Evaluation of CAR19 T-cells as an Optimal Bridge to Allogeneic Transplantation

Patients with Diffuse Large B Cell Lymphoma (DLBCL) resistant to or relapsing following rituximab-containing chemotherapy regimens have a poor prognosis. Patients may receive salvage chemotherapy and possibly an autologous stem cell transplant (auto-SCT). A proportion of these patients, however, will not respond to the chemotherapy or may relapse after the auto-SCT and therefore require novel treatment options. Such patients may benefit from an allogeneic stem cell transplantation (allo-STC).

In this study the investigators aim to administer CAR19 T-cells to act as a bridge to the transplant strategy. Specifically, (1) the feasibility of generating CD19 specific Chimeric Antigen Receptor T-cells called CAR19 T-cells, (2) the safety of administering the CD19 CAR T-cells in this setting, (3) how well the CAR19 T-cells engraft and (4) to evaluate how effective these cells are as a bridge to allogeneic transplantation.

Following informed consent and registration to the trial, patients will undergo an unstimulated leucapheresis for generation of the CAR19 T cells. Whilst the cells are being generated, patients will proceed with a further cycle of standard salvage (recommended ifosfamide, epirubicin and etoposide (i.e. the IVE regime), and should not receive rituximab. Patients will receive pre-conditioning with intravenous fludarabine and cyclophosphamide prior to infusion of a single dose of CAR-modified T-cells. An escalating dose protocol will be employed to identify a minimum effective dose of CAR19 T-cells.

Inclusion criteria

• Age 16-65 years
• Confirmed diagnosis of CD19+ DLBCL
• Primary resistant or relapsed disease failing to achieve metabolic Complete Response (CR) to 1st line salvage, or relapse post autograft failing to achieve metabolic CR following a single further cycle of salvage
• Potential allogeneic transplant candidate
• Agreement to have a pregnancy test, use adequate contraception for 12 months post-CAR19 T-cell infusion
• Karnofsky performance status >60
• Written informed consent

Exclusion criteria

• Women who are pregnant or lactating
• Prior allogeneic transplantation
• Progressive disease following most recent salvage prior to planned leucapheresis (those with mixed response are eligible)
• Prior history of ischaemic heart disease, dysrhythmias, abnormal electrocardiogram (ECG)(Left Bundle Branch Block (LBBB)), Multiple Gated Acquisition (MUGA) left ventricular ejection fraction (LVEF) <40%
• Exclusions for proceeding to allogeneic transplantation (active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV); liver function test (LFT) >3 x upper limit of normal (ULN); Creatinine Clearance (CrCl) <40 ml/min; or other comorbidity that precludes transplantation)
• Known central nervous system (CNS) involvement or cerebral vascular accident (CVA) within prior 3 months
• Patients receiving corticosteroids at a dose of > 10mg prednisolone per day (or equivalent)
• Use of rituximab within the last 2 months prior to CAR19 T-cell infusion
• Active autoimmune disease requiring immunosuppression
• Life expectancy <3 months
• Known allergy to albumin or dimethylsulfoxide (DMSO)
• Any contraindication to the administration and use of ifosfamide, epirubicin, etoposide, fludarabine and cyclophosphamide.