Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL 3)
Conditions
Keywords
Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL 3), Munc13.4, Gene Therapy, Lentiviral Vector
Brief summary
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.
Interventions
GENETICMUNC-CD34
* Dosage: ≥ 2 x10e6 CD34/kg after thawing, dose limit: 20x10e6 CD34+ cells/kg * Route of administration: intravenous, on D0
GENETICMUNC-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
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 45 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Transplantation Related Mortality (TRM) | up to 6 months post treatment | — |
| Frequency and severity of clinical AEs and laboratory parameters | throughout the whole period of the research, up to 60 months | Adverse event will be measured using CTCAE |
| Incidence of clinically detectable malignancy and/or abnormal clonal dominance assessed as related to study treatment | At 12 months post treatment | Bone marrow analysis and VISA |
| Detection of Replication -Competent Lentivirus (RCL) | at 3, 6 and 12 months post treatment, then yearly up to 60 months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neutrophil and platelet recovery | throughout the whole period of the research, up to 60 months | ANC\> 500/µl, Platelets \> 20.000/µl on two consecutive days without transfusion |
| 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 | at 1, 2, 3, 6, 9, 12, 18 and 24 post treatment | by Q-PCR |
| 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 | at 6, 12 and 24 months post treatment | by western blot |
| Disease-free survival (DFS). evaluate the Persistent HLH remission | at M6 and 24 months post treatment. | Disease-free survival (DFS). |
| Vector Copy Number (VCN) in Peripheral Blood Mononuclear Cells (PBMC) | At M6 and 24 months post treatment. | \> 0.2. |
| Determination of the total number of T-cells and distribution of different subpopulations. | At 1, 2, 3, 6, 12, 18 and 24 months post treatment | 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. |
| 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 | — |
| Estimate of the 24 months total cost. | up to 24 months post treatment | — |
Countries
France
Contacts
CONTACTMarina CAVAZZANA, MD, PhD
CONTACTAline DECHANET, Project Manager
STUDY_DIRECTORJean-Sébastien DIANA, MD, PhD
Assitance publique - Hôpitaux de Paris
STUDY_DIRECTORChantal LAGRESLE, PHD
Inserm Institut Imagine
Outcome results
None listed