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

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment method for individuals with difficult-to-treat acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). The goal is to assess the safety and effectiveness of the treatment using a Treg-enriched donor cell transplant alongside chemotherapy and radiation. The trial includes different groups to evaluate the treatment on various types of high-risk AML and MDS. Candidates may qualify if they have relapsed or high-risk AML or MDS and have not succeeded with at least one other treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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 prior data suggests that the IS-free Treg-cell graft-engineered haplo transplant method is safe for patients with AML or MDS?

Research is exploring whether infusions of special donor cells, called Treg-enriched cells, can reduce the risk of leukemia returning while avoiding common side effects. This treatment is very new, with information available only from early testing regarding its safety. As this is an early-phase study, the primary goal is to identify any side effects or issues.

For regular donor T cells, studies have shown that these cell therapies are generally well-tolerated by patients with blood cancers like leukemia. Some research has found that these cells can effectively fight cancer, but monitoring for any side effects remains important.

As these treatments are still in development, it is crucial to monitor participant responses. This phase of the study focuses on ensuring the treatments are safe for people. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments because they integrate Treg-enriched donor cells in stem cell transplants, which could potentially reduce graft-versus-host disease (GVHD) — a common complication in current treatments for leukemia like conventional stem cell transplants. Unlike typical transplants that may use unmodified donor cells, this experimental approach enriches the graft with regulatory T cells (Tregs) to enhance immune tolerance and improve outcomes. Additionally, targeting specific genetic mutations such as TP53 provides a tailored treatment for ultra-high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), addressing challenges faced by traditional therapies that often have limited success with these genetic profiles.

What evidence suggests that this trial's treatments could be effective for AML or MDS?

In this trial, participants will receive treatments involving donor cells enriched with Tregs, which studies have shown can reduce the risk of cancer recurrence while also lowering common side effects. This approach uses regulatory T cells to help manage the immune system during treatment. Additionally, some participants will receive unmodified donor T cells, which research has shown can effectively target and destroy leukemia cells. These T cells act like trained soldiers, seeking out cancer cells and helping the body fight back. Together, these treatments in the various trial arms aim to tackle leukemia by boosting the immune response and reducing the chance of cancer returning. ^{1 2 3 4 5}

Who Is on the Research Team?

John Koreth, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: IS-FREE TREG GRAFT_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. This arm (Cohort A) included patients with rel/ref AML/MDS, with active disease despite at least 1 prior line of therapy. Treatment plan and follow up schedule: Day -15 to -6: Myeloablative conditioning regimen Radiation: Total Myeloid and Lymphoid Irradiation (TMLI) on Days -15 to -11 OR Total Body Irradiation (TBI) on Days -13 to -11 Chemotherapy: Fludarabine on Days -10 to -6, Thiotepa on Days -10 to -9, and Cyclophosphamide and Mesna on Days -8 and -7 Day -4: Treg-enriched donor cell infusion and GVHD assessment Day -1: Unmodified donor T Cell infusion and GVHD assessment Day 0: CD34+ Haplo Peripheral Blood Stem Cell Transplant and GVHD assessment Days 30, 60, 100, 180, 365 post-HSCT, participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD).

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

This arm (Cohort B) includes patients with ultra-high-risk AML/MDS that meets the definition of "Myeloid Neoplasms with mutated TP53" per the 2022 International Consensus Classification, regardless of remission status at the time of transplant. Treatment plan and follow up schedule: Day -15 to -6: Myeloablative conditioning regimen Radiation: Total Myeloid and Lymphoid Irradiation (TMLI) on Days -15 to -11 OR Total Body Irradiation (TBI) on Days -13 to -11 Chemotherapy: Fludarabine on Days -10 to -6, Thiotepa on Days -10 to -9, and Cyclophosphamide and Mesna on Days -8 and -7 Day -4: Treg-enriched donor cell infusion and GVHD assessment Day -1: Unmodified donor T Cell infusion and GVHD assessment Day 0: CD34+ Haplo Peripheral Blood Stem Cell Transplant and GVHD assessment Days 30, 60, 100, 180, 365 post-HSCT, participants will undergo testing and assessment of minimal residual disease (MRD) and (GVHD).

Group III: IS-FREE TREG GRAFT_ENGINEERED HaploHCT for Ultra high-risk AML or MDS with multi-hit or CK+ mut-TP53 Experimental Treatment 7 Interventions

This arm (Cohort C) includes patients with ultra-high-risk AML/MDS that meets definition of 'Myeloid Neoplasms with multi-hit or complex karyotype (CK+) mutated TP53' per 2022 International Consensus Classification, with response (AML with \<5% BM blasts/MDS with \<10% BM blasts). Treatment plan and follow up schedule: Day -11 to -5: Reduced intensity conditioning regimen Chemotherapy: Thiotepa on Day -11, Fludarabine on Days -10 to -7, and Melphalan on Day -6 Radiation: Total Body Irradiation (TBI) on Day -5 Day -4: Treg-enriched donor cell infusion and GVHD assessment Day -1: Unmodified donor T Cell infusion and GVHD assessment Day 0: CD34+ Haplo Peripheral Blood Stem Cell Transplant and GVHD assessment Days 30, 60, 100, 180, 365 post-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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04678401

Study Details | NCT04678401 | IS-free Treg HaploHCT This study is assessing whether the IS-free Treg-cell graft-engineered haplo HSCT) approach will reduce risk of relapse while preventing usual toxicities ...

2. withpower.com withpower.com/trial/phase-1-leukemia-myeloid-2021-5862e

Treg-Enriched Stem Cell Transplant for Leukemia This research study is evaluating the safety and efficacy of the IS-free Treg-cell graft-engineered haplo transplant method in people with ...

3. dana-farber.org dana-farber.org/clinical-trials/20-336

A Pilot/Phase 1 Study of Immunosuppression-free ... 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 ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04678401/is-free-treg-haplohct

IS-free Treg HaploHCT | Clinical Research Trial Listing This research study is evaluating the safety and efficacy of the IS-free Treg-cell graft-engineered haplo transplant method in people with ...

5. cancer.gov cancer.gov/clinicaltrials/NCI-2021-00578

Immunosuppression-Free Regulatory T Cell Graft ... This phase Ib trial is to find out the best dose, possible benefits and/or side effects of immunosuppression-free regulatory T cell graft-engineered ...