CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Patient must have a CD19-expressing hematologic malignancy, relapsed or refractory after receiving at least 2 lines of standard therapy and not eligible for current commercial CD19 CAR T cells per Israeli MOH health basket:

  1. Relapse following standard relapse protocol (2nd relapse)
  2. Primary refractory, i.e. failed to achieve morphologic remission after 2 lines of induction chemotherapy.
  3. Patients who have histologically confirmed large B-cell lymphoma, according to the World Health Organization 2016 classification criteria, that are refractory to first-line treatment or that have relapsed from complete remission no more than 12 months after the completion of first-line chemo-immunotherapy including an anti-CD20 monoclonal antibody and anthracycline-containing regimen.
  4. Very high risk 1st relapse of ALL, defined as (a) relapse within 18 months of initial diagnosis; (b) relapse with the following cytogenetic abnormalities: KMT2a-R, TCF3::HLF, TCF3::PBX1, TP53-alterations.
* Age 1-80 years
* For ALL, CD19 expression shown by flow cytometry or immunohistochemistry on at least 70% of leukemic blasts.
* Adequate CD3 count (above 120 CD3+ cells per microliter blood)
* Clinical performance status: Patients \> 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy.
* Females of child-bearing potential must have a negative pregnancy test
* Cardiac function: LV ejection fraction \>45% or shortening fraction \>28%
* At least 60 days after autologous or allogeneic BMT
* No prior CD19 CAR T cell administered
* Prior therapy:

  1. Patients should be off steroids for at least 2 weeks prior to apheresis
  2. Patients should be off systemic anti-neoplastic treatment for 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy. Patients who received prior clofarabine and fludarabine should have a wash out period of 3 months prior to apheresis.
  3. Patients should have recovered from all toxicities attributed to prior therapy. Cytopenias that are considered disease related rather than therapy related are exempt from this exclusion.
  4. Radiation therapy should be completed at least 3 weeks prior to apheresis.

Exclusion Criteria:

* Hyperleukocytosis (WBC\>50,000) or rapidly progressive disease that in the judgment of the PI can compromise the ability of the patient to complete the study
* Pregnant or breast-feeding females
* Hepatic dysfunction, defined as bilirubin \> x2 upper normal limit (except when explained by hemolysis or Gilbert) or SGOT \> x2.5 upper normal limit.
* Active HIV infection, HBV or HCV infection which is identified by positive PCR of viral sequences. Patients who are positive for HCV Abs, HBsAg and/or positive to HBcAbs total, will be evaluated by PCR of viral sequences. If PCR is positive, the patient will be excluded.

主要终点：Safety Evaluation: Treatment Related Toxicities · An evaluation of safety of the use of SHB-02-CD19 manufactured at the Sheba Medical Center, in patients with relapsed/refractory B-cell malignancies. Safety will be determined by evaluation of participants with treatment-related adverse events, as assessed by CTCAE 5.0. · From enrollment to 3 months post treatment.；Efficacy Evaluation · An evaluation of the feasibility and efficacy of administering SHB-02-CD19 in patients with B-cell malignancies at the Sheba Medical Center. Efficacy will be determined by an evaluation of disease response in participants post treatment. Disease response will be assessed by blasts percentage and minimal-residual disease (MRD) in the bone marrow for ALL patients, and by PET-CT scan based on the Lugano classification for NHL patients. · 1 month to 1 year post treatment.；Minimal toxic dose evaluation · An evaluation of the minimal toxic dose of SHB-02-CD19. This will be determined by evaluation of participants with treatment-related adverse events, as assessed by CTCAE 5.0, and according to different dose levels administered. · From first dose to end 3 months post treatment.

• Single arm, open label, dose escalation: SHB-02-CD19 (anti CD19 CAR-T) · EXPERIMENTAL · anti CD19 CAR-T cells

This is a phase I/II trial of SHB-02-CD19, T-cell expressing an anti-CD19 Chimeric-Antigen-Receptor (CAR) in patients with CD19 expressing B-cell malignancies. This trial is an open label, single-arm, for pediatric and adult patients with relapsed/refractory B-cell malignancies.