Stem Cell Transplant with TCRab Depletion for Sickle Cell Disease and Beta Thalassemia

Overseen By Timothy Olson, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Investigational drugs

Disqualifiers: Previous HSCT, Pregnancy, Severe alloimmunization, others

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

Compensation: Varies

Number of Visits: Unknown

9 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm pilot study of peripheral stem cell transplantation (PSCT) with ex vivo t-cell receptor alpha beta+(TCRαβ+) T cell and cluster of differentiation 19+ beta (CD19+ B) cell depletion of unrelated donor (URD) grafts using the CliniMACS device in patients with sickle cell disease (SCD) and beta thalassemia major (BTM).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must stop any investigational drugs before starting the transplant therapy.

What data supports the effectiveness of the treatment CliniMACS, TCRαβ+ T cell and CD19+ B cell depletion for Sickle Cell Disease and Beta Thalassemia?

Research shows that using TCRαβ+ and CD19+ cell depletion in stem cell transplants for children with blood disorders like sickle cell disease and beta thalassemia has promising results, with high survival rates and satisfactory immune recovery. This approach has been effective in reducing complications and improving outcomes in these conditions. ^{1 2 3 4 5}

Is the stem cell transplant with TCRab depletion generally safe for humans?

The safety of TCRαβ+ T cell and CD19+ B cell depletion has been evaluated in various studies, showing that while there are risks like graft-versus-host disease (when donor cells attack the recipient's body), these can be managed with specific gene-editing techniques. Clinical trials have demonstrated that these treatments can be safe, with some patients experiencing manageable side effects such as temporary neurotoxicity or skin reactions. ^{6 7 8 9 10}

How does the treatment with TCRαβ+ T cell and CD19+ B cell depletion differ from other treatments for sickle cell disease and beta thalassemia?

This treatment is unique because it uses a specific type of stem cell transplant that removes certain immune cells (TCRαβ+ T cells and CD19+ B cells) to reduce complications like graft-versus-host disease, making it safer for patients who do not have a perfectly matched donor. It offers a promising option for children with sickle cell disease and beta thalassemia, especially when traditional bone marrow transplants are not feasible. ^{1 2 4 11 12}

Research Team

Timothy Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for patients with severe forms of sickle cell disease or beta thalassemia major who have had strokes, frequent pain episodes, or require regular blood transfusions. It's not open to those who've had a previous stem cell transplant, are pregnant, or can't receive blood transfusions due to severe allergies.

Inclusion Criteria

I have had a stroke or lasting neurological issues for more than a day.

My spleen is enlarged and my hemoglobin levels have dropped.

My genetic test confirms I have Beta Thalassemia.

Exclusion Criteria

I have had a stem cell transplant before.

I have stopped any clinical trial treatments before starting transplant therapy.

I cannot receive blood transfusions due to severe reactions to them.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy Conditioning

Participants receive disease-specific chemotherapy-based conditioning regimens prior to hematopoietic stem cell transplantation

2-3 weeks

Transplantation

Peripheral stem cell transplantation with TCRαβ+ T cell and CD19+ B cell depletion of unrelated donor grafts

1 week

Follow-up

Participants are monitored for safety and effectiveness after transplantation, including assessments for engraftment, GvHD, and survival outcomes

1 year

Long-term Follow-up

Participants are monitored for chronic GvHD and long-term survival outcomes

Up to 3 years

Treatment Details

Interventions

• CliniMACS
• TCRαβ+ T cell and CD19+ B cell depletion

Trial Overview The study tests a peripheral stem cell transplantation technique using the CliniMACS device to remove certain T cells and B cells from donor grafts in patients with sickle cell disease and beta thalassemia major.

Participant Groups

Group I: Sickle Cell Disease Experimental Treatment 1 Intervention

Patients with Sickle Cell Disease (SCD) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors.

Group II: Beta Thalassemias Major Experimental Treatment 1 Intervention

Patients with Beta Thalassemias Major (BTM) will be given previously established, disease-specific chemotherapy based conditioning regimens prior to hematopoietic stem cell transplantation using TCRalpha/beta and B cell depleted peripheral blood stem cells from closely matched unrelated donors.

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Timothy Olson

Lead Sponsor

Trials

1

Recruited

9+

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]

Related haploidentical hematopoietic stem cell transplant (HCT) offers a promising alternative for treating sickle cell disease (SCD), expanding the donor pool to about 90% of eligible patients, including adults with significant health issues.

Three emerging haploidentical HCT strategies show potential for curative therapy in SCD, with nonmyeloablative approaches allowing for better tolerance in adults and reducing treatment-related deaths compared to traditional myeloablative methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The range of haploidentical transplant protocols in sickle cell disease: all haplos are not created equally. Kassim, AA., DeBaun, MR.[2023]

In a pilot clinical trial involving 9 patients with relapsed or chemotherapy-refractory B-cell acute lymphocytic leukemia (B-ALL), genetically modified T cells targeting the CD19 antigen showed a 56% overall survival rate at 18 weeks.

The study demonstrated that donor-derived anti-CD19 CAR T cells can lead to significant regression of both hematopoietic and extramedullary B-ALL, although some patients experienced grade 2-3 graft-versus-host disease (GVHD) after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Dai, H., Zhang, W., Li, X., et al.[2021]

CRISPR/Cas9-mediated knockout of the T-cell receptor (TCR) in anti-CD19 CAR T cells significantly reduces the risk of graft-versus-host disease while maintaining strong antileukemic activity against B-precursor acute lymphoblastic leukemia (ALL) in a patient-derived xenograft model.

However, while TCR-KO CAR T cells show high functionality and reduced alloreactivity, the presence of the endogenous TCR enhances the long-term persistence and effectiveness of T cells in controlling leukemia, suggesting a trade-off between safety and durability of response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. Stenger, D., Stief, TA., Kaeuferle, T., et al.[2022]

Allogeneic CAR T therapies, which use T cells from healthy donors, may address the limitations of autologous CAR T therapies, such as long manufacturing times and potential complications.

The study demonstrated that allogeneic BCMA CAR T cells, engineered with gene-editing technology and an off switch for safety, showed sustained antitumor responses in mice, making them a promising candidate for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma. Sommer, C., Boldajipour, B., Kuo, TC., et al.[2020]

References

1. China pubmed.ncbi.nlm.nih.gov

[HLA haploidentical peripheral blood stem cells transplantation for β thalassemia major]. [2019]

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

HLA-haploidentical hematopoietic stem cell transplantation in pediatric patients with hemoglobinopathies: current practice and new approaches. [2022]

3. 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]

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

Bone marrow transplantation for thalassemia from alternative related donors: improved outcomes with a new approach. [2021]

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

The range of haploidentical transplant protocols in sickle cell disease: all haplos are not created equally. [2023]

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

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. [2021]

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

Genome-edited allogeneic donor "universal" chimeric antigen receptor T cells. [2023]

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

Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. [2022]

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

Preclinical Evaluation of Allogeneic CAR T Cells Targeting BCMA for the Treatment of Multiple Myeloma. [2020]

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

Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia. [2023]

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

A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex-mismatched bone marrow transplantation. [2021]

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

Stem cell transplantation and gene therapy for hemoglobinopathies. [2012]