Autologous Mobilized Peripheral Blood CD34+ Hematopoietic Stem and Progenitor Cells (HSPC) Transduced With the Elongation Factor Alpha Short Promoter (EFS) - Adenosine Deaminase (ADA) Gene (EFS-ADA) Lentiviral Vector for Adenosine Deaminase Severe Combined Immune Deficiency (ADA SCID)

Efficacy and Safety of Cryopreserved Autologous Mobilized Peripheral Blood CD34+ Hematopoietic Stem and Progenitor Cells Transduced Ex Vivo With the EFS-ADA Lentiviral Vector in Patients With Severe Combined Immune Deficiency Due To Adenosine Deaminase Deficiency

The aim of this study is to assess the safety and efficacy of autologous transplantation of hematopoietic stem cells (CD34+ cells) from mobilized peripheral blood (mPB) of ADA-deficient SCID infants and children following human ADA gene transfer by the EFS-ADA lentiviral vector. The level of gene transfer in blood cells and immune function will be measured as endpoints.

Study Overview

• Status: Recruiting
• Conditions: Adenosine Deaminase Severe Combined Immune Deficiency
• Intervention / Treatment: Combination product: A cryopreserved formulation of autologous mPB CD34+ hematopoietic stem and progenitor cells transduced ex vivo with the EFS-ADA lentiviral vector encoding the human ADA enzyme

Detailed Description

The study is open to twenty (20) infants and children diagnosed with ADA-deficient SCID who did not have a medically eligible, human leukocyte antigen (HLA)-identical sibling donor for bone marrow transplantation. The EFS-ADA lentiviral vector with the human ADA complementary DNA (cDNA) will be used to transduce autologous CD34+ cells from Granulocyte Colony Stimulating Factor (G-CSF)/Plerixafor mobilized Peripheral Blood (mPB) of these subjects. The subjects will receive pharmacokinetically-adjusted busulfan reduced intensity conditioning prior to re-infusion of their gene-modified cells. Overall survival at two years is the primary endpoint. During the follow-up phase, the investigators aim to determine whether the cells could engraft and produce mature cells that contain and express the corrected ADA gene in the absence of pegylated adenosine deaminase (PEG-ADA) enzyme replacement therapy (ERT), which will be withheld starting on Day +30 following transplant. Efficacy studies to evaluate the level of immune reconstitution, will be performed in the two years of the study. Patients will be asked to enroll into a long-term follow-up study to reach a total of 15 years follow-up after gene therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Satiro De Oliveira, MD; Phone Number: 1-310-825-6708; Email: sdeoliveira@mednet.ucla.edu
• Study Contact Backup: Name: Augustine Fernandes, PhD; Phone Number: 1-310-267-4948; Email: afernandes@mednet.ucla.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles (UCLA)
      • Contact: Augustine Fernandes, PhD; Phone Number: 310-267-4948; Email: AFernandes@mednet.ucla.edu
      • Contact: Satiro De Oliveira, MD; Phone Number: 310-825-6708; Email: sdeoliveira@mednet.ucla.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All subjects must fulfill the following criteria to be included in the study:

1. Provision of written informed consent prior to any study related procedures. In this study consent must be provided by the parents/legal guardians and, where applicable according to local laws, a signed assent from the child,
2. Subjects ≥30 days of age,

3. With a diagnosis of ADA-SCID based on:

   Evidence of ADA deficiency, defined as:

   i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-SCID as determined by the reference laboratory, or ii. Identified mutations in ADA alleles consistent with a severe reduction in ADA activity,

   Evidence of ADA-SCID based on either:

   i. Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on

   1. Lymphopenia (absolute lymphocyte count (ALC) <400 cells/mL) OR absence or low number of T cells (absolute CD3+ count < 300 cells/mL), or
   2. Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, or <10% of the response of the normal control of the day, or stimulation index <10), or
   3. Identification of SCID by neonatal screening revealing low T Cell Receptor Excision Circles (TREC) levels.
4. Ineligible for matched family allogeneic bone marrow (BM) transplantation, defined as the absence of a medically eligible HLA-identical sibling or family donor, with normal immune function, who could serve as an allogeneic bone marrow donor.
5. Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.
6. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

Exclusion Criteria:

Subjects will not be eligible for the study if any of the following criteria is fulfilled:

