CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Has voluntarily given informed consent, signed the informed consent form, and is willing and able to comply with the scheduled visits, study treatment, laboratory tests, imaging examinations, and other necessary trial procedures as required in the protocol;
2. Patients with relapsed/refractory (R/R) B-cell lymphoma/leukemia confirmed by histopathology, cytogenetics, molecular biology, clinical judgment, medical history, and other assessment methods in accordance with the WHO 2016 classification criteria, who have experienced disease progression under standard treatment regimens, are intolerant to standard treatment regimens, or lack effective standard treatment options;
3. Must meet the following criteria for R/R B-cell malignant tumors:

(1) B-cell tumors include 3 categories:

* B-cell acute lymphoblastic leukemia (B-ALL);

  ② Indolent B-cell lymphomas, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), hairy cell leukemia (HCL), etc.;

  ③ Aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL); (2) R/R B-ALL (meeting any 1 of the 4 criteria below):
* Relapse within 6 months after the first complete response (CR);

  * Primary refractory patients who failed to achieve CR after 2 cycles of standard chemotherapy;

    * Failure to achieve CR or relapse after first-line or multi-line salvage chemotherapy; ④ Relapse after hematopoietic stem cell transplantation (HSCT); (3) R/R B-cell lymphoma (meeting any 1 of the first 4 criteria below plus criterion 5):
* Tumor reduction \< 50% or disease progression after 4 courses of standardized chemotherapy per standard regimens;

  * Relapse within 6 months after achieving CR with standard chemotherapy;

    * ≥ 2 relapses after CR;

      * Relapse after HSCT; ⑤ Adequate prior treatment received, including at least anti-CD20 monoclonal antibody and anthracycline-containing combination chemotherapy regimens; 4. Aged 18-85 years (inclusive), male or female; 5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; 6. Expected survival \> 14 days from the date of signing the informed consent form; 7. Hemoglobin (HGB) ≥ 60 g/L (transfusion allowed); 8. Absolute neutrophil count (ANC) ≥ 1,000/μl and platelet count ≥ 45,000/μl in peripheral blood (transfusion allowed); 9. Hepatic, renal, cardiac, and pulmonary functions meeting the following requirements:

        1. Total Bilirubin (TBIL) ≤ 1.5 × Upper Limits of Normal (ULN), excluding subjects with Gilbert's syndrome;
        2. Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 × ULN;
        3. Serum Creatinine (Cr) ≤ 1.5 × ULN or Creatinine Clearance Rate (CCr) ≥ 60 mL/min (CCr estimated by the Cockcroft-Gault formula);
        4. Left Ventricular Ejection Fraction (LVEF) ≥ 50%; echocardiogram (ECHO) confirms no clinically significant severe pericardial effusion or severe arrhythmia;
        5. Baseline transcutaneous oxygen saturation \> 90% under room air;
        6. No clinically significant severe pleural effusion; 10. Subjects with pregnancy plans must agree to use contraceptive measures from before study enrollment until 6 months after the end of the study;

Exclusion Criteria:

1. Previous receipt of any form of chimeric antigen receptor (CAR) cell therapy or other genetically modified T-cell therapies;
2. History of severe immediate-type hypersensitivity reactions to commonly used drugs such as aminoglycoside antibiotics;
3. Known history of Human Immunodeficiency Virus (HIV) infection, active Hepatitis B Virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics (active HBV infection is defined as meeting all three of the following criteria: a. HBV DNA quantitation ≥ 2000 IU/ml; b. ALT ≥ 2 × Upper Limits of Normal (ULN); c. Exclusion of hepatitis caused by other factors such as the disease itself or medications. If a patient was diagnosed with active HBV infection initially and converted to inactive HBV infection after anti-HBV treatment, they may be included in this study with adequate ongoing anti-HBV treatment);
4. Hepatic or renal impairment unrelated to hematologic malignancies (e.g., lymphoma): ALT \> 3 × ULN, AST \> 3 × ULN, TBIL \> 2 × ULN, or serum creatinine clearance \< 30 mL/min;
5. History of myocardial infarction, cardiac angioplasty, coronary artery stenting, unstable angina pectoris, active arrhythmia, or other clinically significant cardiovascular diseases within 12 months prior to enrollment;
6. Other severe medical conditions that may affect the study (e.g., poorly controlled diabetes mellitus, gastric ulcer, other severe cardiorespiratory diseases, concurrent severe autoimmune diseases or congenital immunodeficiencies, uncontrolled severe infections, etc.), as well as other diseases with a high risk of condition deterioration; patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and still have acute graft-versus-host disease (GVHD) 1 month after discontinuing immunosuppressants. The decision is at the investigator's discretion;
7. History of severe immediate-type hypersensitivity reactions to any specific drugs required in this study; or history of severe hypersensitivity to biological products (including antibiotics);
8. Female subjects who are pregnant or lactating (due to potential risks of treatment to the fetus or infant);
9. Subjects judged by the investigator to be unable to complete all scheduled visits, investigations, or diagnostic and therapeutic procedures required by the study protocol (including medium- and long-term follow-up visits), those with poor willingness to participate, those who are unwilling to join or fully cooperate with the study arrangements, or those with insufficient compliance of the subject and their family members. The decision is at the investigator's discretion;
10. Concurrent progressive malignant tumors of other types; or a history of other malignant tumors, except for non-melanoma skin cancers and carcinoma in situ (e.g., of the cervix, bladder, or breast). Subjects with a history of other malignant tumors are ineligible unless they have been disease-free and not received any form of anti-tumor treatment for at least 3 consecutive years;
11. History of live vaccine vaccination within 6 weeks prior to the start of the conditioning regimen;
12. Receipt of major surgical procedures (excluding lymph node biopsy) within the past 14 days, or anticipated need for major surgery during the treatment period;
13. Other severe physical or mental illnesses or laboratory abnormalities that may increase the risk of study participation or interfere with study results, as well as patients deemed unsuitable for participation by the investigator.

主要终点：the safety and maximum tolerated dose of CAR-T cell immunotherapy mediated by polymer-lipid nanoparticles delivering CD19/CD20 dual-targeting InViVoCAR1920 mRNA in patients with relapsed/refractory B-cell lymphoma/leukemia · 3 months after treatment
次要终点：30-day response rate；90-day response rate；overall survival (OS)；progression free survival (PFS)；time to progression (TTP)；disease free survival (DFS)；duration of response (DOR)；event free survival (EFS)

• Patients with R/R B-Cell Lymphoma/Leukemia who accepted CD19/CD20 Dual-Targeting InViVoCAR-T · EXPERIMENTAL

The purpose of this study is to determine the efficacy and safety of the CAR-T cell immunotherapy utilizing polymer-lipid nanoparticles for delivering CD19/CD20 dual-targeting InViVoCAR1920 mRNA, for the first-line consolidation therapy of relapsed/refractory B-cell lymphoma/leukemia.