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

Early Phase 1

Active, not recruiting

• Conditions: Transplant-Related Hematologic Malignancy; Post-transplant Lymphoproliferative Disease
• Interventions: Biological: Autologous EBV-CTL transduced with vector SFG-CNA12; Biological: Autologous EBV-CTL transduced with control vector SFG-CNA8; Procedure: Leucapheresis

• Registration Number: NCT03131934
• Lead Sponsor: University College, London

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2017-04-24
• Study First Submitted QC: 2017-04-24
• Study First Posted: 2017-04-27
• Study Start: 2019-05-31
• Primary Completion: 2020-06-30
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-17
• Last Update Posted: 2024-05-17
• Study Completion: 2025-05-15

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1. 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
2. EBV viraemia at enrolment
3. On immunosuppression with tacrolimus
4. Agreement to have a pregnancy test and use of contraception for duration of trial (if applicable)
5. Written informed consent

Exclusion Criteria

1. Fulminant disease
2. Requirement for supplemental oxygen
3. Burkitt's lymphoma/Mature B-acute lymphoblastic leukaemia with IgH-Myc rearrangement
4. T-lineage PTLD
5. Bilirubin > 3 x upper limit of normal
6. Creatinine > 3 x upper limit of normal
7. Active hepatitis B, C or HIV infection
8. Women who are pregnant or breast-feeding
9. ECOG performance score ≥ 4
10. Inability to tolerate leucapheresis

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8	Autologous EBV-CTL transduced with vector SFG-CNA12	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.
Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8	Autologous EBV-CTL transduced with control vector SFG-CNA8	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.
Autologous EBV-CTL transduced with SFG-CNA12/SFG-CNA8	Leucapheresis	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Disease free survival	2 years	Disease free survival at 1 and 2 yrs
Organ graft Rejection	2 years	Organ graft Rejection at 1 and 2 yrs
Relapse rate	2 years	Relapse rate at 1 and 2 years
Disease response	6 weeks	Disease response at 6 weeks

Trial Locations

Locations (2)

King's College Hospital; 🇬🇧 London, United Kingdom

Great Ormond Street Hospital; 🇬🇧 London, United Kingdom