ENABLE-1 (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)

Prior treatment

• Confirmed active or prior central nervous system (CNS) involvement by lymphoma. In patients with a clinical suspicion of CNS disease, lumbar puncture and MRI brain must be performed
• Prior solid organ transplantation
• Allogeneic stem cell transplantation within the preceding three months or still requiring systemic immunosuppression
• Current grade II - IV acute graft versus host disease (GVHD), any prior grade IV acute GVHD, or current moderate or severe chronic GVHD
• Systemic corticosteroids at doses of ≥ 20mg prednisone daily or equivalent within 7 days of enrolment
• Participants with known sensitivity to immunoglobulin or to components of the investigational product (IP)
• History of active malignancy other than B-cell malignancy within two years prior to enrolment, with the exception of: adequately treated in situ carcinoma of the cervix; adequately treated basal cell carcinoma (BCC) or localized squamous cell carcinoma (SCC) of the skin; other localised malignancy surgically resected (or radically treated with another treatment modality) with curative intent
• Current or prior human immunodeficiency virus (HIV) infection
• Treatment with a purine analogue within the preceding four weeks
• Treatment with alemtuzumab within the preceding 12 weeks
• Cytotoxic chemotherapy, radiotherapy or monoclonal antibody therapy (other than alemtuzumab) within 2 weeks of enrolment
• Prior gene therapy, including prior anti-CD19 chimeric antigen receptor T-cell therapy
• Significant concomitant illnesses which would in the investigator's opinion make the patient an unsuitable candidate for the trial
• Participant does not provide consent to enrol onto International Cellular Therapy Registry

Other illness

• Active CNS pathology including: epilepsy, seizure within the preceding year, aphasia, paresis, stroke, dementia, psychosis within the preceding year, severe brain injury, Parkinson disease, or cerebellar disease
• Richter Syndrome
• Active autoimmune disease requiring systemic immunosuppression
• Inadequately controlled systemic infection
• Serologic status reflecting active viral hepatitis B or any history of hepatitis C infection as follows:
  • Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (\< 20 IU), and if they are willing to receive appropriate anti-viral prophylaxis.
  • Presence of hepatitis C virus (HCV) antibody
• Presence of New York Heart Association (NYHA) class 2 or higher cardiac symptoms not related to lymphoma

Lab values

• Peripheral blood lymphocytes \< 0.3 x 10\^9/L as assessed by complete blood count
• Peripheral blood CD3+ T cells \< 150/μL as assessed by lymphocyte subset analysis

Other

• Pregnant or lactating female
• Women of child-bearing potential who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration
• Men who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration
• Men who have a pregnant partner and are not willing to use a condom while performing sexual activity during study participation and for at least 3 months after WZTL-002 administration
• Vaccination with a live virus within the preceding four weeks
• Receipt of an investigational medicine within another clinical trial within the preceding four weeks
• Participants who have diminished capacity or any circumstance that would prohibit them from understanding and providing informed consent in accordance with ICH-GCP (International Conference on Harmonisation, Good Clinical Practice)

• Age 16 to 75 years (inclusive)
• Biopsy-proven relapsed or treatment refractory aggressive B-cell non-Hodgkin lymphoma of the following subtypes per World Health Organisation (WHO) classification: DLBCL and its variants, PMBCL, tFL, FL, MCL
• Requirement for treatment in the opinion of the investigator
• Presence of measurable disease as per Lugano 2014 Criteria
• No other curative treatments available, or not suitable due to patient or disease characteristics or lack of stem cell donor
• Malignancy documented to express CD19 based on flow cytometric or immunohistochemical staining
• Provision of written informed consent for this study
• Lymphoma-related life expectancy at least 12 weeks, and life-expectancy from non-lymphoma related causes of \> 12 months
• European Cooperative Oncology Group (ECOG) performance status of 0 to 2 inclusive
• Adequate haematologic function, defined by neutrophils ≥ 1.0 × 10\^9/L and platelets ≥ 50 × 10\^9/L
• No serious cardiac, pulmonary, hepatic or renal disease.
  • Serum bilirubin \< 2.5 times Upper limit of normal (ULN)
  • Estimated creatinine clearance (CrCl) ≥ 50 mL/min using the modified Cockroft Gault estimation or as assessed by direct measurement
  • Cardiac Ejection Fraction ≥ 50% as determined by Echocardiogram or MUGA Scan
  • Oxygen saturations \> 92% on room air
  • Diffuse Capacity of the lungs for carbon monoxide (DLCO) or Carbon monoxide transfer coefficient (KCO), Forced expiratory volume in one second (FEV1) and Forced Vital Capacity (FVC) are all ≥ 50% of predicted by spirometry after correcting for haemoglobin and/or volume on lung function testing.