Memory-like NK Cells after Haploidentical Transplant for AML

(ABCD-NK Trial)

Overseen By Jeffrey Bednarski, M.D., Ph.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Glucocorticoids, Immunosuppressants

Disqualifiers: Active GvHD, Non-hematologic malignancy, CNS disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

48 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that might interfere with the activity of the ML NK cells, such as glucocorticoids and other immunosuppressants.

What data supports the effectiveness of the treatment Memory-like NK Cells after Haploidentical Transplant for AML?

Research shows that using TCR-alpha/beta and CD19 depletion in stem cell transplants for children with acute myeloid leukemia (AML) has led to promising survival rates, with a 2-year overall survival of 67% and event-free survival of 60%. Additionally, NK cells (a type of immune cell) have been shown to play a crucial role in fighting leukemia after haploidentical stem cell transplants, suggesting potential benefits of this treatment approach. ^{1 2 3 4 5}

Is the treatment using memory-like NK cells after haploidentical transplant for AML generally safe in humans?

The treatment involving TCR-alpha/beta and CD19 depletion in haploidentical transplants has shown promising safety data. Studies report low rates of severe graft-versus-host disease (a condition where the donor cells attack the recipient's body) and manageable transplant-related mortality, indicating it is generally safe for both children and adults. ^{3 4 6 7 8}

How is the TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft treatment different from other treatments for AML?

This treatment is unique because it involves a specific type of stem cell transplant that depletes certain immune cells (TCR alpha beta and CD19+ cells) to reduce complications and enhance the effectiveness of natural killer (NK) cells, which can help fight leukemia. It allows for the infusion of mature immune cells, including NK cells, which are crucial for targeting leukemia cells while minimizing the risk of graft-versus-host disease. ^{2 9 10 11 12}

What is the purpose of this trial?

This phase I/II pilot study aims to enhance the effectiveness of stem cell transplant for children and young adults with high-risk acute myeloid leukemia (AML). Patients will undergo a stem cell transplant from a half-matched family donor. One week later, patients will receive an additional infusion of immune cells and a drug called interleukin-2. To mitigate the potential complications associated with graft-versus-host-disease, the donated stem cell product undergoes a process that removes a specific type of immune cell. After transplant, recipients are administered additional immune cells known as memory-like natural killer (ML NK) cells. These cells are derived by converting conventional natural killer cells obtained from the donor. The infusion of a modified stem cell product, along with administration of ML NK cells may help prevent the development of GvHD while simultaneously improving the efficacy of the treatment.

Research Team

Thomas Pfeiffer

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for children and young adults (≤30 years) with high-risk acute myeloid leukemia, either in remission or a specific free state. They must have good organ function, agree to use contraception, and have a half-matched family donor. It's not for those with active GvHD, other cancers, CNS disease, significant allergies to similar treatments, or who are pregnant/breastfeeding.

Inclusion Criteria

I had a bone marrow transplant and am currently in remission.

I am 30 years old or younger.

My liver, kidneys, heart, and lungs are working well.

Exclusion Criteria

History of allergic reactions to similar compounds

Presence of significant anti-donor HLA antibodies

Donor not meeting specific eligibility criteria

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplant

Patients undergo Myeloablative or Reduced Intensity Conditioning followed by infusion of the TCRαβ/CD19+ depleted haploidentical HPC graft

9 days

Daily visits for conditioning

ML NK Cell Infusion

Infusion of memory-like NK cells and administration of IL-2

12 days

Visits every other day for IL-2 administration

Follow-up

Participants are monitored for safety, effectiveness, and development of GvHD

12 months

Regular follow-up visits

Treatment Details

Interventions

• Memory-like Natural Killer Cells
• TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft

Trial Overview The study tests the effectiveness of stem cell transplants from half-matched donors followed by an infusion of memory-like natural killer cells in patients with AML. The process includes removing certain immune cells from the graft to reduce complications and administering interleukin-2 after transplant.

Participant Groups

Group I: Recipient, Reduced Intensity Conditioning (RIC) Experimental Treatment 8 Interventions

Patients will undergo Reduced Intensity Conditioning (RIC) consisting of rabbit antithymocyte globulin (rATG), Fludarabine, Melphalan, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7. Fludarabine is administered from day -8 to day -5, followed by Thiotepa on day -4 and Melphalan on days -3 and -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously starting 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.