1. Ineligible for autologous HSCT as per clinical site criteria
2. Other conditions which in the opinion of the Principal Investigator and/or Co Investigators, contraindicate the mobilization of peripheral blood or the leukapheresis process, the administration of busulfan and the infusion of transduced cells, or which indicate an inability of the subject or subject's parent/legal guardian to comply with the protocol

3. Hematologic abnormality, defined as:

   • Anemia (Hb <8.0 g/dl).
   • Neutropenia (ANC <500/mm3). Note: ANC <500 with absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are acceptable for eligibility.
   • Thrombocytopenia (platelet count <50,000/mm3, at any age).
   • Prothrombin time or international normalized ratio (INR) and partial thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a correctable deficiency controlled on medication will not be excluded).
   • Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
   • Prior allogeneic HSCT with cytoreductive conditioning.

4. Pulmonary abnormality, defined as:

   • Resting O2 saturation by pulse oximetry <90% on room air.
   • Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X ray indicating residual signs of treated pneumonitis is acceptable for eligibility.

5. Cardiac abnormality, defined as:

   • Abnormal ECG indicating cardiac pathology.
   • Uncorrected congenital cardiac malformation with clinical symptoms.
   • Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
   • Poor cardiac function as evidenced by left ventricular ejection fraction <40% on echocardiogram.

6. Neurologic abnormality, defined as:

   • Significant neurologic abnormality revealed by examination.
   • Uncontrolled seizure disorder.

7. Renal abnormality, defined as:

   • Renal insufficiency: serum creatinine ≥1.2 mg/dl (106 µmol/L), or ≥3+ proteinuria.
   • Abnormal serum sodium, potassium, calcium, magnesium or phosphate levels at >2 x ULN.

8. Hepatic/gastrointestinal abnormality, defined as:

   • Serum transaminases >5 x ULN.
   • Serum bilirubin >2 x ULN.
   • Serum glucose >1.5 x ULN.

9. Oncologic disease, defined as:

   • Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP).
   • Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells (if anti-neoplastic therapy has been completed, a subject with a history of DFSP can be included).
   • Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells.
10. Known sensitivity to Busulfan.

11. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) positive at time of assessment for the following:

    • HIV-1,
    • Hepatitis B,
    • Parvovirus B19.
12. The subject is pregnant or has a major congenital anomaly.
13. Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
14. The subject has previously received another form of gene therapy.

