Wiskott-Aldrich Syndrome (WAS)
Conditions
Keywords
Lentiviral vector, Gene therapy, Wiskott-Aldrich Syndrome, TLT003, Previously GSK2696275, Previously OTL-103
Brief summary
This is phase I/II protocol to evaluate the safety and efficacy of WAS gene transfer into hematopoietic stem/progenitor cells for the treatment of Wiskott Aldrich Syndrome.
Detailed description
Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene which encodes the WAS protein (WASP), a cytoskeletal regulator which is expressed exclusively in hematopoietic cells.
Interventions
GENETICTLT003
TLT003 is an autologous CD34+ cells collected from bone marrow and/or peripheral blood and transduced with a lentiviral vector encoding Wiskott-Aldrich syndrome (WAS) protein
Sponsors
Ospedale San Raffaele
Fondazione Telethon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This will be a single-arm study. All subjects will receive OTL-103 gene therapy and will be followed up for 15 years post gene therapy
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of WAS defined by genetic mutation and at least one of the following criteria: * Severe WAS mutation * Absence of WASP expression * Severe clinical score (Zhu clinical score ≥ 3 2. No HLA-identical sibling donor 3. Negative search for a matched unrelated donor (10/10) or an adequate unrelated cord blood donor (5-6/6) within 4-6 months * Patients of \> 5 years of age who are not candidate to unrelated allogeneic transplant based on clinical conditions. 4. Parental/guardian/patient signed informed consent.
Exclusion criteria
1. Patients positive for HIV-infection. 2. Patients affected by neoplasia. 3. Patients with cytogenetic alterations typical of MDS/AML. 4. Patients with end-organ functions or any other severe disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study. 5. Patients who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months. 6. Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years) | Participant survival was monitored throughout the study. |
| Safety of Reduced Conditioning Regimen | Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years) | The absence of prolonged aplasia (defined as ANC \<0.5×10\^9/L \[\<500/μL\] at Day +60, with no evidence of BM recovery and requiring backup administration) was assumed as demonstrating the safety of the RIC regimen. |
| Safety of Lentivirus Gene Transfer Into HSC | after 48 hours after Telethon003 infusion | Safety and tolerability of lentiviral-transduced cell infusion. This will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion. |
| Sustained Engraftment of Genetically Corrected Haematopoietic Stem Cells in Peripheral Blood and/or in Bone Marrow | at 1 year after Telethon003 infusion | Engraftment is characterized by the presence of gene modified cells in the BM or PB compartments. The main indicator of gene correction is detection of the WAS LVV sequences in the HSPCs and their progeny. The VCN, which is the mean number of integrated copies of the vector sequences per cell genome, was measured using PCR-based methods in DNA samples extracted from BM and PB cell populations at various timepoints post-treatment. Adequate engraftment was defined as either ≥0.04 VCN/cell in BM CD34+ cells or ≥0.01 VCN/cell in PB CD3+ cells. |
| Presence of Detectable Vector-derived WASP | Median duration: 11.1 years (range: 8.01 -13.3 years) | The percentage of subjects who present the proportion of PB cells expressing WASP was assessed by flow cytometry analysis. |
| Improved T-cell Functions | Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years) | Improvement in in vitro T-cell proliferation was assessed upon stimulation with 3 doses of anti-immobilized CD3 (CD3i) monoclonal antibodies ≥1 year after Telethon003 infusion (as compared with pre-GT values) in PBMC and/or T-cell lines. The degree of correction was evaluated with respect to healthy controls. |
| Antigen-specific Responses to Vaccination | Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years) | The ability to mount a protective humoral response to at least 4 out of 5 nominal antigens including antibodies to T-cell dependent antigens and conjugated or unconjugated polysaccharide antigens was measured after vaccination (planned \>1 year after Telethon003 infusion). If results were available on n \<5 antigens, the rule of at least n-1 applied to define success. |
| Improved Platelet Count and MPV Normalization | up to 3 years after Telethon003 infusion | Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduced Frequency of Severe Infections | up to 3 years after Telethon003 infusion | Decrease in number of severe infections as evaluated in the second and third year after the treatment by clinical history, complete physical examinations, hematological and microbiological tests. |
| Reduced Bruising and Bleeding Episodes | 3 years | Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history |
| Reduced Autoimmunity Phenomena and Eczema | 3 years | Reduction in laboratory markers (number and titer of antibody when available) and/or clinical manifestations of autoimmunity, as evaluated by organ-specific and systemic autoantibodies, imaging and clinical follow-up, compared to clinical history. Reduction in eczema as evaluated by clinical score |
| Improved Quality of Life | 3 year | Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities. |
| Multilineage Engraftment of Genetically Corrected Cells | 3 years | ≥0.04 VCN/cell on all the available peripheral blood and/or bone marrow cell subpopulations (BM subpopulations: GlyA+, CD15+, CD61+, CD3+, CD19+, CD56+; PB subpopulations: CD15+, CD19+, CD56+) |
| Overall Safety of the Treatment | 8 years | Recording of AE, AR, SAE/SAR, UAR, SUSAR |
| Lack of Immune Response to Transgene | up to 3 years after Telethon003 infusion | Anti-WASP and anti-HIV-1 antibodies (anti-p24) were monitored to evaluate response to transgene and to vector, respectively. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OTL-103 Gene Therapy Eligible subjects will receive intravenous (IV) infusion of OTL-103 gene therapy. Subjects affected by WAS who don't have a suitable matched donor for allogenic hematopoietic stem cell transplantation will be included
OTL-103: OTL-103 is an autologous CD34+ cells collected from bone marrow and/or peripheral blood and transduced with a lentiviral vector encoding Wiskott-Aldrich syndrome (WAS) protein | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | OTL-103 Gene Therapy |
|---|---|
| Age, Categorical <=18 years | 8 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment Italy | 8 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 8 / 8 |
Outcome results
Primary
Antigen-specific Responses to Vaccination
The ability to mount a protective humoral response to at least 4 out of 5 nominal antigens including antibodies to T-cell dependent antigens and conjugated or unconjugated polysaccharide antigens was measured after vaccination (planned \>1 year after Telethon003 infusion). If results were available on n \<5 antigens, the rule of at least n-1 applied to define success.
