Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplant

Study Overview
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Brief Summary
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This is an open label, non-randomised, multicentre Phase I to determine the safety of tacrolimus-resistant autologous EBV-specific cytotoxic T-cells (EBV CTL) and compare their expansion/persistence with control EBV CTL in solid organ transplant patients with post-transplant lymphoproliferative disease (PTLD). Each patient will receive an infusion of two ATIMPs - autologous EBV CTL retrovirally transduced with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8).

Detailed Description
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This is a multi-centre, non-randomised, open label Phase 1 clinical trial of Advanced Therapy Investigational Medicinal Products (ATIMPs) in adult and paediatric (age 1-70 years) solid organ transplant recipients with histologically proven B-lineage EBV+ post-transplant lymphoproliferative disease (PTLD). The ATIMPs for this study are autologous EBV CTL transduced with the (a) the retroviral vector SFG-CNA12 encoding a calcineurin A mutant (CNA12) that confers resistance to tacrolimus and (b) the retroviral vector SFG-CNA8 encoding a control calcineurin A mutant (CNA8). Following informed consent and registration to the trial, patients will undergo an unstimulated leucapheresis for generation of both ATIMPs. Patients will receive an equal dose of each ATIMP (10x7 CNA8+ or CNA12+ CTL/m2) which will be administered intravenously. Other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels.The trial will evaluate the safety of the ATIMPs in organ transplant recipients developing EBV+ PTLD and compare the persistence and frequency of circulating CNA12 and CNA8 CTL in the peripheral blood. Our hypothesis is that in the presence of ongoing immunosuppression with tacrolimus, CNA12 CTL will show preferential expansion and prolonged persistence compared with CNA8 CTL. If successful this will result in durable clearance of PTLD without the need to reduce tacrolimus, thus reducing the risk of graft rejection. Patients will be followed up regularly during the interventional phase of the study until 1 year post EBV CTL infusion. During the long-term follow-up phase of the study (from 1-5 years post EBV CTL infusion) patients will be followed up annually.

Official Title
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Immunotherapy With Tacrolimus Resistant EBV CTL for Lymphoproliferative Disease After Solid Organ Transplant

Conditions
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Post-transplant Lymphoproliferative Disease, Transplant-Related Hematologic Malignancy

Intervention / Treatment
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* Biological: Autologous EBV-CTL transduced with vector SFG-CNA12
* Biological: Autologous EBV-CTL transduced with control vector SFG-CNA8
* Procedure: Leucapheresis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult and paediatric (age 1-70 years) solid organ transplant recipients with histologically proven B-lineage EBV+ post-transplant lymphoproliferative disease (PTLD) either de novo or resistant to Rituximab EBV viraemia at enrolment On immunosuppression with tacrolimus Agreement to have a pregnancy test and use of contraception for duration of trial (if applicable) Written informed consent Exclusion Criteria: Fulminant disease Requirement for supplemental oxygen Burkitt's lymphoma/Mature B-acute lymphoblastic leukaemia with IgH-Myc rearrangement T-lineage PTLD Bilirubin > 3 x upper limit of normal Creatinine > 3 x upper limit of normal Active hepatitis B, C or HIV infection Women who are pregnant or breast-feeding ECOG performance score ≥ 4 Inability to tolerate leucapheresis

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8<br>All patients will receive the autologous EBV CTL retrovirally transduced with with (a) a calcineurin mutant (CNA12) that confers resistance to tacrolimus and (b) a control calcineurin mutant (CNA8). For each patient two ATIMPs will be generated: Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12 Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8 An equal dose (10x7/m2) of CNA12+ EBV CTL and CNA8+ EBV CTL will be administered intravenously on day 0. While awaiting ATIMP generation, patients may receive a single dose of Rituximab and other immunosuppressants (e.g. MMF) will be reduced, but tacrolimus will be maintained at therapeutic levels. | Biological: Autologous EBV-CTL transduced with vector SFG-CNA12<br>* Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12 conferring resistance to tacrolimus<br>Biological: Autologous EBV-CTL transduced with control vector SFG-CNA8<br>* Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8<br>Procedure: Leucapheresis<br>* Patients will undergo an unstimulated leucapheresis to isolate the required immune cells to produce the EBV-CTLs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity at 6 weeks post infusion | Toxicity as assessed by NCI Common toxicity criteria within 6 weeks of infusion | 6 weeks | 
| Persistence and frequency of circulating EBV CTL | Persistence and frequency of circulating EBV CTL transduced with CNA12 compared with control vector CNA8 in the peripheral blood | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease response | Disease response at 6 weeks | 6 weeks | 
| Relapse rate | Relapse rate at 1 and 2 years | 2 years | 
| Disease free survival | Disease free survival at 1 and 2 yrs | 2 years | 
| Organ graft Rejection | Organ graft Rejection at 1 and 2 yrs | 2 years |