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