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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for sickle cell disease and beta thalassemia using a specific type of stem cell transplant. The treatment removes certain immune cells from donor stem cells to improve management of these conditions. Specifically, it employs TCRαβ+ T cell and CD19+ B cell depletion, facilitated by the CliniMACS system. This trial targets individuals with severe sickle cell disease who experience frequent pain episodes or require regular blood transfusions, as well as those with beta thalassemia needing frequent transfusions. Stem cells from closely matched unrelated donors are used. As an unphased trial, this study presents a unique opportunity to contribute to groundbreaking research that could lead to new treatment options.

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 prior data suggests that this method is safe for patients with sickle cell disease and beta thalassemia?

Research has shown that a specific process used in stem cell transplants for sickle cell disease and beta thalassemia is generally safe. This process reduces the risk of graft-versus-host disease (GVHD), a common complication where donor cells attack the recipient’s body. Patients with these conditions have tolerated this approach well, experiencing only minor side effects after the transplant. Studies also support its safety and effectiveness, making it a viable option for these diseases. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the use of stem cell transplants with TCRαβ and CD19+ B cell depletion for treating Sickle Cell Disease (SCD) and Beta Thalassemia because these treatments offer a targeted approach to improve outcomes. Unlike traditional treatments, such as regular blood transfusions and iron chelation therapy for Beta Thalassemia or hydroxyurea and pain management for SCD, this method uses hematopoietic stem cells from closely matched donors, which are carefully depleted of certain immune cells. This depletion reduces the risk of graft-versus-host disease, a common complication in transplants. By focusing on the immune cell types involved, this approach has the potential to be safer and more effective, offering hope for a more permanent solution to these challenging conditions.

What evidence suggests that this trial's treatments could be effective for sickle cell disease and beta thalassemia?

This trial will evaluate the CliniMACS system's use in removing specific immune cells from stem cell transplants for treating sickle cell disease (SCD) and beta thalassemia major (BTM). Participants with SCD will receive transplants using TCRαβ and B cell depleted peripheral blood stem cells. Studies have shown that this approach can lead to better outcomes with a lower risk of graft-versus-host disease (GVHD), a common transplant complication. Participants with BTM will also receive these specialized transplants, which aid in the recovery of healthy stem cells, crucial for successful treatment. These findings suggest improved disease control and overall survival for both conditions, highlighting the promise of targeting specific immune cells to enhance patient outcomes. ^{2 6 7 8 9}

Who Is on the Research Team?

Timothy Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

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clinicaltrials.gov

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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 ...

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pmc.ncbi.nlm.nih.gov/articles/PMC6944939/

Depletion of αβ+ T and B Cells Using the CliniMACS Prodigy

Overall, we found the TCRαβ and CD19 depletion procedure on the CliniMACS Prodigy easy to handle and reliable, providing reproducible good ...

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Profound depletion of TCRαβ(+) T cells can be achieved with the CliniMACS system. Recovery of CD34(+) stem cells is in the same range than after CD34(+) ...

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researchgate.net/publication/256329960_Depletion_of_T-cell_receptor_alphabeta_and_CD19_positive_cells_from_apheresis_products_with_the_CliniMACS_device

Depletion of T-cell receptor alpha/beta and CD19 positive ...

Profound depletion of TCRαβ(+) T cells can be achieved with the CliniMACS system. Recovery of CD34(+) stem cells is in the same range than after ...

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

T-cell receptor αβ+ and CD19+ cell–depleted ...

The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12061755/

αß T-cell depleted haploidentical stem cell transplantation ...

Here, we report the outcome of 20 TDT patients receiving a T-depleted haplo-HSCT (mostly TCRαβ/CD19+) compared to a MSD HSCT to determine the ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8702395/

Results of a multicenter phase I/II trial of TCRαβ and CD19- ...

The median log depletion of TCRαβ+ T-cells and CD19+ B cells was 4.7 (range 3.6–5.3) and 3.4 (range 2.3–4.5), respectively (Fig. 1). The ...

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clinicaltrials.gov/study/NCT05968170

TCRαβ/CD19 Depletion of Stem Cell Grafts for Transplant

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(PDF) αß T-cell depleted haploidentical stem ...

PDF | Life expectancy of patients with severe transfusion-dependent beta-thalassemia (TDT) remains below that of the general population.