Time frame: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TLT003 Gene Therapy | Antigen-specific Responses to Vaccination | 7 participants |
Primary
Improved Platelet Count and MPV Normalization
Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile
Time frame: up to 3 years after Telethon003 infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Improved Platelet Count and MPV Normalization | 8 Participants |
Primary
Improved T-cell Functions
Improvement in in vitro T-cell proliferation was assessed upon stimulation with 3 doses of anti-immobilized CD3 (CD3i) monoclonal antibodies ≥1 year after Telethon003 infusion (as compared with pre-GT values) in PBMC and/or T-cell lines. The degree of correction was evaluated with respect to healthy controls.
Time frame: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Improved T-cell Functions | 8 Participants |
Primary
Overall Survival
Participant survival was monitored throughout the study.
Time frame: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Overall Survival | 8 Participants |
Primary
Presence of Detectable Vector-derived WASP
The percentage of subjects who present the proportion of PB cells expressing WASP was assessed by flow cytometry analysis.
Time frame: Median duration: 11.1 years (range: 8.01 -13.3 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Presence of Detectable Vector-derived WASP | 8 Participants |
Primary
Safety of Lentivirus Gene Transfer Into HSC
Safety and tolerability of lentiviral-transduced cell infusion. This will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion.
Time frame: after 48 hours after Telethon003 infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Safety of Lentivirus Gene Transfer Into HSC | 8 Participants |
Primary
Safety of Reduced Conditioning Regimen
The absence of prolonged aplasia (defined as ANC \<0.5×10\^9/L \[\<500/μL\] at Day +60, with no evidence of BM recovery and requiring backup administration) was assumed as demonstrating the safety of the RIC regimen.
Time frame: Follow up phase - Median duration: 11.1 years (range: 8.01 -13.3 years)
Population: Mobilization Set (MS) for Safety analysis. Intent-to-treat (ITT) population for Efficacy analysis. All eight enrolled participants were included in the ITT and MS populations
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Safety of Reduced Conditioning Regimen | 8 Participants |
Primary
Sustained Engraftment of Genetically Corrected Haematopoietic Stem Cells in Peripheral Blood and/or in Bone Marrow
Engraftment is characterized by the presence of gene modified cells in the BM or PB compartments. The main indicator of gene correction is detection of the WAS LVV sequences in the HSPCs and their progeny. The VCN, which is the mean number of integrated copies of the vector sequences per cell genome, was measured using PCR-based methods in DNA samples extracted from BM and PB cell populations at various timepoints post-treatment. Adequate engraftment was defined as either ≥0.04 VCN/cell in BM CD34+ cells or ≥0.01 VCN/cell in PB CD3+ cells.
Time frame: at 1 year after Telethon003 infusion
Population: count of participants with sustained engraftment of genetically corrected HSPCs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Sustained Engraftment of Genetically Corrected Haematopoietic Stem Cells in Peripheral Blood and/or in Bone Marrow | 8 Participants |
Secondary
Improved Quality of Life
Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.
Time frame: 3 year
Secondary
Lack of Immune Response to Transgene
Anti-WASP and anti-HIV-1 antibodies (anti-p24) were monitored to evaluate response to transgene and to vector, respectively.
Time frame: up to 3 years after Telethon003 infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TLT003 Gene Therapy | Lack of Immune Response to Transgene | 8 Participants |
Secondary
Multilineage Engraftment of Genetically Corrected Cells
≥0.04 VCN/cell on all the available peripheral blood and/or bone marrow cell subpopulations (BM subpopulations: GlyA+, CD15+, CD61+, CD3+, CD19+, CD56+; PB subpopulations: CD15+, CD19+, CD56+)
Time frame: 3 years
Secondary
Overall Safety of the Treatment
Recording of AE, AR, SAE/SAR, UAR, SUSAR
Time frame: 8 years
Secondary
Reduced Autoimmunity Phenomena and Eczema
Reduction in laboratory markers (number and titer of antibody when available) and/or clinical manifestations of autoimmunity, as evaluated by organ-specific and systemic autoantibodies, imaging and clinical follow-up, compared to clinical history. Reduction in eczema as evaluated by clinical score
Time frame: 3 years
Secondary
Reduced Bruising and Bleeding Episodes
Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history
Time frame: 3 years
Secondary
Reduced Frequency of Severe Infections
Decrease in number of severe infections as evaluated in the second and third year after the treatment by clinical history, complete physical examinations, hematological and microbiological tests.
Time frame: up to 3 years after Telethon003 infusion