CD4^LVFOXP3 for IPEX Syndrome

Overseen By Rosa Bacchetta, MD

Age: < 65

Sex: Male

Trial Phase: Phase 1

Sponsor: Bacchetta, Rosa, MD

Disqualifiers: Medical instability, Life expectancy <6 months, Cardiac, renal, pulmonary, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 60 days post-infusion

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CD4^LVFOXP3 for individuals with IPEX Syndrome, a rare genetic disorder affecting the immune system. The main goal is to determine the treatment's safety and reliability, as well as to observe its effects on the disease. Participants will receive varying doses to monitor for side effects. Suitable candidates include those with a known FOXP3 gene mutation and ongoing IPEX symptoms requiring medication. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive it.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants may or may not be on immunosuppressive medication when starting the study.

Is there any evidence suggesting that CD4^LVFOXP3 is likely to be safe for humans?

Research shows that a type of cell treatment, called CD4^LVFOXP3, is safe for children and young adults with IPEX syndrome. Studies have found that these cells are ready for clinical use and are generally well-tolerated in treating IPEX. Importantly, previous studies have not reported any major side effects, which is encouraging for those considering participation. This trial marks the first time CD4^LVFOXP3 is tested in humans, so researchers are carefully monitoring safety to quickly identify any potential side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for IPEX syndrome?

Researchers are excited about CD4^LVFOXP3 for IPEX Syndrome because it uses a unique approach by leveraging gene therapy to correct immune system dysfunction. Unlike typical treatments that mainly focus on managing symptoms with immunosuppressive drugs like corticosteroids, this treatment aims to address the root cause by modifying CD4+ T cells to express the FOXP3 gene. This innovative mechanism has the potential to restore immune balance and provide a long-lasting solution, offering hope for more effective management of IPEX Syndrome compared to standard therapies.

What evidence suggests that CD4^LVFOXP3 might be an effective treatment for IPEX Syndrome?

Research shows that special cells called CD4^LVFOXP3 can help manage IPEX Syndrome by targeting the gene mutation that causes the disease. In lab tests, these engineered cells have controlled harmful immune cells while preserving normal immune functions. Animal studies have demonstrated that these cells can significantly extend life by reducing damaging immune reactions. This trial will test CD4^LVFOXP3 in two separate cohorts based on age: Cohort A includes participants aged 12 years and older, and Cohort B includes participants under 12 years. Researchers hope that CD4^LVFOXP3 could offer a new treatment for IPEX by addressing its genetic cause and calming the immune system. Although research in humans is ongoing, early results are promising for a potential future treatment. ^{1 6 7 8 9}

Who Is on the Research Team?

Jessie Alexander, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for individuals with IPEX Syndrome who have persistent symptoms despite medication, weigh over 8 kg, and can tolerate leukapheresis. Participants should have a FOXP3 gene mutation and be at least 50% functional on the Lansky/Karnofsky Scale. They cannot join if they have severe unrelated diseases, allergies to study treatments, certain cancer histories, are medically unstable or expected to live less than six months.

Inclusion Criteria

Uncontrolled IPEX disease but unable to tolerate immune suppressive medication

My organ and bone marrow functions are within normal ranges.

I can do most activities but may need help.

Exclusion Criteria

I am eligible and willing to undergo a stem cell transplant from a matched donor.

I cannot take the required dose of steroids.

I have no heart, kidney, lung, liver, or blood diseases unrelated to my cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CD4^LVFOXP3 infusion to replace defective Treg cells and restore immune control

Up to 60 days post-infusion

Daily visits for the first month, followed by monthly visits

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes

Up to 15 years

Monthly visits for the first year, then periodic visits

What Are the Treatments Tested in This Trial?

Interventions

• CD4^LVFOXP3

Trial Overview The trial is testing CD4^LVFOXP3 in people with IPEX Syndrome to see if it's safe and how it affects their disease. It's a Phase 1 trial focused on evaluating the manufacturing feasibility of this treatment and its administration safety in up to 36 participants.

How Is the Trial Designed?

Group I: Cohort B (<12 years) Experimental Treatment 1 Intervention

Participants in Cohort B will always follow treatment of participants in Cohort A for the same dose level. Cohort B will start at Dose Level 2 and be administered 3 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants.

Group II: Cohort A (≥12 years) Experimental Treatment 1 Intervention

The first participant in Dose Level 1 will be administered 1.0 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in the first participant, the following participants in Dose Level 1 will be administered the same dose of 1.0 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 1, participants will be enrolled into Dose Level 2 and administered 3 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If there is no toxicity observed in any participants in Dose Level 2, participants will be enrolled into Dose Level 3 and administered 10 x 10\^6 CD4\^LVFOXP3 /kg (± 20%). If in any dose level 1 of 2 participants show toxicity, that dose level will be expanded to 6 participants.

Who Is Running the Clinical Trial?

Bacchetta, Rosa, MD

Lead Sponsor

Trials

1

Recruited

30+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

Published Research Related to This Trial

Masiuk et al. (2019) present a promising method to effectively eliminate the symptoms of IPEX, a severe X-linked autoimmune disorder caused by mutations in the FOXP3 gene, in mouse models.

