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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a double lung transplant followed by a special type of stem cell transplant (CD3/CD19 negative allogeneic hematopoietic stem cells) can benefit individuals with primary immunodeficiency and severe lung disease. The treatment uses stem cells from a partially matched donor to assess improvements in lung function and overall health. Ideal participants have a known primary immunodeficiency and serious lung issues that qualify them for a lung transplant. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this innovative treatment.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that using specially prepared stem cells from donors is generally safe for patients with primary immunodeficiency (PID). Studies have demonstrated that children with severe PIDs have been successfully treated with this type of stem cell transplant, which has become a main treatment for many with these conditions. A large review of 58 studies involving 7,931 patients found a high overall survival rate after similar stem cell treatments.

The stem cells used in this study are carefully prepared to reduce the risk of immune system problems by removing certain cells (CD3/CD19) that might cause harm, using a system called CliniMACS®.

Overall, these findings suggest that the treatment is well-tolerated in people with conditions similar to those in this study. However, since this is a Phase 1/2 trial, it is the first time this specific treatment combination is being tested on humans, so there may still be unknown risks. Participants will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about using CD3/CD19 negative allogeneic hematopoietic stem cells for treating immunodeficiency because this approach offers a novel way to reconstitute a patient's immune system. Unlike traditional treatments that generally rely on medication to manage symptoms, this method involves a stem cell transplant from a partially HLA-matched cadaveric donor, which could potentially offer a more permanent solution by rebuilding the immune system itself. Additionally, the use of a CliniMACS® depletion device to remove specific cell types (CD3/CD19) from donor marrow minimizes the risk of graft-versus-host disease, a common complication of stem cell transplants. This innovative approach could significantly improve outcomes for patients with immunodeficiency disorders.

What evidence suggests that this treatment might be an effective treatment for primary immunodeficiency?

Research has shown that using donor stem cells to treat primary immunodeficiencies (PIDs) has been successful. Studies with children who have severe PIDs have demonstrated good results with this treatment. A large review of 58 studies found that 94% of patients who received this treatment survived. In this trial, participants will receive CD3/CD19 negative allogeneic hematopoietic stem cells. These cells replace faulty immune system cells with healthy ones from a donor, helping the body fight infections more effectively. The use of specific donor cells aims to reduce complications by removing certain immune cells that might cause problems. ^{1 3 6 7 8}

Who Is on the Research Team?

Paul Szabolcs, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6225386/

Successful outcome following allogeneic hematopoietic ... Children with severe PIDs have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT), which has been the major therapeutic ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666636725014472

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell ... The meta-analysis of 58 studies (n = 7931) revealed allo-HSCT to have 94%, 86%, 20%, 14%, 9%, and 6% for overall survival (OS), event-free ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05968170

TCRαβ/CD19 Depletion of Stem Cell Grafts for Transplant Outcome of allogeneic hematopoietic stem cell transplant recipients admitted to the intensive care unit with a focus on haploidentical graft and sequential ...

4. haematologica.org haematologica.org/article/view/5609/25823

Long-term immune deficiency after allogeneic stem cell ... This new study considers these clinical and biological advances in a reassessment of long-term immune deficiency after allogeneic hematopoietic stem cell ...

5. jacionline.org jacionline.org/article/S0091-6749%2817%2931202-2/abstract

T-cell receptor αβ + and CD19 + cell–depleted ... Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01852370

Sequential Cadaveric Lung and Bone Marrow Transplant ... Negative selection for CD3/CD19 will be performed on a CliniMACS® depletion device within 36 hours of collection and given at time no less than 8 weeks post ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9534375/

The safety and short‐term outcomes of allogeneic ... The safety and short‐term outcomes of allogeneic hematopoietic stem cell transplantation with donor vaccination for COVID‐19

8. astctjournal.org astctjournal.org/article/S1083-8791(07)00383-7/fulltext

Allogeneic Hematopoietic Stem Cell Transplant Using ... Preliminary data has demonstrated the potential for use of adoptive cellular immunity and selective allodepletion in rapidly reconstituting immunity without ...