Cell Depletion using CliniMACS for Primary Immunodeficiencies

Overseen By Megan Atkinson

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Uncontrolled infections, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to assist individuals with certain immune system problems. It involves preparing stem cells from donors using a technique called Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells, aiming for improved outcomes in conditions like severe combined immunodeficiencies or Wiskott-Aldrich syndrome. Treatment plans vary based on the specific condition and the individual's treatment tolerance. Suitable candidates for this trial have serious immune system issues that complicate daily life and lack a fully matched family donor. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for this trial?

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

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 trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using specially prepared stem cells in transplants is generally safe. This method reduces the risk of graft-versus-host disease (GVHD), a common issue where donor cells attack the patient's body. The CliniMACS system effectively removes certain immune cells that might cause problems.

Other trials indicate that side effects are manageable. Patients receiving these transplants have demonstrated good results, making this treatment a promising option for those with primary immune system problems. However, like any medical treatment, risks and side effects can occur, so participants should discuss these with their healthcare team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments in this trial because they utilize the CliniMACS device to specifically deplete alpha/beta T and CD19+ peripheral stem cells, which is a novel approach for primary immunodeficiencies. Unlike traditional treatments that might rely heavily on broad immunosuppression or chemotherapy, this method targets specific cell types, potentially reducing the risk of complications and improving outcomes. The use of immunotherapy and different conditioning regimens tailored to patient diagnosis and age, including myeloablative, reduced intensity, and immunotherapy-only options, offers a more personalized treatment that could enhance engraftment success while minimizing side effects.

What evidence suggests that this trial's treatments could be effective for primary immunodeficiencies?

Research has shown that specially prepared stem cells can effectively treat primary immunodeficiencies. In this trial, participants will receive stem cell transplants using the CliniMACS device to deplete alpha/beta T and CD19+ peripheral stem cells. Studies have found that this type of stem cell transplant reduces the risk of graft-versus-host disease, a common complication where donor cells attack the patient's body. The treatment includes high levels of natural killer cells and other important immune cells, which help protect against infections. This approach is considered a practical option for children with various immune system disorders. Overall, early data suggest this method holds promise for improving patient outcomes. ^{1 2 6 7 8}

Who Is on the Research Team?

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for young people (ages 0-25) with severe immune system conditions like SCID, IPEX, XLP, CGD, WAS, and others. Participants need to be in a stable condition without untreated infections or available matched donors. They should have normal organ function and females of childbearing age must not be pregnant.

Inclusion Criteria

I have a disorder where my immune system attacks my body and standard treatments haven't worked.

I have a severe immune system disorder that requires a stem cell transplant.

I can do most activities but may need help.

Exclusion Criteria

I do not have any untreated serious infections.

I have a family member who can donate bone marrow to me.

I have a donor match for a stem cell transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Participants receive a conditioning regimen based on diagnosis and age, which may include reduced intensity, myeloablative, or immunotherapy regimens

1-2 weeks

Stem Cell Infusion

Infusion of alpha/beta T and CD19+ depleted donor peripheral stem cells

1 day

Follow-up

Participants are monitored for stable engraftment, chimerism, and immune reconstitution

1-2 years

What Are the Treatments Tested in This Trial?

Interventions

• Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells
• Cell Depletion using CliniMACS device

Trial Overview The study tests if a less intense treatment before transplanting stem cells that had alpha/beta T-cells and CD19+ cells removed can help the body accept these new cells. The process uses CliniMACS device on stem cell grafts from unrelated or half-matched related donors.

How Is the Trial Designed?

Group I: Reduced intensity regimen Experimental Treatment 1 Intervention

Conditioning regimen is dependent on patient diagnosis and age. Reduced intensity conditioning with chemotherapy followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Standard of care reduced intensity conditioning will include Busulfan, Fludarabine, Thiotepa followed by stem cell infusion.

Group II: Myeloablative regimen Experimental Treatment 1 Intervention

Conditioning regimen is dependent on patient diagnosis and age. Patients with chronic granulomatous disease or Wiskott-Aldrich syndrome will receive cyclophosphamide in lieu of thiotepa to ensure engraftment. Myeloablative regimen with chemotherapy followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Standard of care myeloablative regimen will include Busulfan, Fludarabine, Thiotepa, or Cyclophosphamide followed by stem cell infusion.

Group III: Immunotherapy Experimental Treatment 1 Intervention

Conditioning regimen is dependent on patient diagnosis and age. Severe combined immunodeficiency (SCID) patients will be conditioned with immunotherapy only followed by stem cell transplant using the CliniMACs device to deplete alpha/beta T and CD19+ peripheral stem cells. Immunotherapy regimen will include anti-thymocyte globulin followed by stem cell infusion.

Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells is already approved in European Union, United States for the following indications:

Approved in European Union as TCRαβ/CD19-depleted allogeneic hematopoietic progenitor cells for:

• Primary immunodeficiencies
• Nonmalignant diseases
• Hematological malignancies

Approved in United States as Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells for:

• Primary immunodeficiencies
• Nonmalignant diseases
• Hematological malignancies

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

The CliniMACS Prodigy® system successfully performed TCRαβ+ T cell and B cell depletion in ten haploidentical stem cell transplants, achieving a median log reduction of TCRαβ+ cells of -4.21, indicating effective cell removal.

The procedure demonstrated reliability and ease of use, with a median CD34 recovery of 83%, although B cell depletion was slightly less efficient with a median log reduction of -3.72.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depletion of αβ+ T and B Cells Using the CliniMACS Prodigy: Results of 10 Graft-Processing Procedures from Haploidentical Donors. Haastrup, E., Ifversen, MRS., Heilmann, C., et al.[2022]

A novel treatment for severe combined immunodeficiency (SCID) using haploidentical hematopoietic stem cell transplantation (HSCT) with selective depletion of GvHD-inducing T-cells showed rapid engraftment and no signs of graft-versus-host disease (GvHD) in a 9-month-old patient.

