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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Post-transplant Lymphoproliferative Disease; Transplant-Related Hematologic Malignancy
• Intervention / Treatment: Biological: Autologous EBV-CTL transduced with vector SFG-CNA12; Biological: Autologous EBV-CTL transduced with control vector SFG-CNA8; Procedure: Leucapheresis

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 Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Great Ormond Street Hospital
  • London, United Kingdom
    • King's College Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Autologous EBV-CTL transduced with SFG-CNA12/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.

Biological: Autologous EBV-CTL transduced with vector SFG-CNA12; Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the retroviral vector SFG-CNA12 conferring resistance to tacrolimus; Biological: Autologous EBV-CTL transduced with control vector SFG-CNA8; Autologous EBV-specific cytotoxic T-cells (CTL) transduced with the control retroviral vector SFG-CNA8; Procedure: Leucapheresis; Patients will undergo an unstimulated leucapheresis to isolate the required immune cells to produce the EBV-CTLs

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: bluebird bio
• Investigators: Principal Investigator: Prof. Persis Amrolia, Great Ormond Street Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 31, 2019
• Primary Completion (ACTUAL): June 30, 2020
• Study Completion (ANTICIPATED): May 15, 2025

Study Registration Dates

• First Submitted: April 24, 2017
• First Submitted That Met QC Criteria: April 24, 2017
• First Posted (ACTUAL): April 27, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 20, 2022
• Last Update Submitted That Met QC Criteria: January 19, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Lymphoproliferative Disorders
• Other Study ID Numbers: UCL/16/0529

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No