Diabetes, Type IPhase 1/2IMMUNOSTEMNCT06938334
A First-in-human Clinical Trial Using a Gene Therapy With Patient's Own Stem Cells to Treat Early Type 1 Diabetes
A Phase 1/2 study testing Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNA in people with Diabetes, Type I, run by Altheia Science at 1 site in Italy.
Trial summary
Purpose: The purpose of the trial is to assess the safety profile of the study treatment and to evaluate its efficacy in terms of improvement in key diabetes management parameters, including insulin requirements and β-cell function, and immunological parameters, in patients with T1D at recent onset / diagnosis and… Read more about this study
- Who is it for?
- Ages 18 to 40 years
- Conditions the study is for
- Diabetes, Type I
- What is being tested?
- Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNA
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteItaly
- Study dates
- 15 Aug 2025to 15 Jun 2029
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Capable of giving signed informed consent, compliance with the requirements and restrictions listed in the Informed Consent Form and the protocol.
- Male and or female patients.
- Age ≥18 and ≤40 years
- Patient able to comply with all protocol procedures for the duration of the study.
- Recent T1D onset/diagnosis (patients should receive the DP within 180 days from the 1st insulin administration).
- HbA1c ≥53 and ≤150 mmol/mol
- Positivity to at least 2 autoantibodies (i.e., anti-insulin, IAA; anti-glutamic acid decarboxylase 65, GAD65; anti-islet antigen 2, IA-2A; anti-zinc transporter 8, ZnT8; anti-islet cell antibody, ICA).
- Basal C-peptide levels ≥0.2 nmol/L or ≥0.6 ng/mL; if basal C-peptide levels <0.2 nmol/L, stimulated C-peptide peak ≥0.2 nmol/L or ≥0.6 ng/mL during a 2-hour MMTT; MMTT should not be performed within one week of resolution of a diabetic ketoacidosis event.
Who cannot join
- Unwillingness to sign the informed consent.
- Type 2 diabetes
- Any other unstable chronic disease
- Significant systemic infection during the four weeks before requiring hospitalisation, administration of intravenous antibiotics, surgery
- Present administration of chemotherapeutic anti-neoplastic drugs.
- QTcF >470 msec.
Show all 16Show fewer
- Occurrence of an episode of ketoacidosis or hypoglycaemic coma in the past two weeks.
- Presence of a ≥grade 3 adverse event (including laboratory analyses) according to CTCAE version 5.0.
- Evidence of clinically significant abnormalities at bone-marrow aspirate
- Body Mass Index (body weight*height2 )>27 kg⁄m2
- A positive result to Biological Screening testing for Anti-HCV Antibody (Ab), HCV nucleic acid test (NAT) (if anti-HCV Ab positive), HIV-1/-2 p24 Ab and antigen (Ag), HIV RNA NAT, anti-Treponema pallidum total Ig, HbsAg (Australia Ag), HBV DNA NAT, total anti-HB core Ab (if HBV DNA NAT positive), anti-HTLV I, and anti-HTLV II (if applicable).
- Active SARS-CoV-2 infection.
- Allergy to mobilizing agents (G-CSF and plerixafor).
- Pregnancy or lactation
- Absence of an efficacious method of contraception
- Any condition that in the opinion of investigator contraindicate apheresis or infusion of transduced HSPCs or affects patient's compliance.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
About this study
Official title: A Single-arm, Open-label, Phase I/II Clinical Trial of Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) Genetically Modified With a Lentiviral Vector (LVV) Encoding for the Human Programmed Death-ligand 1 (hPD-L1) Complementary Deoxyribonucleic Acid (cDNA) for the Treatment of Patients With Type 1 Diabetes (T1D) at Recent Onset and With Residual β-cell Function (IMMUNOSTEM)
Purpose:
The purpose of the trial is to assess the safety profile of the study treatment and to evaluate its efficacy in terms of improvement in key diabetes management parameters, including insulin requirements and β-cell function, and immunological parameters, in patients with T1D at recent onset / diagnosis and with residual β-cell function.
Read more
Rationale:
The study treatment consists of an autologous CD34+-enriched population that contains HSPCs transduced ex vivo with a third generation VSV-G pseudotyped LVV encoding the hPD-L1 cDNA. The drug product (DP) is composed of genetically modified autologous CD34+ HSPCs formulated in cryopreservation medium, transferred to the final container closure, and cryopreserved.
The mechanism of action is based on the ability of the PD-L1-expressing HSPCs to exert immunoregulatory properties activity and ablate suppress the autoimmune reaction induced by auto-reactive T lymphocytes, by homing to the site of inflammation, i.e., the pancreas.
PD-L1 is the ligand for the PD-1 receptor, expressed primarily on activated T cells. Crosslinking of PD-L1 and PD-1 inhibits T cell activation and favours their exhaustion/apoptosis and in mice deficient in PD-L1/PD-1 develop accelerated diabetes. HSPCs have been extensively used as an effective therapeutic approach in haematological malignancies and have demonstrated to be safe in human subjects.
