Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary CNS Lymphoma

Inclusion Criteria: 1. Age ≥16 2. Patients with a histologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) confined to the CNS (Primary CNS Lymphoma (PCNSL)) 3. Relapsed\* or refractory CD19+ PCNSL, defined as disease progression following CR/CRu/PR, or failure to achieve PR, after one or more lines of a high-dose methotrexate-containing protocol \*Histological confirmation by re-biopsy at relapse is recommended if feasible. However, patients will be eligible without re-biopsy provided the initial diagnostic material is available and current MRI imaging features are consistent with PCNSL by neuroradiology review. 4. Measurable disease on contrast-enhanced MRI 5. Unsuitable for alternative salvage therapies as determined by their treating physician 6. Agreement to have a pregnancy test, use highly effective contraception (if applicable) 7. Written informed consent\*\* \*\* Some patients with PCNSL may be incapable of providing their own consent due to the neurological effects of their disease. In these cases a legal representative may be sought to provide consent'. Exclusion Criteria (Registration): 1. CD19 negative disease 2. Evidence of secondary CNS lymphoma 3. Prior allogeneic haematopoietic stem cell transplant 4. Active hepatitis B, C or HIV infection 5. Oxygen saturation ≤90% on air 6. Bilirubin \>2 x upper limit of normal 7. Glomerular Filtration Rate (GFR) \<50ml/min 8. Women who are pregnant or breast feeding 9. Inability to tolerate leucapheresis 10. ECOG 3-4 11. Known allergy to albumin or Dimethyl sulfoxide (DMSO) 12. Life expectancy \<3months 13. Arrhythmias or significant cardiac disease and left ventricular ejection fraction \<40% 14. Pre-existing neurological disorders (other than CNS involvement of underlying haematological malignancy) 15. Any contraindications to PD-1 antibody Pembrolizumab 16. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 24 months 17. Evidence of active pneumonitis on chest computed tomography (CT) or positron emission tomography (PET)-CT scan at screening or history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis obliterans), or idiopathic pneumonitis. Prior radiation pneumonitis in the radiation field (fibrosis) is allowed (if \>24 weeks since the event) Exclusion criteria: for CD19CAR T-cell infusion ( Dose 1/i.v. and Dose 2/intraventricular): 1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion 2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion 3. Theme 2 only: 1. presence of grade 3 or 4 ICANS casually related to the ATIMP following infusion of Dose 1 2. grade 1-2 neurotoxicity (if occurred) following Theme 1 dosing (Dose 1/i.v CD19CAR Tcell dose) that has not fully resolved prior to proposed administration of 2nd CD19CAR T-cell infusion (Dose /intraventricular) for theme 2 3. grade 3-4 CRS following infusion of Dose 1 4. persisting grade 2 CRS following Theme 1 dosing (Dose 1/i.v CD19CAR T-cell dose) that has not resolved to ≤ grade 1 CRS prior to proposed administration of 2nd CD19CAR Tcell infusion (Dose 2/intraventricular) for theme 2 5. pregnancy