Treg-Enriched Stem Cell Transplant for Leukemia

Overseen By John Koreth, MBBS, DPhil

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Antiretrovirals, Investigational agents

Disqualifiers: HIV, Hepatitis B/C, Psychiatric illness, others

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

Compensation: Varies

Number of Visits: 30

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is evaluating the safety and efficacy of the IS-free Treg-cell graft-engineered haplo transplant method in people with relapsed/refractory and Ultra-high risk acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) receiving a haploidentical donor allogeneic hematopoietic stem cell transplant (HSCT). The names of the study interventions involved in this study are: * Radiation-Total Myeloid and Lymphoid Irradiation (TMLI * Chemotherapy (Fludarabine, Thiotepa, Cyclophosphamide plus Mesna) * Infusion of haplo Treg-enriched donor cells (experimental therapy) * Infusion of unmodified haplo donor T cells (includes cancer-fighting T effector cells) * Infusion of haplo donor CD34+ Peripheral Blood Stem Cells

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications, but it mentions that you must avoid certain medications that interact with specific enzymes during a specific period (day -10 through day -5). It's best to discuss your current medications with the study team to ensure they don't interfere with the trial.

What data supports the effectiveness of the Treg-Enriched Stem Cell Transplant for Leukemia treatment?

Research shows that using fludarabine and thiotepa as part of a conditioning regimen can lead to successful engraftment and stable donor chimerism in patients, even those who are poor candidates for conventional treatments. Additionally, cyclophosphamide has been shown to enhance anti-tumor effects by reducing regulatory T cells, which may contribute to the effectiveness of the treatment. ^{1 2 3 4 5}

Is the Treg-Enriched Stem Cell Transplant for Leukemia generally safe for humans?

Research indicates that the combination of thiotepa and fludarabine, used in conditioning regimens for stem cell transplants, is generally well tolerated, with some studies reporting no major toxicity. However, other studies have noted regimen-related toxicity, including delayed pulmonary toxicity and graft-versus-host disease, which can be serious. Safety outcomes can vary based on the specific regimen and patient condition. ^{2 3 4 6 7}

What makes the Treg-Enriched Stem Cell Transplant for Leukemia treatment unique?

This treatment is unique because it combines Treg-enriched donor cells with traditional chemotherapy and radiation to enhance immune regulation and reduce complications like graft-versus-host disease (GVHD). The use of regulatory T cells (Tregs) is a novel approach that aims to improve the safety and effectiveness of stem cell transplants by promoting immune tolerance and reducing harmful immune responses. ^{4 8 9 10 11}

Research Team

John Koreth, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults aged 18-65 with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), who have a compatible family donor, can join this trial. Participants need good heart, lung, and kidney function and must not be pregnant or breastfeeding. They should agree to use contraception during the study.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

My liver function tests are within normal range, except for bilirubin which may be high due to Gilbert's Syndrome.

Pulmonary Function: FEV1, FVC and DLCO ≥ 60% of predicted (corrected for hemoglobin)

Exclusion Criteria

I do not have any uncontrolled infections.

I do not have hepatitis B or C.

I do not have cancer in areas like the brain, eyes, or testes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation and Chemotherapy

Participants receive Total Myeloid and Lymphoid Irradiation (TMLI) and chemotherapy with Fludarabine, Thiotepa, Cyclophosphamide, and Mesna as a preparatory regimen

10 days

Daily visits for radiation and chemotherapy administration

Transplantation

Participants receive Treg-enriched donor cell infusion, unmodified donor T Cell infusion, and CD34+ Haplo Peripheral Blood Stem Cell Infusion

5 days

Daily visits for cell infusions and GVHD assessments

Follow-up

Participants are monitored for safety and effectiveness, including assessments of minimal residual disease (MRD) and graft vs host disease (GVHD)

12 months

Visits on days 30, 60, 100, 180, and 365 post-transplant

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• Radiation
• Thiotepa
• Treg-enriched donor cell
• Unmodified donor T Cell

Trial Overview The trial is testing an experimental stem cell transplant method using radiation, chemotherapy (Fludarabine, Thiotepa, Cyclophosphamide plus Mesna), and infusions of Treg-enriched donor cells along with unmodified haplo donor T cells and CD34+ Peripheral Blood Stem Cells in patients with AML/MDS.

