Autologous Gene Therapy for Artemis-Deficient SCID

ConditionSevere Combined Immunodeficiency

Trial statusRecruiting

Trial phasePhase 1, Phase 2

Trial typeInterventional

Biological sexAll

Age2+

SponsorUniversity of California, San Francisco

About this trial

This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco in this single-site trial and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

≥2.0 months of age at initiation of busulfan conditioning

Artemis deficiency with bi-allelic pathogenic or likely pathogenic mutations in DCLRE1C; AND

CD3 count < 50 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count >50/µL and <300/uL and with restricted T cell receptor Vb diversity; AND

CD45 cell response to mitogens (PHA) < 50% of the lower limit of normal range for the lab (leaky ART-SCID).

Disqualifiers

Presence of a medically eligible HLA-matched sibling

Evidence of HIV infection by polymerase chain reaction or p24 antigen testing.

Unable to tolerate general anesthesia and/or marrow harvest or insertion of central venous catheter.

Any one of liver function tests AST, ALT, gamma-glutamyl transpeptidase (GGT) >5X the upper limit of normal for lab and/or total bilirubin >2.0 mg/dl (not due to Gilbert's) at the time of planned initiation of busulfan conditioning unless the elevated LFTs are considered to be due to medication, a viral infection for which there is no treatment other than reconstituting T cell immunity, or maternal GVHD.

Trial design

Design model

Single group

Treatments tested in this trial

AProArt-CD34
Drug
Participants will undergo infusion with autologous hematopoietic cells transduced with a lentiviral vector, AProArt, which contains the correct form of DCLRE1C complementary deoxyribonucleic acid DNA, after receiving sub-ablative, exposure-targeted busulfan conditioning.
CliniMACS® CD34 Reagent System cell sorter device
Device
Processing of hematopoietic progenitor cells to select CD34 cells, using the CliniMACS® CD34 Reagent System, prior to infusion.
Busulfan
Drug
Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Patients will receive low-dose busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg\*hr/L.

Treatment groups

24 Participants

are divided into 1 treatment group

Group A: Gene therapy (AProArt)Experimental treatment 3 interventions

Trial outcomes

Primary outcomes

To demonstrate that ART-SCID patients receiving AProArt-CD34 infusion have superior overall survival (OS) at 24 months post treatment with AProArt-CD34 versus the established outcome of 0% OS for patients who receive no treatment for ART-SCID

Patient survival status and (if applicable) cause of death will be recorded to assess overall survival.

Time frame

24 months

Secondary outcomes

B cell immune reconstitution by 24±2 months compared with historical control cohort of allogeneic transplant recipients

B cell immune reconstitution will be defined as cessation of immunoglobulin replacement therapy

Time frame

24 months

Number of participants with T cell immune reconstitution compared with historical controls who received allogeneic transplants to treat ART-SCID.

T cell immune reconstitution will be defined as presence of both of the following: 1) a. CD3\>1000/mm3; 2) CD4\>500/mm3.

Time frame

24 months

Event Free Survival

Events are defined as death, use of a repeat infusion of gene-corrected cells to enhance T/B cell immune reconstitution or requirement for performance of an allogeneic HCT.

Time frame

24 months

Other outcomes

Adverse event (AE) profile associated with the study intervention from treatment through 15 years after the gene transfer procedure

Clinical and laboratory AEs as measured by CTCAE V4

Time frame

15 years

Number of participants with B cell reconstitution beyond 24 months, including B cell numbers and function

B cell reconstitution will be defined as presence of at least two of the following: 1) B cell number \>40/mm3; 2) Cessation of immunoglobulin replacement therapy; 3) Protective specific antibody responses. The number of participants who meet the definition for B cell reconstitution will be tabulated.

Time frame

15 years

Efficacy of targeting low exposure busulfan in infants and children, calculated by percentage of participants whose treatment meets study parameters using a validated population pharmacokinetic model to calculate individualized busulfan clearance.

Achievement of final target cumulative AUC of 20±2 mg\*hr/L in approximately 90% of subjects

Time frame

42 days

Repertoire diversity of T and B cells, as assessed by analyzing T cell receptor gene variable beta sequence (TCR-Vb) and immunoglobulin heavy chain (IGH) rearranged receptors and calculating diversity Shannon Index.

Measured by deep sequencing of the T cell receptor (TCR) gene variable beta sequence (TCR-Vb) and immunoglobulin heavy chain (IGH) rearranged receptors. The diversity Shannon Index is expected to be above 7.5 by 24±2 months post treatment in 90% of patients.

Time frame

24 months

Sponsors and contacts

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University of California, San Francisco

Lead sponsor

Source ClinicalTrials.gov

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