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

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age.

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.

What data supports the idea that Cell Depletion using CliniMACS for Primary Immunodeficiencies is an effective treatment?

The available research shows that Cell Depletion using CliniMACS is effective in reducing the risk of graft-versus-host disease (GvHD) in patients undergoing stem cell transplantation for severe combined immunodeficiency (SCID). This treatment involves removing specific immune cells that can cause complications, leading to better outcomes. Compared to other methods, the CliniMACS system provides higher purity and recovery of necessary cells, which is crucial for successful transplantation. Additionally, it has been shown to facilitate satisfactory transplant outcomes by reducing harmful immune reactions. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment using CliniMACS for primary immunodeficiencies?

The CliniMACS system has been shown to effectively deplete specific immune cells, such as TCRαβ+ T cells and B cells, which helps reduce the risk of graft-versus-host disease (a condition where transplanted cells attack the recipient's body) in stem cell transplants. This method has been used successfully in treating severe combined immunodeficiency and other conditions, demonstrating its potential to improve transplant outcomes by reducing complications. ^{1 2 3 4 5}

What safety data exists for cell depletion using CliniMACS for primary immunodeficiencies?

The safety data for cell depletion using CliniMACS, including TCRαβ/CD19 depletion, indicates that it is an effective method for reducing the risk of graft-versus-host disease (GvHD) in haploidentical hematopoietic stem cell transplantation. Studies have shown that this method can efficiently deplete T and B cells without adversely affecting the biological function of hematopoietic stem cells. In children with acute myeloid leukemia, TCRαβ and CD19 depletion has been associated with a 100% primary engraftment rate, a 39% incidence of acute GvHD, and a 30% incidence of chronic GvHD. Transplant-related mortality was reported at 10%, with event-free survival at 60% and overall survival at 67% at two years. These findings suggest that the CliniMACS system is a robust and safe method for graft manipulation in clinical settings. ^{1 2 3 6 7}

Is the CliniMACS cell depletion method safe for humans?

The CliniMACS system, used for depleting specific immune cells from stem cell grafts, has been shown to efficiently reduce the risk of graft-versus-host disease (a condition where transplanted cells attack the recipient's body) without negatively affecting the function of the remaining stem cells. Studies have reported successful outcomes in various conditions, indicating that the procedure is generally safe, though there is a risk of delayed immune recovery and infections. ^{1 2 3 6 7}

Is the treatment Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells a promising treatment?

Yes, the treatment is promising because it helps in successful stem cell transplants by reducing harmful immune cells, which can lead to better outcomes for patients with immune system problems. ^{1 2 3 5 6}

What makes the Alpha/Beta T and CD19+ Depleted Peripheral Stem Cells treatment unique for primary immunodeficiencies?

This treatment is unique because it involves selectively removing specific immune cells (alpha/beta T-cells and CD19+ B-cells) from donor stem cells, which helps reduce the risk of complications like graft-versus-host disease (a condition where donor cells attack the recipient's body) while maintaining the ability to fight infections. It uses an advanced automated system (CliniMACS Prodigy) to efficiently process the cells, making it less labor-intensive compared to older methods. ^{1 2 3 5 6}

Research Team

Timothy S Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. Switzerland 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. [2022]

2. England 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. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Automatic generation of alloreactivity-reduced donor lymphocytes and hematopoietic stem cells from the same mobilized apheresis product. [2023]

4. England 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. [2004]

5. Slovakia 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. [2006]

6. China 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]. [2017]

7. England 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. [2022]