Participant Groups

Group I: IS-FREE TREG CRAFT_ENGINEERED HaploHCT for relapsed/refractory AML or MDS EB-2 (Closed to Accrual) Experimental Treatment 8 Interventions

Please note that this arm is closed due to meeting accrual goal as of June 2024. After meeting eligibility criteria and being enrolled, patients will receive: Day -15 to -6 prior to hematopoietic stem cell transplant (HSCT), preparatory regimen of radiation and chemotherapy: Total Myeloid and Lymphoid Irradiation (TMLI): Days -15 to -11 prior to HSCT; - Chemotherapy (infusion): Day -10 to day -6 prior to HSCT: Fludarabine (all days), Thiotepa (days -10 and -9) and Cyclophosphamide and Mesna (days -8 and -7) Day -4 prior to (HSCT), a Treg-enriched donor cell infusion and graft vs host disease (GVHD) assessment Day -1 prior to (HSCT), a unmodified donor T Cell infusion and (GVHD) assessment Day of (day 0) (HSCT), CD34+ Haplo Peripheral Blood Stem Cell Infusion/Transplant and (GVHD) assessment Days 30, 60,100, 180, 365 post hematopoietic stem cell transplant (HSCT), participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD)

Group II: IS-FREE TREG CRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with mutated TP53 Experimental Treatment 8 Interventions

After meeting eligibility criteria and being enrolled, patients will receive: Day -15 to -6 prior to hematopoietic stem cell transplant (HSCT), preparatory regimen of radiation and chemotherapy: Total Myeloid and Lymphoid Irradiation (TMLI): Days -15 to -11 prior to HSCT; - Chemotherapy (infusion): Day -10 to day -6 prior to HSCT: Fludarabine (all days), Thiotepa (days -10 and -9) and Cyclophosphamide and Mesna (days -8 and -7) Day -4 prior to (HSCT), a Treg-enriched donor cell infusion and graft vs host disease (GVHD) assessment Day -1 prior to (HSCT), a unmodified donor T Cell infusion and (GVHD) assessment Day of (day 0) (HSCT), CD34+ Haplo Peripheral Blood Stem Cell Infusion/Transplant and (GVHD) assessment Days 30, 60,100, 180, 365 post hematopoietic stem cell transplant (HSCT), participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD)

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Findings from Research

In a study using a nonmyeloablative stem cell transplantation model in mice, cyclophosphamide treatment led to a significant reduction in regulatory T cells (Tregs), which was linked to enhanced anti-tumor activity against bladder tumors.

The reduction of Tregs allowed for the expansion of donor T cells that produced IFN-γ, contributing to the effective graft versus tumor (GVT) response, suggesting that manipulating Treg levels can improve outcomes in cancer treatments involving stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti-tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice. Takeuchi, A., Eto, M., Yamada, H., et al.[2016]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a study of 30 patients undergoing matched sibling or alternative donor transplantation with a conditioning regimen of fludarabine, thiotepa, and total body irradiation, most patients achieved prompt engraftment, but there were significant complications, including regimen-related toxicity leading to 18 deaths.

The 12-month progression-free survival rates were 47% for HLA-identical sibling transplants and 30% for all patients, but due to high rates of complications and relapses, the researchers decided to discontinue this conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. van Besien, K., Devine, S., Wickrema, A., et al.[2013]

The new conditioning regimen using thiotepa and fludarabine (TT-FLUDA) was well tolerated in six patients undergoing allogeneic bone marrow transplantation, with successful engraftment and stable donor chimerism in most cases.

Despite the patients being poor candidates for standard treatments, the TT-FLUDA regimen showed no major toxicity, although one patient died from acute graft-versus-host disease (GVHD), indicating a need for careful monitoring of GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Alessandrino, EP., Bernasconi, P., Colombo, AA., et al.[2019]

Nonmyeloablative conditioning with total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS), combined with cyclophosphamide (CTX), significantly enhances the recovery of immune cells that promote tolerance after bone marrow transplantation (BMT), improving outcomes in a preclinical model of graft-versus-host disease (GVHD).

