Safety and Efficacy of Gene Therapy of FHL Type 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA (MUNC13-4)

A Phase I/II Open Label Non Randomized Study, Monocentric, Single Arm, Evaluating Safety and Efficacy of Gene Therapy of FHL 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA

The investigators propose to replace HLA- partially compatible allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for FHL type 3 patients, with autologous transplantation of immunoselected gene-modified CD34+ cells, combined with transduced autologous T-cell each time this is possible and also to propose this alternative treatment as salvage in case of failure of a previous allogeneic HSCT. This approach should avoid the severe immunological complications (failure to engraft, acute or chronic graft versus host disease (GVHD)) and conditioning toxicities such as severe Veno-Occlusive Disease (VOD). As the clinical manifestations of FHL type 3 patients are triggered by opportunistic viral infections (often EBV) and can be poorly controlled or only transiently controlled by the available drugs , providing the patient after the conditioning with immediately functional autologous cytotoxic T-cells could be key to maintain the control of the viral infection and hopefully its eradication awaiting for the hematopoietic reconstitution . This procedure should avoid any reactivation of the viral infection and thus improving the patients' overall survival and event-free survival while clearing the ongoing triggering infections.

Study Overview

• Status: Not yet recruiting
• Conditions: Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3)
• Intervention / Treatment: Genetic: MUNC-CD34; Genetic: MUNC-T3

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marina CAVAZZANA, MD, PhD; Phone Number: +33 01 44 49 50 68; Email: m.cavazzana@aphp.fr
• Study Contact Backup: Name: Aline DECHANET, Project Manager; Phone Number: +33 01 71 19 61 69; Email: aline.dechanet@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Department of Biotherapy, Hopital Necker Enfants Malades
    • Contact: Marina CAVAZZANA, MD, PhD; Phone Number: +33 01 44 49 50 68; Email: m.cavazzana@aphp.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patient aged from 3 months up to 45 years old.
2. Patient with a FHL caused by mutation of the UNC13D gene.

3. Complete remission is defined by the normalization of clinical and laboratory parameters:

   1. Resolution of fever
   2. Resolution of splenomegaly or reduced and isolated splenomegaly.
   3. Improvement of cytopenia: absolute neutrophil count > 500/µl AND platelets cout > 100 000/ µl (unsupported by transfusion)
   4. Normalization of serum fibrinogen level (Fibrinogen ≥1.5g/l)
   5. Resolution of hyperferritinemia (Ferritin level < 2000µg/l)
   6. Normalization of T-cell activation
4. Patient eligible for an allogeneic HSCT in absence of an HLA geno-identical donor (at diagnostic or 6 months after failure of a previous HSCT (rejection or loss of the graft))
5. Patint or parental, guardian's patient signed informed consent.
6. For patients of childbearing age : willing to use an effective method of contraception* during the trial and for at least 12 months post-infusion
7. Affiliation to Social Security

Exclusion Criteria:

1. Active CNS encephalitis related to HLH
2. Existence of a matched -sibling donor
3. Unwillingness to return for follow-up during the 2 years study and lifelong for off study review.
4. HIV-1 or 2 or HTLV1 infections.
5. Patient on AME (state medical aid) (unless exemption from affiliation)
6. Pregnancy or breast feeding in a post-partum female
7. Diagnosis of significant psychiatric disorder of the subject that could seriously impeded the ability to participate in the study
8. Known allergies, hypersensitivity, or intolerance to any of busulfan, fludarabine, rituximab, G-CSF, plerixafor or excipients, or similar compounds
9. Unable to tolerate general anesthesia and/or apheresis
10. Participation in another clinical study with an investigational drug within 30 days of inclusion.
11. Uncontrolled HLH manifestation

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: MUNC

Genetic: MUNC-CD34; Dosage: ≥ 2 x10e6 CD34/kg after thawing, dose limit: 20x10e6 CD34+ cells/kg; Route of administration: intravenous, on D0; Genetic: MUNC-T3; Dosage: [1.10e4; 5.10e6] T-CD3+/kg after thawing,; Route of administration: intravenous, on D14 post-GT +/- D28 In case of persistent circulating T-cell after the HLH remission at inclusion, the MUNC-CD34 will be completed by MUNC-T3 infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Transplantation Related Mortality (TRM)		up to 6 months post treatment
Frequency and severity of clinical AEs and laboratory parameters	Adverse event will be measured using CTCAE	throughout the whole period of the research, up to 60 months
Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment	Bone marrow analysis and VISA	At 12 months post treatment
Detection of Replication -Competent Lentivirus (RCL)		at 3, 6 and 12 months post treatment, then yearly up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil and platelet recovery	ANC> 500/µl, Platelets > 20.000/µl on two consecutive days without transfusion	throughout the whole period of the research, up to 60 months
Quantification of the transgene copy number (VCN) on drug substance at time of cryopreservation, on PBMC, sorted T-CD3+ and sorted NK cells		at 1, 2, 3, 6, 9, 12, 18 and 24 months post treatment
Quantification of the UNC13D RNA on PBMC	by Q-PCR	at 1, 2, 3, 6, 9, 12, 18 and 24 post treatment
Quantification of Munc13.4 protein level in the drug substance and on peripheral blood mononuclear cells and on sorted CD3+ and CD56+ cells in function of their number	by western blot	at 6, 12 and 24 months post treatment
Correction of degranulation function in T-CD3		at 6 months and 24 months post treatment
Integration site analyse study		at 24 months post treatment
Needs of PICU support		up to 24 months post treatment
Endothelial complications		up to 24 months post treatment
Infectious diseases		up to 24 months post treatment
Estimate of the cost of the complete procedure, from mobilisation to transplant		up to 24 months post treatment
Disease-free survival (DFS). evaluate the Persistent HLH remission	Disease-free survival (DFS).	at M6 and 24 months post treatment.
Vector Copy Number (VCN) in Peripheral Blood Mononuclear Cells (PBMC)	> 0.2.	At M6 and 24 months post treatment.
Determination of the total number of T-cells and distribution of different subpopulations.	Naïve and memory CD4+ and CD8+ T cells will be evaluated using CCR7/CD45RA/RO markers, and the quantification of activation marker will be performed by the expression of DR+, by flow cytometry.	At 1, 2, 3, 6, 12, 18 and 24 months post treatment
Estimate of the 24 months total cost.		up to 24 months post treatment

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Study Director: Jean-Sébastien DIANA, MD, PhD, Assitance publique - Hôpitaux de Paris; Study Director: Chantal LAGRESLE, PHD, Inserm Institut Imagine

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: December 4, 2024
• First Submitted That Met QC Criteria: December 12, 2024
• First Posted (Actual): December 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; Lentiviral Vector; Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL 3); Munc13.4
• Additional Relevant MeSH Terms: Lymphatic Diseases; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphohistiocytosis, Hemophagocytic
• Other Study ID Numbers: APHP240201; 2023-507334-24-00 (Ctis)

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
• product manufactured in and exported from the U.S.: No