Stem Cell Transplant for Immunodeficiency

(BOLT+BMT Trial)

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Paul Szabolcs

Must not be taking: Live vaccines

Disqualifiers: Malignant conditions, HIV, Uncontrolled infections, others

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

Compensation: Varies

Number of Visits: Unknown

16 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment CD3/CD19 negative allogeneic hematopoietic stem cells for immunodeficiency?

Research shows that hematopoietic stem cell transplantation (HSCT) can cure severe combined immunodeficiency (SCID) by restoring immune cell function, with studies indicating long-term survival and improved quality of life for many patients. Additionally, specific conditioning regimens before transplantation can enhance immune recovery and reduce the need for ongoing treatments. ^{1 2 3 4 5}

Is stem cell transplant for immunodeficiency generally safe in humans?

Stem cell transplants, including those using TCRαβ/CD19-depleted grafts, have been shown to prevent severe complications like graft-versus-host disease in patients with immunodeficiencies. While there are risks of infections and other complications, no severe adverse events were reported in the studies, and long-term survival rates are promising, especially with proper conditioning and donor matching. ^{4 5 6 7 8}

How is the CD3/CD19 negative allogeneic hematopoietic stem cell treatment different from other treatments for immunodeficiency?

This treatment uses CD3/CD19 negative allogeneic hematopoietic stem cells, which are unique because they are specifically selected to lack certain immune cells (CD3 and CD19) that can cause complications. This approach may reduce the risk of graft-versus-host disease (a condition where the donor cells attack the recipient's body) compared to traditional stem cell transplants. ^{3 9 10 11 12}

What is the purpose of this trial?

This study is evaluating whether a lung transplant followed by a stem cell transplant is safe and effective for people with primary immunodeficiency.

Research Team

Paul Szabolcs, MD

Principal Investigator

Division of BMT and Cellular Therapy, Children's Hospital of Pittsburgh of UPMC

Eligibility Criteria

This trial is for people aged 5-45 with primary immunodeficiency and severe lung disease needing a lung transplant. They must have normal liver function, heart function, kidney function, not be pregnant or HIV positive, and agree to birth control post-transplant.

Inclusion Criteria

My kidney function is good.

Your liver enzymes (AST, ALT) and bilirubin levels are within a certain range, and your blood clotting time is normal.

I am between 5 and 45 years old.

Exclusion Criteria

I do not have an uncontrolled lung infection.

Past or current medical problems or findings from physical examination or laboratory testing that may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

You have tested positive for HIV or HTLV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lung Transplantation

Participants undergo bilateral orthotopic lung transplantation (BOLT) from a partially HLA-matched cadaveric donor

4-6 weeks

Multiple visits for surgery and post-operative care

Hematopoietic Stem Cell Transplantation (HSCT)

Participants receive CD3+/CD19+-depleted hematopoietic stem cell transplantation from the same donor

4-8 weeks

Frequent visits for transplantation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after stem cell transplantation

Up to 2 years

Regular visits for monitoring graft function and immune status

Treatment Details

Interventions

• CD3/CD19 negative allogeneic hematopoietic stem cells

Trial Overview The study tests if getting new lungs (BOLT) followed by stem cell transplant from a partially-matched donor is safe/effective for immune deficiency diseases. Participants receive CD3/CD19 negative allogeneic hematopoietic stem cells.

Participant Groups

Group I: BOLT+BMT Experimental Treatment 1 Intervention

All patients will receive a double lung transplant followed by a hematopoietic stem cell transplant. The lungs and stem cells are from the same partially HLA-matched cadaveric donor. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device.

Who Is Running the Clinical Trial?

Paul Szabolcs

Lead Sponsor

Trials

8

Recruited

230+

Findings from Research

In patients with severe combined immunodeficiency (SCID) due to RAG or ARTEMIS mutations, using myeloablative conditioning during allogeneic hematopoietic stem cell transplantation (HSCT) significantly increases the likelihood of achieving full immunologic recovery.

For ARTEMIS patients, the use of alkylating chemotherapy agents during treatment is linked to a higher risk of nonimmunologic complications, highlighting the need for safer conditioning strategies or gene therapy to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tearing RAGs apart. Gaspar, HB.[2021]

In a study of 44 patients with severe combined immunodeficiency (SCID) who underwent hematopoietic stem cell transplantation (HSCT), most patients showed normal immune reconstitution, with over 90% achieving normal CD3 counts and 72.7% able to stop intravenous immunoglobulin (IVIG) therapy after HSCT.

Bone marrow transplantation resulted in significantly lower rates of acute graft-versus-host disease (GVHD) compared to peripheral stem cell transplantation, suggesting that bone marrow may be the preferred source for HSCT in SCID patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long Term Follow-Up of the Patients with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation: A Single-Center Study. Demirtas, D., Cagdas, D., Turul Ozgur, T., et al.[2022]

Allogeneic hematopoietic stem cell transplantation is an effective curative treatment for various primary immunodeficiencies, including both well-known and newly identified conditions.

The article highlights the challenges in establishing a universal transplant regimen due to the rarity and diverse pathophysiology of these immunodeficiencies, emphasizing the need for tailored approaches in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation for primary immunodeficiencies. Kang, E., Gennery, A.[2019]

In a study of 52 infants with severe combined immunodeficiency (SCID) who underwent various types of stem cell transplants, TCRαβ-HaploSCT showed a 3-year overall survival rate of 91%, comparable to other donor types, indicating its effectiveness as a treatment option for infants without a matched donor.

Conditioned transplants (using fludarabine/treosulfan) resulted in significantly higher myeloid chimerism and a greater proportion of long-term survivors who were free from immunoglobulin dependency, highlighting the benefits of conditioning in improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCRαβ-Depleted Haploidentical Grafts Are a Safe Alternative to HLA-Matched Unrelated Donor Stem Cell Transplants for Infants with Severe Combined Immunodeficiency. Tsilifis, C., Lum, SH., Nademi, Z., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Tearing RAGs apart. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Long Term Follow-Up of the Patients with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation: A Single-Center Study. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation for primary immunodeficiencies. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Long-term outcome of hematopoietic stem cell transplantation for IL2RG/JAK3 SCID: a cohort report. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Post-Transplantation Immunosuppression After TCRΑβ/CD19 Graft Depletion Does Not Improve HSCT Outcomes in Primary Immunodeficiency. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

TCRαβ-Depleted Haploidentical Grafts Are a Safe Alternative to HLA-Matched Unrelated Donor Stem Cell Transplants for Infants with Severe Combined Immunodeficiency. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia. [2011]

10. United States pubmed.ncbi.nlm.nih.gov

Minimal dose of hematopoietic stem cell transplantation without myelosuppressive conditioning for T-B+NK- severe combined immunodeficiency. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? [2010]

12. England pubmed.ncbi.nlm.nih.gov

Stem cell transplantation for congenital immunodeficiencies using reduced-intensity conditioning. [2005]