The study suggests that this approach could lead to durable treatment options for IPEX, highlighting its potential for long-term efficacy in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

21st Century FOX: Toward Gene Therapy for the Regulatory T Cell Deficiency Syndrome IPEX. Petty, NE., Gill, SI.[2019]

In a study of 173 patients with IPEX syndrome, 44 distinct FOXP3 gene variants were identified, including 9 new variants, highlighting the genetic diversity associated with this disorder.

Among 85 patients with IPEX-like symptoms but normal FOXP3, 19 disease-associated variants in 9 different genes were found, suggesting that a broader genetic analysis can aid in diagnosing similar immune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. Gambineri, E., Ciullini Mannurita, S., Hagin, D., et al.[2019]

IPEX syndrome is a rare genetic disorder caused by mutations in the FOXP3 gene, leading to a deficiency in CD4+CD25+ regulatory T cells, which are crucial for maintaining immune balance and preventing autoimmunity.

The lack of these regulatory T cells results in severe autoimmune conditions, such as enteropathy and type 1 diabetes, often leading to life-threatening complications within the first two years of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IPEX as a result of mutations in FOXP3. van der Vliet, HJ., Nieuwenhuis, EE.[2021]

IPEX syndrome is characterized by a range of autoimmune symptoms, including diarrhea, diabetes, thyroid disorders, and eczema, indicating significant immune dysregulation.

The FOXP3 gene, located on the X chromosome, is crucial for the function of regulatory T-cells, and mutations in this gene disrupt immune homeostasis, leading to the symptoms associated with IPEX.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Gambineri, E., Torgerson, TR., Ochs, HD.[2020]

This study analyzed five Chinese patients with atypical IPEX syndrome caused by FOXP3 mutations, identifying two novel mutations and highlighting the diverse clinical presentations, including one case of immune-related peripheral neuropathy.

Despite three patients having normal Treg cell frequencies, their Treg cell subsets and other immune cell types were imbalanced, suggesting that immune dysregulation in atypical IPEX may not always correlate with Treg cell numbers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and immunological characteristics of five patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China-expanding the atypical phenotypes. Huang, Y., Fang, S., Zeng, T., et al.[2022]

IPEX syndrome is a rare and severe disorder that often leads to early death in infants or children, highlighting the importance of clinical awareness for timely diagnosis.

Mutation analysis of the FOXP3 gene can confirm the diagnosis of IPEX syndrome, as demonstrated in two new patients diagnosed retrospectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and molecular findings in IPEX syndrome. Myers, AK., Perroni, L., Costigan, C., et al.[2018]

Hematopoietic cell transplantation using a low-intensity, nonmyeloablative conditioning regimen was successfully performed in two high-risk patients with IPEX syndrome, leading to stable engraftment and correction of immune deficiency.

Both patients showed full immune function and normal FOXP3 protein expression after transplantation, with minimal toxicity from the conditioning regimen, demonstrating a promising alternative to traditional myeloablative approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Burroughs, LM., Torgerson, TR., Storb, R., et al.[2022]

Patients with IPEX syndrome show a consistent increase in Treg-cell-Specific Demethylated Region (TSDR) demethylation in FOXP3, particularly in those with typical IPEX, indicating a potential biomarker for disease progression.

The study identified a unique inflammatory signature in IPEX patients, characterized by elevated cytokines associated with macrophage activation and TH2 polarization, which may help in understanding the disease's clinical variability and guiding treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation. Narula, M., Lakshmanan, U., Borna, S., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05241444

NCT05241444 | CD4^LVFOXP3 in Participants With IPEX This Phase 1 (feasibility and safety) trial will gather data about CD4^LVFOXP3 in vivo persistency and early signs of impact on symptoms of IPEX. Official Title.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7688376/

Human‐engineered Treg‐like cells suppress FOXP3‐deficient ... Overall, these data show that human‐engineered CD4LVFOXP3 cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo, providing a ...

3. nyaspubs.onlinelibrary.wiley.com nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111%2Fnyas.13011

From IPEX syndrome to FOXP3 mutation: a lesson on immune ... IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus- ...

4. isct-cytotherapy.org isct-cytotherapy.org/article/S1465-3249(19)30728-5/fulltext

towards the proof-of-concept application in IPEX syndrome CD4LV-FOXP3 T cells can significantly extend the survival of xeno GVHD model mice, both in autologous and allogenic conditions and they can suppress xeno GVHD ...

5. cell.com cell.com/cell-stem-cell/fulltext/S1934-5909(18)30593-9

Lentiviral Gene Therapy in HSCs Restores Lineage ... ... FoxP3 LV or from the FoxP3-Tg mouse) has negative outcomes. FoxP3-Tg mice were reported to be viable, had normal thymocyte development, and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33304583/

Human-engineered Treg-like cells suppress FOXP3 ... Conclusion: These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune-mediated diseases caused by ...

7. jacionline.org jacionline.org/article/S0091-6749(23)01512-9/fulltext

IPEX syndrome from diagnosis to cure, learning along the ... The data showed that FOXP3 mutation was concordant with increased TSDR ... (CD4LVFOXP3) isolated from patients with IPEX syndrome. The ...

8. clinicaltrial.be clinicaltrial.be/en/details/32711?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

CD4^LVFOXP3 in Participants With IPEX That CD4^LVFOXP3 are safe in children and young adults with IPEX, and determine its effects, both good and bad,; That CD4^LVFOXP3 can improve ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4443799/

Gene/Cell Therapy Approaches for Immune Dysregulation ... Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches.