Allogeneic Immunotherapy of Hematological Malignancies Using Regulatory T-cell Selective Depletion (ILDTreg2)

Since the discovery that Treg suppress anti-tumor immune responses, inhibiting their function has become a major challenge for the development of efficient immunotherapy for cancer. In humans, we previously reported the positive results of a first clinical trial using Treg depletion for anti-tumor response amplification in the field of allogeneic hematopoietic stem cell transplantation (HSCT). The present project aims at developing this anti-tumor immunotherapeutic strategy in the same setting, i.e. donor lymphocyte infusion (DLI) for relapsing hematological malignancies after HSCT, using a new selection marker: CD127. The choice of this new strategy is supported by our results of a retrospective clinical study and pre-clinical data. Using human cells, this studies demonstrated, in vitro and in vivo in animal murine models, that Treg depletion through CD127 positive selection is much more efficient to improve allogeneic immune responses of donor T-cells as compared to the previous strategy using the CD25 marker.

Study Overview

• Status: Not yet recruiting
• Conditions: Hematological Malignancies; Relapse; Regulatory T Cell Depletion
• Intervention / Treatment: Drug: T-reg depleted DLI

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: sébastien maury, PhD; Phone Number: +33 01.49.81.20.57; Email: sebastien.maury@aphp.fr
• Study Contact Backup: Name: elodie lemadre, M.Sc; Phone Number: +33 01 44 84 17 34; Email: elodie.lemadre@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patient (older than 18 years old without upper limit of age) diagnosed with leukemia, myelodysplasia, myeloproliferative disorder or lymphoproliferative disorder (CLL, myeloma, lymphoma)
• Previous allogeneic HSCT from a matched sibling, haplo-identical or unrelated donor (any type of conditioning regimen)
• Haematological relapse (molecular, cytogenetic or cytological) after HSCT
• Patient refractory (no or partial response) to one or several previous standard unmanipulated DLI
• Availability of cryopreserved lymphapheresis
• No loss of chance by using of DLI rather than more incisive anti-tumor agents according to investigator appreciation
• Written informed consent before any intervention necessary for the trial
• Affiliation to a social security regime
• Negative pregnancy test for women of childbearing age participating in the study
• Effective contraceptive methods for men / women in line with the current CTFG recommendations version 1.1

Exclusion Criteria:

• Acute grade ≥ II or moderate/severe chronic GVHD at the time of inclusion
• Patient receiving immunosuppressive treatment for GVHD or any other reason
• Creatinine clearance< 50 ml/min
• Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 5.0 x upper limit of normal (ULN)
• Serum total bilirubin > 50µM (expect for unconjugated hyperbilirubinemia due to Gilbert's disease)
• Performance status ECOG>1
• Severe infection according to CTCAE grading (grade>2)
• Pregnant or lactating women
• Patient under tutorship, curatorship or legal protection
• Ongoing participation in another interventional research protocol within the same field of immune modulation (through cell therapy or not)
• State medical aid

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T-reg depleted DLI	Drug: T-reg depleted DLI; Treg depleted Donor Lymphocytes Infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative incidence of GVHD in its acute grade ≥ II and/or severe chronic form (according Glucksberg-Thomas and NIH scales, respectively), and uncontrolled after a 14-day immunosuppressive course including steroids.	Composite criteria. In this evaluation, death from non-GVHD cause will be taken as a competitive event	occurring within the 2 months following d-DLI infusion

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of acute and/or chronic GVHD, with corresponding grades according to NIH and Glucksberg-Thomas scales	at 2 and 12 month
Date of putative relapse/progression for estimation of cumulative incidence (taking into account the competitive risk of death not related to relapse)	at 2 and 12 month
Date of putative relapse/progression for estimation disease-free survival	at 2 and 12 month
Number, causes and date of deaths	at 2 and 12 month

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: elodie lemadre, M.Sc, APHP

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: December 12, 2023
• First Submitted That Met QC Criteria: December 12, 2023
• First Posted (Actual): December 22, 2023

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Relapse; DLI; Hematological malignancies; Regulatory T cells depletion
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Disease Attributes; Hematologic Diseases; Neoplasms; Hematologic Neoplasms; Recurrence
• Other Study ID Numbers: P120103

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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