CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

Must meet all the following inclusion criteria:

1. Male or female 18-75 years (inclusive);
2. Patients can understand this study and capable of providing informed consent;
3. Patients with willingness to be in the study and comply with the study visit procedures and other protocol requirements;
4. Diagnosed with CD19-positive large B-cell lymphoma (LBCL) based on cytology or histology according to the WHO 2016 standards, including diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), grade 3b follicular lymphoma (FL), transformed diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), high-grade B-cell lymphoma (HGBL) with MYC, BCL-2, and/or BCL-6 rearrangements, and high-grade B-cell lymphoma not otherwise specified (HGBL-NOS). For CD19 expression status, subjects with a clear past record of tumor histological diagnosis as CD19-positive (within 6 months prior to screening with no CD19-related treatment in the last 6 months) and tumors showing CD19-positive lymphoma levels ≥ 50% by IHC or CD19-positive lymphoma levels ≥ 70% by flow cytometry. If there is no previous CD19 tumor testing or the result is over 6 months prior to screening, a new tumor pathology sample must be provided or re-collected for CD19-positive diagnosis by the institution, with IHC showing CD19-positive lymphoma levels ≥ 50% or flow cytometry showing CD19-positive lymphoma levels ≥ 70%.
5. For refractory or relapsed large B-cell lymphoma subjects, must have received at least anthracycline-based therapy and rituximab (or other CD20-targeted drugs, excluding CD20-negative cases). If previously treated with R-CHOP or other CD20-targeted therapy, the best treatment outcome prior to relapse must have been complete remission (CR). Subjects should meet the criteria for relapse, progression, or failure after second-line therapy; or relapse after autologous hematopoietic stem cell transplantation (auto-HSCT). If the subject has undergone previous auto-HSCT, the best treatment outcome prior to relapse must have been CR, and the relapse should occur more than 12 months after the previous treatment. (Refractory is defined as the best response to the most recent treatment being disease progression or stable disease after at least 2 cycles of the last-line therapy).
6. According to the 2014 Lugano Treatment Response Assessment Criteria, at least one measurable tumor lesion should be present (lesions can be measured with PET results; lymph node lesions \[long axis LDi \> 15mm\] or extra nodal lesions \[long axis LDi \> 10mm\]);
7. Expected survival time greater than 12 weeks;
8. ECOG score of 0-1;
9. Able to establish an intravenous route for PBMC collection, meeting the following hematologic parameters before screening: Hemoglobin ≥ 80 g/L, absolute neutrophil count ≥ 1.0 × 10\^9/L, platelet count ≥ 75 × 10\^9/L, lymphocyte count ≥ 0.5 × 10\^9/L (if using bone marrow stimulants or blood transfusion, a washout period of 7 days is required; for granulocyte colony-stimulating factor \[G-CSF\] or granulocyte-macrophage colony-stimulating factor \[GM-CSF\], a washout period of 4 weeks or 5 half-lives is required);
10. Liver and kidney function, as well as heart and lung function, should meet the following requirements:

    1. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (using the Cockcroft-Gault formula);
    2. Ejection fraction ≥ 50%, with no clinically significant pericardial effusion or pleural effusion detected;
    3. Oxygen saturation ≥ 92% without oxygen support;
    4. Total bilirubin ≤ 1.5 × ULN (for patients with Gilbert's syndrome or lymphoma involving the liver, ≤ 3 × ULN);
    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN;
    6. Fibrinogen ≥ 1.0 g/L; activated partial thromboplastin time ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN;
11. No more than 1 month prior to screening, the subject must have participated in another interventional clinical study and recovered to a severity level of ≤ 1 for any treatment-related adverse events.

Exclusion Criteria:

1. History of receiving allogeneic hematopoietic stem cell transplantation, adoptive cell therapy (such as CAR-T therapy), or other gene-modified cell therapies;
2. Any active central nervous system (CNS) involvement (including symptomatic and asymptomatic), or a history of CNS disease (such as epilepsy, cerebral ischemia/hemorrhage, dementia, cerebellar disorders, or any autoimmune diseases involving the CNS);
3. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA positivity, or subjects with HBV titers above the upper limit of the normal range for the study center; positive for hepatitis C virus (HCV) antibody and peripheral blood HCV RNA positivity; positive for cytomegalovirus (CMV) DNA; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis test;
4. Any unstable systemic disease, including but not limited to unstable angina, cerebrovascular accident or transient ischemic attack (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ III), active bleeding, severe arrhythmias requiring drug treatment, liver, kidney, or metabolic disorders;
5. Presence of malignant tumors other than large B-cell lymphoma, except for cured non-melanoma skin cancer, carcinoma in situ of the cervix, localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ, and other cancers with a disease-free survival of more than 5 years;
6. Presence of gastric lymphoma, bulky disease, a history of CD19+ leukemia, or active autoimmune diseases (e.g., systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Hashimoto's thyroiditis, etc.);
7. Presence of uncontrolled active infections requiring treatment (e.g., sepsis, bacteremia, fungemia, viremia) (mild urinary tract infections or upper respiratory tract infections are exceptions), with the exception of prophylactic anti-infection treatment (for bacterial, fungal, viral infections, etc.);
8. Subjects who have received systemic steroid treatment within 2 weeks before PBMC collection and are determined by the investigator to require long-term systemic steroid treatment during the treatment period (except for inhaled, local application, or physiological replacement doses \[hydrocortisone ≤7 mg·d-1 or equivalent prednisone ≤5 mg·d-1 or dexamethasone ≤0.5 mg·d-1\]);
9. Subjects who have received anti-tumor treatment within 8 weeks or 5 half-lives (specific medications need to be assessed in detail) before PBMC collection, including chemotherapy, CD20-targeted therapy, etc.; local radiotherapy within 12 weeks;
10. Subjects who have used granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 4 weeks before PBMC collection or within at least 5 half-lives (whichever is shorter);
11. Subjects who have received alendronate treatment within 6 months before PBMC collection, or who have received fludarabine, cladribine, or bendamustine treatment within 3 months before PBMC collection;
12. Subjects who have undergone major surgery within 4 weeks prior to screening (as defined by "Clinical Application Measures of Medical Technology" and "Grade 3 and 4 surgeries") or who have not fully recovered from any previous invasive procedure;
13. Subjects who have received a live vaccine within 28 days before PBMC collection;
14. Pregnant or breastfeeding women, or those who plan to become pregnant during the treatment period or within 2 years after treatment, or male subjects whose partners plan to become pregnant within 2 years after male subject's cell injection;
15. Subjects whom the investigator deems unsuitable to participate in this trial.

主要终点：MTD (maximum tolerated dose) of C402-CD19-CAR · To evaluate the DLT (dose limiting toxicities), attributed to C402-CD19-CAR per cohort and determine the RP2D (recommended phase 2 dose). · 28 days following injection；AE (Adverse Event), AESI (Adverse Event of Special Interest), SAE (Severe Adverse Event) · The incidence, severity and duration of AE, AESI and SAE as determined by NCI-CTCAE v5.0 · up to 2 years post injection
次要终点：ORR (Objective Response Rate)；DOR (Duration of response)；PFS (Progression free survival)；DCR (Disease control rate)；OS (Overall Survival)；PK (Pharmacokinetics): AUCinf；PK: AUC(0-t)；PK: AUC0-28d

• C402-CD19-CAR · EXPERIMENTAL · To determine the safety, tolerability, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of C402-CD19-CAR cell therapy in patients with relapsed or refractory large B cell lymphoma. Dose cohorts: * Dose level 1: 0.3x105 CD19 CAR positive cells/kg body weight, subcutaneous injection * Dose level 2: 1 x105 CD19 CAR positive cells/kg body weight, subcutaneous injection * Dose level 3: 3 x105 CD19 CAR positive cells/kg body weight, subcutaneous injection

This study is to investigate the safety and tolerability of C402-CD19-CAR treatment in subjects with relapsed or refractory large B-cell lymphoma and further determine the recommended Phase 2 dose of C402-CD19-CAR.