CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Age ≥ 18 years
* Diagnosis of B-cell NHL or B-ALL with relapsed, refractory disease and no available standard therapeutic options (including commercially accessible CAR T products), including:

  * Acute B-lymphoblastic leukaemia
  * Burkitt lymphoma
  * Primary CNS lymphoma
  * DLBCL or high-grade lymphoma of any subtype
  * Primary mediastinal B cell lymphoma (including grey zone lymphoma)
  * Mantle Cell lymphoma
  * Low-grade B-cell NHLs: Follicular lymphoma, chronic lymphocytic leukaemia (CLL)/ small lymphocytic lymphoma (SLL), marginal zone lymphoma, hairy cell leukaemia, splenic B-cell lymphoma/leukaemia with prominent nucleoli, and lymphoplasmacytic lymphoma
* CD19 and/or CD20 positive disease on most recent evaluation (by immunohistochemistry or flow cytometry)
* ECOG clinical performance status ≤2
* Able to provide written informed consent.
* Adequate organ function and bone marrow reserve, unless clearly caused by lymphoma and considered reversible, defined as:

  * Adequate hepatic function: Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤3.0 × (ULN) and serum bilirubin ≤2.0 × ULN (except in congenital hyperbilirubinemia, such as Gilbert syndrome, where direct bilirubin ≤3.0 × ULN is allowed)
  * Adequate renal function: creatinine clearance ≥30 mL/min/1.73 m2
  * Adequate pulmonary function: Forced Expiratory Volume in 1 second (FEV1) ≥50% (with adequate compliance) and pulse oxygenation \> 91% with room air.
  * Adequate cardiac function: Left Ventricular Ejection Fraction (LVEF) ≥ 40%, and no clinically significant arrhythmia
  * Adequate bone marrow reserve (Hemoglobin ≥80 g/L (with or without recombinant erythropoietin or red blood cell transfusions), Platelets ≥ 50×10\^9/L (with or without platelet transfusions), Absolute Neutrophil Count (ANC) 1.0 ×10\^9/L (prior growth factor support is permitted but must be without support in the 7 days before the laboratory test), Absolute Lymphocyte Count ≥0.3 ×10\^9/L)
* Willingness to practice highly effective methods of birth control, and, in females of childbearing potential, negative urine or serum pregnancy test before study inclusion, lymphapheresis, and lymphodepleting chemotherapy.

Exclusion Criteria:

* Requirement for systemic corticosteroids, i.e. ≥20 mg of prednisone or equivalent daily. Other immunosuppressive drugs
* Any organ failure, respectively not meeting the inclusion criteria of adequate organ function, or active, BKuncontrolled autoimmune disease.
* Uncontrolled coronary artery disease or uncontrolled arrhythmias
* Stroke within the previous 6 months, a history of neurodegenerative disorder or overt clinical evidence of dementia or altered mental status.
* Seizure within 6 months of signing the ICF unless related to the primary disease (e.g. CNS lymphoma).
* Active secondary malignancy that progressed or required treatment in the last 24 months, other than basal or squamous cell carcinomas of the skin. Further allowed exceptions are: Non-muscle-invasive bladder cancer, non-invasive cervical cancer, or other malignancy that is considered cured or to have a minimal risk of recurrence (e.g. a history of localized prostate or localized and treated breast cancer).
* Uncontrolled active bacterial, fungal, or viral infections, particularly active hepatitis B, hepatitis C, or HIV infection.
* Contraindications, known life-threatening allergies, hypersensitivity, or intolerance to any of the study treatments, including previous severe reactions to dimethyl-sulfoxide
* Cytotoxic chemotherapy within 14 days before apheresis collection for CAR-T cells, respectively 12 weeks for Bendamustin and Fludarabine, and 6 months for Alemtuzumab and ATG.
* Cytotoxic chemotherapy (except for lymphodepletion) within 14 days of CAR-T cell infusion.
* Patients who have undergone allogeneic hematopoietic stem cell transplantation less than 12 weeks ago, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
* Previous CAR-T cell therapy within 12 weeks of planned CAR-T cell infusion.
* Investigational treatments within other trials ≤ 4 weeks before enrollment.
* Lack of safe contraception; Women who are pregnant or breastfeeding; and men who plan to father a child while enrolled in this study within 1 year of receiving bispecific anti-CD20, anti-CD19 CAR T cells.

主要终点：Evaluation of Adverse Events · All adverse events will be assessed in a structured manner (time of onset, duration, resolution, action been taken, assessment of intensity, relationship with study treatment), using the CTCAE Version v5.0. · up to 3 months after CAR T cell infusion；Evaluation of Adverse Events of special interest (CRS) · All adverse events of special interest (CRS) will be assessed in a structured manner (time of onset, duration, resolution, action been taken, assessment of intensity, relationship with study treatment), using the ASTCT CRS Consensus Grading (Grade 1 up to Grade 4; with Grade 4 as most severe CRS Grade) · up to 3 months after CAR T cell infusion；Evaluation of Adverse Events of special interest (ICANS) · All adverse events of special interest (ICANS) will be assessed in a structured manner (time of onset, duration, resolution, action been taken, assessment of intensity, relationship with study treatment), using the Immune-effector Cell-associated Encephalopathy (ICE) test, which was developed to provide objectivity for screening and grading the severity of ICANS. The ICE score is performed at least every 8 hours during in-patient care and at every outpatient visit. A higher score indicates better cognitive function, with a perfect score of 10 signifying no impairment. · up to 3 months after CAR T cell infusion；Evaluation of Adverse Events of special interest (ICAHT) · Evaluation of Adverse Events of special interest (ICAHT) will be assessed in a structured manner (time of onset, duration, resolution, action been taken, assessment of intensity, relationship with study treatment), using the EHA/EBMT consensus grading. The EHA/EBMT consensus grading score is a classification system based on depth and duration of neutropenia. · up to 3 months after CAR T cell infusion
次要终点：Objective response rate (ORR): Change in metabolic response in FDG-PET/CT scan；Objective response rate (ORR): Change in minimal residual disease (MRD) negativity in blood；Objective response rate (ORR): Change in minimal residual disease (MRD) negativity in bone marrow；Objective response rate (ORR): Change in sustained MRD-negative Complete Remission (CR)；Progression-free survival；Event free survival；Overall survival；Cumulative incidence of non-relapse mortality

• Experimental Intervention: Bispecific anti-CD19, anti-CD20 CAR T cells · EXPERIMENTAL · Bispecific anti-CD19, anti-CD20 CAR T cells administration

This study is to provide locally produced, bispecific CD19 CD20 CAR T cells to patients with B-cell lymphoma/leukemia who have no access to commercial CAR T cells or who have relapsed thereafter. The primary objective is to assess the safety of bispecific anti-CD19, anti- CD20 CAR T cell-therapies after lymphodepleting chemotherapy in patients with B cell malignancies with exhausted standard treatment options.