Immunologically based clinical trials performed thus far have failed to cure T1D, in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4+ T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in PD-L1, an important immune checkpoint, in the T1D non-obese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. The Investigators therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro.
The Investigators therefore hypothesized that targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D or slow the progression of β-cell destruction.
- Conditions
- Diabetes, Type I
- Being tested
- Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNA
- Keywords
- type 1 diabetes (T1D), HSPCs genetically modified, lentiviral vector (LVV)
- Medical subject headings
- Diabetes Mellitus, Type 1
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNAGenetic
The intervention is intended for newly diagnosed T1D patients with residual beta-cell function, who can receive the Drug Product (DP) within 180 days from the first insulin administration. Mobilized autologous HSPCs, collected by leukapheresis, are ex vivo transduced with a LVV encoding for hPD-L1 and formulated in a cryopreservation medium containing DMSO (DP). After release, the DP is thawed and administered to the patient at a dose ranging between 5 and 20 million of cells per kilogram of body weight. The intervention plans for a single DP injection.
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Evaluation of the safety and efficacy of autologous CD34+ HSPCs transduced ex vivo with LVV encoding hPD-L1 cDNA in patients with T1D at recent onset and with residual β-cell function Receives: Genetic: Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0
For each participant, number, description and grading of any adverse event, including expected and unexpected adverse events, meeting or not meeting the definition of "serious".
Measured: Up to 24 months
Secondary outcomes (7)
Vector Copy Number
Longitudinal analysis of vector copy number (VCN) in peripheral blood samples to assess frequency and persistence of infused cells and their progenies
Measured: Up to 24 months
Safety and efficacy
Changes over time of the 3-hour area under curve (AUC) and ΔAUC normalised by baseline glucose blood levels of C-peptide response to a mixed meal tolerance test (MMTT) over 12 and 24 months
Measured: on month 12 and 24 month
Safety and efficacy
Changes over time of glucose metrics from continuous glucose monitoring (CGM) over 12 and 24 months
Measured: on month 12 and 24 month
Safety and efficacy
Exogenous insulin requirement defined as a daily average in units per kilogram per day (U/kg/day) during the previous 14 days
Measured: Up to 24 months
Pharmacodynamic
Longitudinal analysis of vector copy number (VCN) in peripheral blood samples to assess frequency and persistence of infused cells and their progenies
Measured: from Treatment to end of study
Safety and efficacy
Changes over time of HbA1c levels over 12 and 24 months
Measured: on month 12 and 24 month
Safety and efficacy
Number of self-reported episodes of severe (CTCAE version 5.0 grade 3) hypoglycaemia
Measured: Up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Apr 2025
- Study start15 Aug 2025 (estimated)
- Primary completion15 Jun 2029 (estimated)
- Study completion15 Jun 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes, Type IStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Altheia Science
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Evidenze Health S.r.l.
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06938334
- Sponsor's protocol ID
- IMMUNOSTEM
- Other IDs
- 2025-521304-21-00, 2025
- Acronym
- IMMUNOSTEM
- Status last verified
- Apr 2025
- First submitted
- 7 Apr 2025
- Last updated
- 22 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD that underlie results in a publication.
Publications
Ben Nasr M, Tezza S, D'Addio F, Mameli C, Usuelli V, Maestroni A, Corradi D, Belletti S, Albarello L, Becchi G, Fadini GP, Schuetz C, Markmann J, Wasserfall C, Zon L, Zuccotti GV, Fiorina P. PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes. Sci Transl Med. 2017 Nov 15;9(416):eaam7543. doi: 10.1126/scitranslmed.aam7543.
PubMed 29141886Lin TM, Chang HF, Lin TC, Lin CH, Sun YL, Lin CS. Gene Therapy and Gene Editing in Type 1 Diabetes: CRISPR-Based beta-Cell Replacement and Treg Immune Modulation Approaches. Diabetes Obes Metab. 2026 Jul;28(7):5476-5491. doi: 10.1111/dom.70800. Epub 2026 Apr 23.
PubMed 42023429
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single-arm, Open-label, Phase I/II Clinical Trial of Autologous Hematopoietic Stem and Progenitor Cells (HSPCs) Genetically Modified With a Lentiviral Vector (LVV) Encoding for the Human Programmed Death-ligand 1 (hPD-L1) Complementary Deoxyribonucleic Acid (cDNA) for the Treatment of Patients With Type 1 Diabetes (T1D) at Recent Onset and With Residual β-cell Function (IMMUNOSTEM)
- ClinicalTrials.gov ID
- NCT06938334
- Acronym / sponsor ID
- IMMUNOSTEM / IMMUNOSTEM
- Conditions
- Diabetes, Type I
- Keywords
- type 1 diabetes (T1D), HSPCs genetically modified, lentiviral vector (LVV)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 15 participants (estimated)
- Lead sponsor
- Altheia ScienceIndustry (pharma, biotech, devices)
- Collaborators
- Evidenze Health S.r.l.
