00 × 10^6, 3.00 × 10^6, 9.00 × 10^6 CAR+ T cells/kg), and 6.00×10^8 CAR+T cells as maximum dose, aiming to evaluate the safety, tolerability of anti-PD1 armored CD19 CAR-T Cells in r/r DLBCL, explore Maximum Tolerated Dose (MTD) and determine the recommended dose for Phase II. Besides, efficacy, pharmacokinetics and persistence profile of CAR-T cells are also study objectives.

Inclusion Criteria:

• 1. Subjects voluntarily participate in clinical research and sign informed consent.
• 2. Adult subjects (age ≥18 ) with relapsed or refractory diffuse large B-cell lymphoma: a) failure to achieve CR after 6 cycles, or PR after 3 cycles, of first-line therapy, or achieve CR after first-line therapy but relapse within 12 months; b) achieve CR after systemic treatment, but are refractory or relapsed, and no plan to transplant, or prepare for transplantation but cannot meet transplantation criteria after second-line therapy; c) not achieve CR after at least two courses of second-line treatment (including autologous stem cell transplantation).
• 3. Expected survival ≥ 3 months.
• 4. At least one measurable lesion as per revised IWG response criteria for malignant lymphom (2014 Lugano criteria).
• 5. CD19 positive expression are detected on tumor cells of subjects by flow cytometry or immunohistochemistry.
• 6. ECOG score ≤ 2.
• 7. Subjects with adequate organ functions prior to enrollment, meet the following laboratory values:
• Renal function: serum creatinine ≤ 1.5 × ULN or estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m².
• Hepatic function: Serum alanine aminotransferase (ALT) ≤ 5 × age-specific ULN and total bilirubin ≤ 2.0 mg/dL, except in subjects with Gilbert-Meulengracht syndrome. If total bilirubin ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN, subjects with Gilbert-Meulengracht syndrome are included.
• Pulmonary reserve: ≤ Grade 1 dyspnea and oxygen saturation >95% on room air.
• 8. Stable hemodynamics and left ventricular ejection fraction (LVEF) ≥ 45 % assessed by echocardiography or multi-gated radionuclide angiography (MUGA).
• 9. Adequate bone-marrow reserve without blood transfusion as defined by:
• Absolute neutrophil count (ANC) ≥ 1 x 10^9/L.
• Absolute lymphocyte count (ALC) ≥ 0.1 x 10^9/L.
• Platelets ≥ 50 x 10^9/L.
• Hemoglobin >80g/L.
• 10. In the investigator's judgment, subjects' general condition and all biochemical values are either normal or sufficiently compensated to receive lymphodepletion and CAR-T cell therapy.

Exclusion Criteria:

• 1. Women who are pregnant or breastfeeding, or planned pregnancy within 6 months.
• 2. Infectious disease(HIV, Active Tuberculosis ect.).
• 3. Active infection: hepatitis B, hepatitis C.
• 4. Abnormal vital signs or refuse to receive examination.
• 5. Subjects with psychiatric or psychological disorders are unable to complete treatment or efficacy assessment.
• 6.History of severe hypersensitivity or known hypersensitivity to IL-2.
• 7. Systemic or local severe infection requiring antimicrobial therapy.
• 8. Significant dysfunction of vital organs (heart, lung, brain, kidney, etc.), or in the investigator's judgment, subjects are unable to be enrolled with any other condition.