Group II: Recipient, Myeloablative Conditioning (MAC) Experimental Treatment 8 Interventions

Patients will undergo Myeloablative Conditioning (MAC) consisting of rabbit antithymocyte globulin (rATG), Busulfan, Fludarabine, and Thiotepa. All agents are administered intravenously. rATG is administered from days -9 to -7, followed by Busulfan and Fludarabine from days -6 to -3, and Thiotepa on day -2. On Day 0, patients will undergo infusion of the ex vivo TCRαβ/CD19+ depleted haploidentical HPC graft. On Day +7, patients will undergo infusion of the memory-like NK (ML NK) cells, followed by IL-2 subcutaneously 4 hours after the ML NK infusion. IL-2 will continue every other day through Day +19 for a maximum of 7 doses.

Group III: Donor Experimental Treatment 2 Interventions

Donors will undergo 2 leukapheresis collections. First, patients will be mobilized using G-CSF for 5 days followed by leukapheresis on the day prior to planned stem cell transplant. The second collection will occur on Day +6 after stem cell transplant and will be non-mobilized.

TCR alpha beta / CD19+ depleted haploidentical hematopoietic progenitor cell graft is already approved in United States, European Union for the following indications:

Approved in United States as haploidentical hematopoietic stem cell transplant for:

• Acute Myeloid Leukemia (AML)
• High-risk AML

Approved in European Union as haploidentical hematopoietic stem cell transplant for:

• Acute Myeloid Leukemia (AML)
• High-risk AML

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

St. Louis Children's Hospital Foundation

Collaborator

Trials

1

Recruited

50+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Rising Tide Foundation

Collaborator

Trials

17

Recruited

6,200+

Findings from Research

T-cell-depleted hematopoietic stem cell transplantation (Haplo HSCT) from HLA-haploidentical relatives is an effective treatment for high-risk acute myeloid leukemia (AML) in adults and relapsed acute lymphoblastic leukemia (ALL) in children, as demonstrated by two case studies.

The success of Haplo HSCT is attributed to the anti-leukemia effects of alloreactive NK cells from the donor, and the use of KIR-specific monoclonal antibodies helps identify and quantify these beneficial NK cell subsets, making it easier to select suitable donors and monitor treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. Locatelli, F., Pende, D., Maccario, R., et al.[2009]

In a study of 10 patients with acute myeloid leukemia (AML) who received haploidentical stem-cell transplants, no graft versus leukemia (GvL) effect was observed, indicating a potential issue with NK cell recovery and function post-transplant.

The NK cells from these patients exhibited an immature phenotype with reduced cytotoxicity, which was linked to increased expression of CD94/NKG2A; blocking this receptor improved their ability to kill AML cells, suggesting a mechanism that could be targeted to enhance immune responses after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Nguyen, S., Dhedin, N., Vernant, JP., et al.[2021]

In a study involving 213 children with acute leukemia, TCRαβ/CD19 cell depletion during HLA-haploidentical hematopoietic stem cell transplantation showed promising long-term outcomes, with a projected 10-year overall survival rate of 75.4% and a disease-free survival rate of 71.6%.

The incidence of severe complications such as acute and chronic graft-versus-host disease was low (14.7% and 8.1%, respectively), indicating that this graft manipulation technique is both safe and effective for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. Merli, P., Algeri, M., Galaverna, F., et al.[2023]

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]

In a study of 912 adults aged 45 and older with high-risk acute myeloid leukemia (AML) undergoing haploidentical stem cell transplantation (haplo-SCT), no significant differences in outcomes were found between myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) regimens, with similar rates of relapse and nonrelapse mortality.

The use of posttransplantation cyclophosphamide was linked to lower rates of severe acute graft-versus-host disease (aGVHD) and improved overall survival, while the type of stem cells used influenced the risk of aGVHD, highlighting the importance of GVHD prophylaxis and patient status in transplantation outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of conditioning intensity on outcomes of haploidentical stem cell transplantation for patients with acute myeloid leukemia 45 years of age and over. Santoro, N., Labopin, M., Ciceri, F., et al.[2020]

A new 10-color quality control panel was developed to accurately quantify residual TCRαβ+ T cells and CD19+ B cells in stem cell grafts, which is crucial for preventing severe graft-versus-host disease (GvHD) after haploidentical stem cell transplantation (HSCT).