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: Autologous mobilized peripheral blood (mPB) transduced with EFS ADA lentiviral vector; Evaluate safety and efficacy of this autologous gene therapy	Combination product: A cryopreserved formulation of autologous mPB CD34+ hematopoietic stem and progenitor cells transduced ex vivo with the EFS-ADA lentiviral vector encoding the human ADA enzyme; Autologous transplantation of EFS-ADA lentiviral vector transduced, mPB CD34+ cells by central venous infusion, following reduced intensity conditioning with busulfan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	The primary study outcome will be to determine survival for all subjects 2 years after gene therapy	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate Safety from clinical adverse events.	Evaluate safety of the treatment by recording clinical adverse events (AE).	24 months
Evaluate Safety from replication competent lentivirus by quantitative polymerase chain reaction (qPCR) assay.	Evaluate safety by recording incidents of replication competent lentivirus by qPCR assay..	24 months
Evaluate Safety from vector-related clonal expansion by non-restrictive Linear Amplification Polymerase Chain Reaction (nrLAM-PCR)	Evaluate safety by recording incidence of vector-related clonal expansion by nrLAM-PCR	24 months
Record event free survival at 24 months	Record Event Free Survival as a definition of "failure" of the therapy. Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogeneic hematopoietic stem cell transplant (HSCT), or death.	24 months
Determine incidence of Infection over two years after gene therapy	Determine the incidence and severity of infections post-gene therapy (subsequent to hematopoietic reconstitution). Over 2 years, record the incidence of hospitalizations or outpatient-based treatments for systemic bacterial, fungal, or viral infections (including, but not limited to Cytomegalovirus (CMV) infections).	24 months
Neuro-developmental Outcomes by neurodevelopmental testing (subjects 5-7 yeas of age)	Measure neuro-developmental status post-gene therapy. Perform age-appropriate neuro-developmental assessments testing (5- 7 years of age) at baseline and 2 years post-gene therapy - Wechsler Scale of Intelligence	24 months
Neuro-developmental Outcomes by neurodevelopmental testing (subjects 1 year -42 month of age)	Measure neuro-developmental status post-gene therapy. Perform age-appropriate neuro-developmental assessments testing (1 year to 42 months of age) at baseline and 2 years post-gene therapy - : Bayley Scale of Infant Development	24 months
Neuro-developmental Outcomes by Brain Stem Evoked Response (BAER) testing	Measure neuro-developmental status post-gene therapy - Perform Brainstem Auditory Evoked Response test at baseline and at 2 years.	24 months
Cessation of immunoglobulin replacement therapy (IgRT).	Record time post-gene therapy that immunoglobulin replacement therapy (IgRT) is stopped based on defined criteria.	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Study Objectives to measure biological correlates of efficacy - Vector Copy Number (VCN) in peripheral blood leukocytes	The Exploratory Study Objectives are to measure biological correlates of efficacy. 1. Quantify gene marking by vector copy number (VCN) in peripheral blood leukocytes by droplet digital polymerase chain reaction (ddPCR).	24 months
Exploratory Study Objectives to measure biological correlates of efficacy (Vector integrant diversity)	The Exploratory Study Objectives are to measure biological correlates of efficacy. 2. Quantify clonal diversity of vector integrants by non-restrictive Linear Amplification polymerase chain reaction (nrLAM-PCR). nrLAM-PCR identifies all distinct vector integrants in a cell sample from patients. The presence of >1,000 unique integration sites in a sample indicates diversity of hematopoietic stem cell of clonal engraftment	24 months
Exploratory Study Objectives to measure biological correlates of efficacy (expressed ADA enzyme in erythrocytes)	The Exploratory Study Objectives are to measure biological correlates of efficacy. 3. Measure ADA enzyme activity in erythrocytes as an indicator of expression of functional ADA enzyme from the vector.	24 months
Exploratory Study Objectives to measure biological correlates of efficacy Deoxyadenosine nucleotides in erythrocytes)	The Exploratory Study Objectives are to measure biological correlates of efficacy. 4. Measure total deoxyadenosine nucleotides in erythrocytes.	24 months
Exploratory Study Objectives to measure biological correlates of efficacy (Immune reconstitution - quantify T and B cell)	The Exploratory Study Objectives are to measure biological correlates of efficacy. 5. Assess immune reconstitution by measuring absolute numbers of T and B cells .	24 months
Exploratory Study Objectives to measure biological correlates of efficacy (Immune reconstitution - measure serum immunoglobulins)	The Exploratory Study Objectives are to measure biological correlates of efficacy. 6. Assess immune reconstitution by measuring serum immunoglobulin levels	24 months
Exploratory Study Objectives to measure biological correlates of efficacy (Immune reconstitution - response to tetanus vaccine)	The Exploratory Study Objectives are to measure biological correlates of efficacy. 7. Assess immune reconstitution by measuring response to tetanus vaccine by measuring serum anti-tetanus antibody titers after tetanus vaccination	24 months
Exploratory Study Objectives to measure biological correlates of efficacy Parent report Quality of Life	The Exploratory Study Objectives are to measure biological correlates of efficacy. 8. Parent-Reported Quality of Life (PedsQL 4.0) at baseline and 2 years.	24 months

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Investigators: Principal Investigator: Satiro De Oliveira, MD, Assistant Professor

Publications and helpful links

General Publications

• Carbonaro DA, Zhang L, Jin X, Montiel-Equihua C, Geiger S, Carmo M, Cooper A, Fairbanks L, Kaufman ML, Sebire NJ, Hollis RP, Blundell MP, Senadheera S, Fu PY, Sahaghian A, Chan RY, Wang X, Cornetta K, Thrasher AJ, Kohn DB, Gaspar HB. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014 Mar;22(3):607-622. doi: 10.1038/mt.2013.265. Epub 2013 Nov 20.
• Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: June 4, 2022
• First Submitted That Met QC Criteria: June 20, 2022
• First Posted (Actual): June 27, 2022

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 24, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Gene Therapy; Hematopoietic Stem Cell; Lentiviral Vector; Reduced Intensity Conditioning with Busulfan
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency
• Other Study ID Numbers: UCLA IRB#21-001814

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