The addition of CTX to TLI/ATS conditioning leads to better survival rates and reduced GVHD symptoms, as it increases the presence of myeloid-derived suppressor cells (MDSCs) and myeloid dendritic cells (MDCs), which are crucial for enhancing donor regulatory T cell recovery and promoting immune tolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-thalassemia. E, S., Seth, A., Vogel, P., et al.[2021]

Allogeneic hematopoietic stem cell transplantation (alloSCT) can potentially cure many blood and immune diseases, but it faces challenges like toxicity and the difficulty of finding compatible donors.

Recent advancements using high-dose post-transplantation cyclophosphamide (PT/Cy) allow for successful transplants from partially HLA-mismatched donors, reducing the risks of graft rejection and severe complications like graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Luznik, L., O'Donnell, PV., Fuchs, EJ.[2021]

Thiotepa (TT) significantly depletes early stem cell clones but spares more primitive stem cells, indicating its selective hematological toxicity, which was assessed in a study using various stem cell subsets in bone marrow transplant models.

When combined with total body irradiation (TBI), TT dramatically improves donor engraftment in allogeneic bone marrow transplants by preventing allograft rejection, suggesting its effectiveness is due to immune suppression rather than toxicity to host stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa improves allogeneic bone marrow engraftment without enhancing stem cell depletion in irradiated mice. Down, JD., Westerhof, GR., Boudewijn, A., et al.[2013]

Post-transplantation cyclophosphamide (PTCy) significantly reduces the incidence and severity of graft-versus-host disease (GVHD) by impairing and suppressing alloreactive T cells, making it a safer option for allogeneic hematopoietic cell transplantation (HCT).

In a murine model, PTCy was found to uniquely reduce the proliferation and activation of alloreactive CD4+ T cells while promoting the recovery of regulatory T cells, indicating its superior efficacy in preventing GVHD compared to other chemotherapeutics like methotrexate and cytarabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation. Hadjis, AD., Nunes, NS., Khan, SM., et al.[2022]

Regulatory T cells (Tregs) are crucial in managing tumor immunity and responses in clinical transplantation, showing promise in adoptive immunotherapy.

Initial clinical studies using Tregs in allogeneic stem cell transplantation have shown encouraging results, suggesting their potential for broader applications in cancer treatment and immune regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory T cells in allogeneic stem cell transplantation. Michael, M., Shimoni, A., Nagler, A.[2021]

In a study comparing 30 patients receiving post-transplant cyclophosphamide (PTCY) and 15 patients receiving anti-thymocyte globulin (ATG) for GVHD prophylaxis after stem cell transplantation, PTCY was associated with delayed platelet recovery but showed higher donor chimerism and lower reactivations of certain viruses like EBV.

The immune reconstitution differed significantly between the two groups, with PTCY leading to higher counts of CD4+ T-cells, Tregs, and α/β T-cells, especially in haplo-identical donor scenarios, while ATG resulted in higher NK cell and monocyte counts, indicating distinct immunological effects of these prophylactic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact on early outcomes and immune reconstitution of high-dose post-transplant cyclophosphamide vs anti-thymocyte globulin after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation. Retière, C., Willem, C., Guillaume, T., et al.[2019]

MHC-mismatched stem cells can successfully engraft in leukemia treatment after nonmyeloablative conditioning with fludarabine and low-dose total body irradiation, reducing the risk of graft rejection and graft-versus-host disease (GVHD).

The study demonstrated that pretransplantation fludarabine and posttransplantation cyclophosphamide are crucial for successful engraftment and can enhance donor chimerism while minimizing harmful GVHD reactions, allowing for effective adoptive immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. Luznik, L., Jalla, S., Engstrom, LW., et al.[2021]

References

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

A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti-tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice. [2016]

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

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

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

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies. [2013]

4. Germany pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. [2019]

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

Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-thalassemia. [2021]

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

Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Thiotepa improves allogeneic bone marrow engraftment without enhancing stem cell depletion in irradiated mice. [2013]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation. [2022]

9. Egypt pubmed.ncbi.nlm.nih.gov

Regulatory T cells in allogeneic stem cell transplantation. [2021]

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

Impact on early outcomes and immune reconstitution of high-dose post-transplant cyclophosphamide vs anti-thymocyte globulin after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation. [2019]

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

Durable engraftment of major histocompatibility complex-incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide. [2021]