The immunomagnetic purification method achieved significant depletion of TCRαβ and CD19 cells, with recovery rates of 82.1% for stem cells, 67.1% for NK cells, and 72.7% for TCRγδ+ T cells, potentially improving transplantation outcomes by ensuring a safer graft composition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation and flow cytometric quality control of clinical-scale TCRαβ/CD19-depleted grafts. Bremm, M., Cappel, C., Erben, S., et al.[2017]

A multicenter phase I/II trial involving 60 patients showed that haploidentical hematopoietic stem cell transplantation (HSCT) using TCRαβ/CD19-depleted grafts is a safe and effective treatment option, with no cases of severe acute graft-versus-host disease (GVHD) and only 10% experiencing mild GVHD.

With a median follow-up of 733 days, the overall survival rate was 63% and the disease-free survival rate was 50% at 2 years, indicating promising outcomes for patients with various high-risk conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients. Bethge, WA., Eyrich, M., Mielke, S., et al.[2022]

Haploidentical hematopoietic stem cell transplantation using the αβTCR+/CD19+ depletion technique has shown promising results in pediatric patients, leading to rapid engraftment and improved immune recovery.

This method also presents a low risk of graft-versus-host disease (GVHD), making it a safer option for patients without a matched donor, although further research is needed to optimize conditioning regimens for better transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical hematopoietic stem cell transplantation with αβTCR+/CD19+ depletion in pediatric patients with malignant and non-malignant disorders. Bielorai, B., Jacoby, E., Varda-Bloom, N., et al.[2022]

After haploidentical hematopoietic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML), immature NK cells initially have impaired function, which can hinder the effectiveness of the treatment.

Over time, NK cells mature and become more effective at killing leukemic cells, suggesting that enhancing NK cell maturation could lead to better outcomes in transplantation for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. Nguyen, S., Beziat, V., Dhedin, N., et al.[2023]

In a phase I/II trial involving 24 acute myeloid leukemia patients, haploidentical stem cell transplantation combined with early transfer of unmodified NK cells resulted in a promising 2-year overall survival rate of 37%.

The study demonstrated that transferred NK cells not only proliferated in the patients' bodies without needing additional IL-2 but also showed a mature phenotype, suggesting that this approach could enhance the effectiveness of treatment against high-risk leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tracking in vivo dynamics of NK cells transferred in patients undergoing stem cell transplantation. Killig, M., Friedrichs, B., Meisig, J., et al.[2020]

In a study of 80 pediatric acute leukemia patients who underwent αβT/B-depleted haplo-HSCT, the presence of alloreactive NK cells significantly contributed to the graft-versus-leukemia effect, enhancing anti-leukemia activity.

The study found that while HCMV reactivation influenced the differentiation of NK cells, there was no significant correlation between the differentiated NK cell phenotype and relapse-free survival, suggesting that other factors may also play a role in patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia. Meazza, R., Falco, M., Loiacono, F., et al.[2020]

In a study of 17 elderly AML patients receiving NK cell infusions after chemotherapy, moderate toxicity was observed, with 9 out of 16 evaluable patients remaining disease-free at a median follow-up of 22.5 months.

The infusion of a higher number of alloreactive NK cells was linked to improved disease-free survival, suggesting that increasing the frequency of these cells can enhance the effectiveness of NK immunotherapy in treating AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients. Curti, A., Ruggeri, L., Parisi, S., et al.[2021]

References

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

Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. [2009]

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

NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. [2021]

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

TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis. [2023]

4. 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]

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

Impact of conditioning intensity on outcomes of haploidentical stem cell transplantation for patients with acute myeloid leukemia 45 years of age and over. [2020]

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

Generation and flow cytometric quality control of clinical-scale TCRαβ/CD19-depleted grafts. [2017]

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

Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Haploidentical hematopoietic stem cell transplantation with αβTCR+/CD19+ depletion in pediatric patients with malignant and non-malignant disorders. [2022]

9. England pubmed.ncbi.nlm.nih.gov

HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Tracking in vivo dynamics of NK cells transferred in patients undergoing stem cell transplantation. [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia. [2020]

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

Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients. [2021]