The addition of donor lymphocyte infusion (DLI) enriched with memory T-cells effectively enhanced the patient's antiviral immunity, leading to increased T-cell counts and clearance of severe viral infections without causing GvHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. Brodszki, N., Turkiewicz, D., Toporski, J., et al.[2018]

A new automated process using the CliniMACS Prodigy successfully depletes alloreactive T cells from hematopoietic stem cell grafts, achieving a high depletion efficiency of 4 log for both CD45RA+ and TCRαβ/CD19+ cells with minimal manual intervention.

The resulting products maintain a high viability of over 90% for stem cells and retain important immune cells like TCRγδ+ and NK cells, which are crucial for immunological surveillance, making them suitable for haplo-identical hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automatic generation of alloreactivity-reduced donor lymphocytes and hematopoietic stem cells from the same mobilized apheresis product. Wiercinska, E., Quade-Lyssy, P., Hümmer, C., et al.[2023]

The study successfully demonstrated the simultaneous depletion of T and B cells from mobilized peripheral blood stem cells (PBSCs) using the CliniMACS device, achieving a T cell depletion efficiency of 99.98% and B cell depletion of over 99.99%.

Importantly, the depletion process did not adversely affect the function of the remaining hematopoietic stem cells, maintaining a high recovery rate of CD34(+) cells and NK cells, which is crucial for the success of haploidentical stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An effective method for T-cell and B-cell simultaneous depletion in vitro from mobilized peripheral blood stem/progenitor cell graft for haploidentical transplantation]. Xiao, J., Li, HH., Jin, XS., et al.[2017]

The study evaluated two methods for T cell depletion in peripheral blood stem cell grafts, finding that the CliniMACS system provided higher purity (94.87%) and recovery (58%) of CD34+ cells compared to the CellPro system, which had a purity of 85.6% and recovery of 24.8%.

Both methods are deemed suitable for preparing stem cell grafts for mismatched transplants in patients with severe hematological disorders and for autologous transplants in autoimmune diseases, but the CliniMACS system is preferred due to its superior efficiency in T cell removal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of two different methods for CD34+ selection and T cell depletion in peripheral blood stem cell grafts--our experiences with CellPro, E rosetting and CliniMACS technique. Poloucková, A., Vodvárková, A., Kobylka, P., et al.[2006]

In a study involving 33 children with high-risk acute myeloid leukemia (AML) who received TCR-alpha/beta and CD19-depleted grafts, primary engraftment was achieved in all patients, indicating the effectiveness of this graft manipulation method.

The cumulative incidence of acute graft-versus-host disease (aGvHD) was 39%, with a 10% transplant-related mortality rate, while the overall survival rate at 2 years was 67%, suggesting that this approach is both safe and effective for improving outcomes in pediatric AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Maschan, M., Shelikhova, L., Ilushina, M., et al.[2022]

A child with X-linked severe combined immunodeficiency successfully underwent haploidentical peripheral blood stem cell transplantation, which is crucial for survival as this condition is rapidly fatal without treatment.

The transplantation utilized a novel method of selecting and depleting T cells from CD34-positive cells, achieving a significant T cell depletion of 4.2 log, which reduces the risk of graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical peripheral blood stem cell transplantation with a combination of CD34 selection and T cell depletion as graft-versus-host disease prophylaxis in a patient with severe combined immunodeficiency. Martín-Hernández, MP., Arrieta, R., Martínez, A., et al.[2004]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05800210

NCT05800210 | Alpha/Beta T Cell and CD19+ B ... This study will assess the safety, efficacy, and feasibility of ⍺/β CD3+ T-cell and CD19+ B-cell depletion in allogeneic stem cell transplantation in ...

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

T-cell receptor αβ+ and CD19+ cell–depleted ... CD3+TCRαβ+ and CD19+ cell–depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs. Key words. Primary ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28780238/

T-cell receptor αβ + and CD19 + cell-depleted ... CD3 + TCRαβ + and CD19 + cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.

4. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/tcr-alpha-beta-cd19-depleted-allogeneic-hematopoietic-progenitor-cells

TCR alpha/beta/CD19-depleted allogeneic hematopoietic ... The TCR alpha/beta/CD19-depleted HPCs contain high amounts of natural killer (NK) cells, gamma/delta T cells, CD34+ stem cells, monocytes, and dendritic cells ( ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6856988/

Mismatched related vs matched unrelated donors in ... TCRαβ+/CD19+ graft depletion effectively prevents graft-versus-host disease (GVHD). In the current study, we compared the outcomes of hematopoietic stem cell ...

6. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/tcr-alpha-beta-cd19-depleted-allogeneic-hematopoietic-progenitor-cells?pn=1

Clinical Trials Using TCR alpha/beta/CD19-depleted ... Review the clinical trials studying tcr alpha/beta/cd19-depleted allogeneic hematopoietic progenitor cells on this list and use the filters to refine the ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497124011625

Outcomes of HLA-mismatched HSCT with TCRαβ/CD19 ... This study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes.

8. researchgate.net researchgate.net/publication/318887354_TCRab_and_CD19_cell_depleted_Haploidentical_and_Mismatched_Hematopoietic_Stem_Cell_Transplantation_in_Primary_Immune_Deficiency?_tp=eyJjb250ZXh0Ijp7InBhZ2UiOiJzY2llbnRpZmljQ29udHJpYnV0aW9ucyIsInByZXZpb3VzUGFnZSI6bnVsbH19

TCRαβ+ and CD19+ cell depleted Haploidentical and ... Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs).