Overview

This study is a single-center, open-label clinical trial of single-dose of CAR T-cells in subjects with relapsed/refractory hematologic malignancy.

Eligibility

Inclusion Criteria:

• Patients must meet all of the following criteria to be eligible for the study:
  1. Voluntarily participate in the clinical study. The individual or the legal guardian fully understands the study, sign the informed consent form (ICF), and is willing and able to follow and complete all trial procedures.
  2. Age ≥ 18 years and < 70 years.
  3. Subjects with refractory or relapsed disease after current standard treatments (including allogeneic or autologous hematopoietic stem cell transplantation) who are not suitable for other treatment options, such as a second stem cell transplant. The definitions of relapsed/refractory lymphoma include one of the following situations:
     1. Relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) is defined as one of the following:
     2. Primary refractory disease.

ii) First relapse if the initial remission is ≤ 12 months.

iii) Relapse or refractory disease after two or more lines of systemic therapy.

          iv) Relapse or refractory disease after allogeneic transplantation, provided
          that at the time of enrollment, the subject is at least 100 days post-stem cell
          transplantation and has not received immunosuppressive drugs for at least 4
          weeks prior to enrollment, except for low-dose steroids (≤ 5 mg of prednisone
          or equivalent).
          b. Subjects with Ph+ B-cell ALL, who are intolerant to or ineligible for
          tyrosine kinase inhibitor (TKI) treatment, or who have relapsed/refractory
          disease after receiving at least two different TKI treatments, are eligible.
          c. Relapsed/refractory B-cell-derived non-Hodgkin lymphoma (NHL) and Hodgkin
          lymphoma (HL) defined as one of the following:
          i) No response to first-line treatment (primary refractory disease, excluding
          subjects intolerant to first-line treatment);
            -  Disease progression (PD) as assessed after first-line treatment.
            -  Best response of SD after at least 4 cycles of first-line treatment (e.g.,
               4 cycles of RCHOP), with SD duration not exceeding 6 months after the last
               dose.
          ii) No response to second-line or more treatments.
            -  PD as the best response to the most recent treatment regimen.
            -  Best efficacy of the last line of treatment as SD after at least 2 cycles,
               with the duration of SD not exceeding 6 months after the last dose.
          iii) Refractory after autologous stem cell transplant (ASCT).
            -  Disease progression or relapse ≤ 12 months post-ASCT (relapsed patients
               must have biopsy-proven relapse).
            -  If salvage treatment is performed after ASCT, the subjects must have no
               response to or relapsed after the last line of treatment.
            -  Relapsed or refractory disease after two or more lines of systemic
               therapy.
       4. Indications included for enrollment in the cohort of anti-CD19-CAR T-cells:
            1. CD19+ ALL patients, with bone marrow smear reports showing tumor cells ≥
               5%.
            2. CD19+ NHL patients meeting one of the following subtypes:
                 -  Diffuse large B-cell Lymphoma, not otherwise specified (DLBCL-NOS)
                 -  Primary mediastinal B-cell lymphoma (PMBCL)
                 -  Transformed follicular lymphoma (TFL), previously treated for
                    follicular lymphoma and then transformed to refractory DLBCL
                 -  Mantle cell lymphoma
                 -  High-grade B-cell lymphoma
                 -  Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
       5. Subtypes of lymphoma included for enrollment in the cohort of anti-CD20/30-CAR
          T-cells:
            -  Previously received anti-CD20/30-CAR T-cell therapy, with CD20 expression
               positive at enrollment.
            -  Lymphoma with dual positive expression of CD20/CD30.
       6. Indications included for enrollment in the cohort of anti-CD30-CAR T-cell:
            -  CD30 positive HL
            -  CD30 positive T-cell lymphoma
       7. ECOG performance status ≤ 2.
       8. Expected survival of at least 12 weeks.
       9. Adequate venous access (for apheresis) and no other contraindications for blood
          cell separation.
      10. Laboratory tests during screening must meet the following requirements, and the
          subject must not have received cell growth factors (long-acting
          colony-stimulating factors (G-CSF/PEG-CSF) require a 2-week interval) and
          platelet transfusions within 7 days prior to hematological assessment:
            1. Absolute neutrophil count ≥ 1.0×10^9/L (the condition of ALL patients is
               determined by the investigator).
            2. Hemoglobin ≥ 60 g/L (without red blood cell transfusion in the last 14
               days).
            3. Platelets ≥ 50×10^9/L (the condition of ALL patients is determined by the
               investigator).
            4. Absolute lymphocyte count (ALC) ≥ 0.5×10^9/L.
            5. Total serum bilirubin ≤ 1.5× the upper limit of normal (ULN).
            6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤
               2.5×ULN.
            7. Creatinine <1.5×ULN and estimated creatinine clearance ≥60 mL/min.
      11. Ejection fraction ≥ 45%, with echocardiogram (ECHO) confirming no pericardial
          effusion (excluding small or physiological amounts), and electrocardiogram
          results with no clinical significance.
      12. Baseline oxygen saturation > 92% without supplemental oxygen.
      13. Women of childbearing potential must have a negative serum or urine pregnancy
          test result (women who have undergone surgical sterilization or have been
          postmenopausal for at least 2 years are not considered of childbearing
          potential).

Exclusion Criteria:

• Subjects are not eligible to participate in this study if they meet any of the following criteria:
  1. ALL patients with central nervous system (CNS) abnormalities, including CNS-2 and CNS-3 that are of clinically significant neurological changes:
     1. CNS-3 disease is defined as detectable tumor cells in the cerebrospinal fluid (CSF) sample with ≥ 5 WBCs/mm^3, with or without neurological changes.
     2. CNS-2 disease is defined as detectable tumor cells in the CSF sample with < 5 WBCs/mm^3 and with neurological changes.

          Note: Subjects classified as CNS-1 (no detectable tumor cells in CSF) and those
          with no clinically significant neurological changes classified as CNS-2 are
          eligible to participate in this study.
       2. Brain MRI evidence shows central nervous system lymphoma. Active primary
          central nervous system DLBL, unless CNS involvement has been effectively
          treated (i.e., participants are asymptomatic) and there has been a local
          treatment interval of >4 weeks prior to enrollment.
       3. Presence of active central nervous system diseases, such as epilepsy,
          cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases, or any
          autoimmune diseases with CNS involvement.
       4. A history of or concurrent presence of other malignancies.
       5. Clinically significant cardiac disease or arrhythmias that cannot be controlled
          with medication.
       6. Presence or suspicion of fungal, bacterial, viral, or other infections that are
          uncontrolled or require intravenous antibiotics for treatment. Uncomplicated
          urinary tract infections and uncomplicated bacterial pharyngitis are allowed.
       7. Positive for hepatitis B (positive for HBsAg, and/or positive for Hepatitis B
          core antibody and HBV DNA >1000 copies/mL) and hepatitis C (positive for HCV
          antibodies), syphilis or human immunodeficiency virus (HIV) infection.
       8. Presence of any indwelling or drainage catheters (such as percutaneous
          nephrostomy tubes, indwelling Foley catheters, bile drainage tubes, or
          pleural/peritoneal/pericardial catheters). The use of specialized central
          venous access devices, such as Port-A-Cath® or Hickman® catheters, is allowed.
       9. Prior medication:
            1. Use of clofarabine or cladribine within 3 months prior to enrollment, or
               use of PEG-asparaginase within 3 weeks prior to enrollment.
            2. Injection of live vaccines within 4 weeks prior to enrollment.
            3. Donor lymphocyte infusion (DLI) within 28 days prior to enrollment.
            4. Any medications used for the treatment of GVHD (such as calcineurin
               inhibitors, methotrexate, mycophenolate, rapamycin, thalidomide) within 4
               weeks prior to enrollment, or immunosuppressive antibodies (such as
               anti-CD20, anti-tumor necrosis factor, anti-interleukin-6, or
               anti-interleukin-6 receptor) used within 4 weeks prior to enrollment.
            5. Immune stimulation or immunosuppressive therapy (such as interferon-α,
               interferon-β, IL-2, etanercept, infliximab, tacrolimus, cyclosporine, or
               mycophenolic acid) within 4 weeks prior to enrollment.
            6. Any systemic immunosuppressive/stimulatory checkpoint molecule therapy
               within 4 weeks prior to enrollment (such as ipilimumab, nivolumab,
               pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc.).
            7. Use of systemic cytotoxic drugs within 2 weeks prior to enrollment,
               including daily or weekly low-dose maintenance chemotherapy (such as
               cyclophosphamide, ifosfamide, bendamustine, chlorambucil, methotrexate,
               vincristine, etc.).
            8. Long-acting growth factors (e.g., pegylated filgrastim) within 14 days
               prior to leukapheresis, or short-acting growth factors or mobilizing
               agents (e.g., granulocyte colony-stimulating factor/filgrastim,
               plerixafor) within 5 days prior to leukapheresis.
            9. Radiation therapy within 2 weeks prior to enrollment.
           10. Use of pharmacological doses of corticosteroids (>5 mg/day of prednisone
               or equivalent doses of other corticosteroids) and other immunosuppressive
               medications must be avoided within 7 days prior to enrollment.
           11. Use of venetoclax (BCL-2 inhibitor) within 4 days prior to leukapheresis.
           12. Short-acting targeted therapy (e.g., tyrosine kinase inhibitors) within 72
               hours prior to leukapheresis.
           13. Idelalisib (oral PI3Kδ inhibitor) within 2 days prior to leukapheresis.
           14. Lenalidomide within 1 day prior to leukapheresis.
      10. Active graft-versus-host disease (GVHD) ≥ grade 2 on the CIBMTR acute GVHD
          grading system or requires systemic steroids at doses greater than
          physiological levels.
      11. A history of autoimmune diseases (such as Crohn's disease, rheumatoid
          arthritis, or systemic lupus) resulting in end-organ injury or requiring
          systemic immunosuppression/systemic disease-modifying agents within the last 2
          years.
      12. A history of myocardial infarction, cardiac angioplasty or stenting, unstable
          angina, or other clinically significant cardiac diseases within 12 months prior
          to enrollment.
      13. A history of a concomitant genetic syndrome associated with bone marrow failure
          such as Fanconi anemia, Kostmann syndrome, and Shwachman-Diamond syndrome.
      14. A history of symptomatic deep vein thrombosis or pulmonary embolism requiring
          systemic anticoagulation within 6 months prior to enrollment. Subjects need to
          be on preventive anticoagulant medication.
      15. A history of other malignancies (except for non-melanoma skin cancer, in situ
          breast/cervical cancer, and other malignant tumors that have been effectively
          controlled without treatment in the past five years).
      16. Use of other investigational products within 30 days prior to screening.
      17. Pregnant or breastfeeding women of childbearing age. Chemotherapy poses
          potential risks to the fetus or infant. Women who have undergone surgical
          sterilization or are postmenopausal for at least 2 years are not considered of
          childbearing potential.
      18. Male and female subjects unwilling to practice birth control from the time of
          consent through 12 months after the completion of lymphodepleting chemotherapy
          or CAR T cells infusion (whichever is longer).
      19. Any medical activities that may interfere with the safety or efficacy
          assessment of the study treatment.
      20. In the investigator's judgment, the subject is unlikely to complete all
          protocol-required procedures and follow-up visits, or to comply with the
          requirements for participating in the study.