Bispecific CAR T Cells for B-cell Malignancies (BaseCAR-01 Trial)

Chimeric antigen receptor (CAR) T cells are engineered T-lymphocytes with artificial receptors, containing domains of a T cell receptor as well as a B cell receptor with predefined specificity to a target antigen. In patients with relapsed or refractory (r/r) B-cell malignancies, who would otherwise have a poor prognosis, CD19-directed CAR T cell therapy showed high response rates. A common cause of relapse is loss of the target antigen on the tumor cells, e.g. CD19. In such cases, further approved treatment options are very limited to date, but recent preclinical and early clinical studies have shown that bispecific anti-CD19, anti-CD20 CAR T cells can overcome this hurdle, adding a second target and leading to excellent outcomes in heavily pretreated patients.

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. A secondary objective is the assessment of efficacy.

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.