Treg Cell Therapy in Liver and Kidney Transplantation - Preclinical Validation of Batches of Treg Cells Amplified in Vitro (PRE-TREG)

Kidney and liver transplantation requires a fine tuning of immune responses in order to achieve long term operational tolerance with immunosuppressants or immune modulators. Numerous experimental findings indicate that CD4+ FOXP3 expressing regulatory T (Treg) cells play a central role in the induction of tolerance to the grafts indicating that the use of Treg cells may be an innovative therapeutic strategy in kidney transplantation that would enable the diminution of immunosuppressive drugs or even their discontinuation, thus decreasing their risk of adverse events.

As human Treg cells represent less than 10% of CD4+ T cells, and because it has been shown in mice that a dose of 2*104 polyclonal Tregs/g was necessary to induce tolerance in animal models of solid organ transplantation, it is mandatory to expand human Treg cells ex vivo, after isolating them from peripheral blood. The investigators previously defined a protocol for Treg cell isolation and expansion in clinical grade conditions (cGMP) that enabled us to obtain the expected number of expanded cells maintaining high levels of FOXP3 (3).

The investigators therefore hypothesize in humans, as it has been already shown in mice, that the infusion of autologous expanded polyclonal Treg cells would lead to the obtaining of operational tolerance in kidney and liver graft in association with classical immunosuppressants and an expectable diminution of those.

To this end, it is necessary to have pre-clinical batches of expanded Treg cells validated by the National Agency for Medicines and Health Products Safety validate (ANSM). The investigators therefore plan to have 4 batches from 2 liver transplant patients and 2 kidney transplant patients validated.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Transplantation; Kidney Transplantation
• Intervention / Treatment: Other: Lymphapheresis

• Study Type: Interventional
• Enrollment (Anticipated): 4
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Pitié Salpêtrière hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For liver transplant patients:

• Liver transplantation carried out for 1 to 3 months for alcoholic cirrhosis;
• Normal liver biological test;
• Normal hepatic morphological assessment;

For kidney transplant patients:

• Renal transplantation carried out for 3 to 6 months for any disease requiring renal transplantation;
• Normal renal biological assessment;
• Normal renal morphological assessment;
• DSA <1500 MFI at inclusion

Common criteria:

• Age ≥ 18 years and ≤ 70 years
• GB ≥1500 / mm3
• Hemoglobin level> 10g / 100ml
• Platelets> 50,000 / μl
• Weight> 40Kg
• Informed and signed consent;
• Patient affiliated to a social security scheme

Exclusion Criteria:

For liver transplant patients:

- Hepatocellular carcinoma or history of another cancer;

For kidney transplant patients:

- Kidney cancer or a history of another cancer

Common criteria:

• Active infectious diseases: positive serology for hepatitis A, B or C, HIV, HTLV, CMV and EBV;
• Associated autoimmune disease, including type 1 diabetes;
• GB <1500 / mm3;
• Any contraindication to citrate and calcium gluconate.
• Pregnancy or lactating woman
• Patient under guardianship or curatorship
• Patient deprived of liberty or under administrative security measure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Lymphapheresis; Blood is drawn from one of the patient's two arms and passes through a separation circuit. After removing the white blood cells, it is reinjected into the other arm.	Other: Lymphapheresis; - From the blood product of lymphapheresis: Autologous naïve regulatory CD45RA+CD4+CD25+FoxP3+ T lymphocytes (Tregs) selected and amplified ex vivo; obtained by selection and sorting of CD4+CD25 +CD127lowCD45RA+ cells, derived from lymphapheresis and amplified ex vivo for 10 +/- 1 days, under cGMP condition in the presence of IL2 and Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validate 4 preclinical batches of Treg cells from 2 liver transplant patients and 2 kidney transplant patients	Treg cells produced according to the expansion protocol defined by verifying the compliance of the batches according to the requirements of the guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Product) by respecting the validation and batch release criteria defined in this protocol.	At day 10

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): April 15, 2023
• Primary Completion (Anticipated): April 30, 2024
• Study Completion (Anticipated): April 30, 2024

Study Registration Dates

• First Submitted: December 3, 2020
• First Submitted That Met QC Criteria: December 3, 2020
• First Posted (Actual): December 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 28, 2023
• Last Update Submitted That Met QC Criteria: March 27, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: APHP200733; 2020-A01871-38 (Other Identifier: ANSM)

Drug and device information, study documents

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