- Study start
- 15 Aug 2025 (estimated)
- Primary completion
- 15 Jun 2029 (estimated)
- Study completion
- 15 Jun 2029 (estimated)
- First posted
- 22 Apr 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Purpose:
The purpose of the trial is to assess the safety profile of the study treatment and to evaluate its efficacy in terms of improvement in key diabetes management parameters, including insulin requirements and β-cell function, and immunological parameters, in patients with T1D at recent onset / diagnosis and with residual β-cell function.
Rationale:
The study treatment consists of an autologous CD34+-enriched population that contains HSPCs transduced ex vivo with a third generation VSV-G pseudotyped LVV encoding the hPD-L1 cDNA. The drug product (DP) is composed of genetically modified autologous CD34+ HSPCs formulated in cryopreservation medium, transferred to the final container closure, and cryopreserved.
The mechanism of action is based on the ability of the PD-L1-expressing HSPCs to exert immunoregulatory properties activity and ablate suppress the autoimmune reaction induced by auto-reactive T lymphocytes, by homing to the site of inflammation, i.e., the pancreas.
PD-L1 is the ligand for the PD-1 receptor, expressed primarily on activated T cells. Crosslinking of PD-L1 and PD-1 inhibits T cell activation and favours their exhaustion/apoptosis and in mice deficient in PD-L1/PD-1 develop accelerated diabetes. HSPCs have been extensively used as an effective therapeutic approach in haematological malignancies and have demonstrated to be safe in human subjects.
Immunologically based clinical trials performed thus far have failed to cure T1D, in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4+ T cells, which destroy β cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in PD-L1, an important immune checkpoint, in the T1D non-obese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. The Investigators therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro.
The Investigators therefore hypothesized that targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D or slow the progression of β-cell destruction.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Genetic: Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNAEvaluation of the safety and efficacy of autologous CD34+ HSPCs transduced ex vivo with LVV encoding hPD-L1 cDNA in patients with T1D at recent onset and with residual β-cell function |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Capable of giving signed informed consent, compliance with the requirements and restrictions listed in the Informed Consent Form and the protocol.
- Male and or female patients.
- Age ≥18 and ≤40 years
- Patient able to comply with all protocol procedures for the duration of the study.
- Recent T1D onset/diagnosis (patients should receive the DP within 180 days from the 1st insulin administration).
Key exclusion criteria (16 listed)
- Unwillingness to sign the informed consent.
- Type 2 diabetes
- Any other unstable chronic disease
- Significant systemic infection during the four weeks before requiring hospitalisation, administration of intravenous antibiotics, surgery
- Present administration of chemotherapeutic anti-neoplastic drugs.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNAThe intervention is intended for newly diagnosed T1D patients with residual beta-cell function, who can receive the Drug Product (DP) within 180 days from the first insulin administration. Mobilized autologous HSPCs, collected by leukapheresis, are ex vivo transduced with a LVV encoding for hPD-L1 and formulated in a cryopreservation medium containing DMSO (DP). After release, the DP is thawed and administered to the patient at a dose ranging between 5 and 20 million of cells per kilogram of body weight. The intervention plans for a single DP injection. | Genetic | Treatment |
Primary outcome
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0
Time frame: Up to 24 months
For each participant, number, description and grading of any adverse event, including expected and unexpected adverse events, meeting or not meeting the definition of "serious".
7 secondary outcomes
Vector Copy Number
Time frame: Up to 24 months
Safety and efficacy
Time frame: on month 12 and 24 month
Safety and efficacy
Time frame: on month 12 and 24 month
Safety and efficacy
Time frame: Up to 24 months
Pharmacodynamic
Time frame: from Treatment to end of study
Safety and efficacy
Time frame: on month 12 and 24 month
Safety and efficacy
Time frame: Up to 24 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2025.
- Background: PubMed 29141886Ben Nasr M, Tezza S, D'Addio F, Mameli C, Usuelli V, Maestroni A, Corradi D, Belletti S, Albarello L, Becchi G, Fadini GP, Schuetz C, Markmann J, Wasserfall C, Zon L, Zuccotti GV, Fiorina P. PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes. Sci Transl Med. 2017 Nov 15;9(416):eaam7543. doi: 10.1126/scitranslmed.aam7543.
- Derived from this study: PubMed 42023429Lin TM, Chang HF, Lin TC, Lin CH, Sun YL, Lin CS. Gene Therapy and Gene Editing in Type 1 Diabetes: CRISPR-Based beta-Cell Replacement and Treg Immune Modulation Approaches. Diabetes Obes Metab. 2026 Jul;28(7):5476-5491. doi: 10.1111/dom.70800. Epub 2026 Apr 23.
- Individual participant dataSharing planned: Yes. All IPD that underlie results in a publication.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Autologous CD34+ cell enriched population containing HSPCs transduced ex vivo using a LVV encoding the hPD-L1 DNA in people with Diabetes, Type I, run by Altheia Science at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 22 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Paolo Rizzardi, MD (+39 335 1935042, paolo.rizzardi@altheiascience.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0 (time frame: Up to 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06938334, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Apr 2025.