Natural Killer Cell Therapy for Acute Myeloid Leukemia

(KARMA Trial)

Overseen By Melinda C Triplet

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nationwide Children's Hospital

Must not be taking: Immunosuppressants

Disqualifiers: AML therapies, Immunosuppressive therapy, others

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

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I/II dose escalation study designed to determine the safety and estimate the efficacy of UD-NK cells combined with FLA chemotherapy in patients age 1-24.99 with relapsed or refractory acute myeloid leukemia. PRIMARY OBJECTIVE: I. To determine the safety and recommended phase II dose of adoptive NK cell therapy using UD-NK cells in pediatric and young adult patients with relapsed/refractory AML. SECONDARY OBJECTIVES: I. To estimate the efficacy of UD- NK cells with FLA chemotherapy in pediatric and young adult patients with relapsed/refractory AML. EXPLORATORY OBJECTIVES: I. To determine the immunophenotype and function of UD-NK cells II. To characterize in vivo expansion of UD-NK cells III. To determine the persistence of UD-NK cells Six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.

Will I have to stop taking my current medications?

The trial requires that you stop any AML-directed therapies at least 2 weeks before starting the study, except for hydroxyurea. You must also stop any systemic immunosuppressive therapy at least 2 weeks before enrolling.

What data supports the effectiveness of the treatment Universal Donor Natural Killer Cells for Acute Myeloid Leukemia?

Research shows that natural killer (NK) cells, when expanded and activated, can effectively fight leukemia. In one study, 4 out of 8 patients with relapsed acute myeloid leukemia achieved complete remission after receiving memory-like NK cells, and some maintained remission for over two years. ^{1 2 3 4 5}

Is Natural Killer Cell Therapy safe for humans?

Research shows that Natural Killer Cell Therapy, under various names, has been tested in patients with acute myeloid leukemia and has generally been safe, with no significant toxicities or severe side effects reported in multiple studies. ^{2 3 4 6 7}

What makes Universal Donor NK Cells treatment unique for acute myeloid leukemia?

Universal Donor NK Cells treatment is unique because it uses specially expanded natural killer cells that are designed to be highly effective against leukemia cells by targeting them based on missing 'self' signals, which is different from traditional chemotherapy that targets rapidly dividing cells. This approach aims to enhance the body's immune response specifically against leukemia, potentially offering a more targeted and less toxic treatment option. ^{1 2 3 8 9}

Research Team

Margaret Lamb, MD

Principal Investigator

Nationwide Children's Hospital

Eligibility Criteria

This trial is for young adults aged 18-24.99 with relapsed or refractory acute myeloid leukemia (AML). Participants must have stable organ function, controlled seizures if present, and no severe treatment-related side effects from previous therapies. They should not be pregnant, agree to use contraception post-treatment, and have no uncontrolled infections or cardiac issues.

Inclusion Criteria

My cancer is limited to the brain or outside the bone marrow.

Negative serology for human immunodeficiency virus (HIV)

My seizures are well controlled with medication.

Exclusion Criteria

I have not received a donor lymphocyte infusion in the last 30 days.

I am currently on medication to suppress my immune system.

I need considerable assistance and medical care.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive Fludarabine and Cytarabine chemotherapy from day -6 to day -2

1 week

In-patient treatment

NK Cell Treatment

Participants receive six doses of universal donor NK cells thrice weekly for two weeks starting on day 0

2-3 weeks

Multiple visits for NK cell infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Weekly samples from day 0 to day +28

Treatment Details

Interventions

• Universal Donor Natural Killer Cells

Trial Overview The study tests the safety and potential effectiveness of Universal Donor Natural Killer (UD-NK) cells combined with FLA chemotherapy in patients with AML that has returned or didn't respond to initial treatments. It's a phase I/II trial where doses are adjusted to find the safest and most effective level.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2000 mg/ m2/day (days -6 to day -2) Six doses of universal donor IL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks starting on day 0. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.

Who Is Running the Clinical Trial?

Nationwide Children's Hospital

Lead Sponsor

Trials

354

Recruited

5,228,000+

Findings from Research

A new protocol successfully expanded adaptive NK cells from superdonors, achieving over 90% purity and a median expansion of 470-fold, which enhances their potential for treating acute myeloid leukemia (AML).

The expanded ADAPT-NK cells demonstrated strong anti-tumor activity, effectively killing AML cells and showing preserved functionality, including robust antibody-dependent cellular cytotoxicity, making them a promising off-the-shelf therapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adaptive single-KIR+NKG2C+ NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia. Haroun-Izquierdo, A., Vincenti, M., Netskar, H., et al.[2023]

In a phase 1 trial involving 9 pediatric and young adult patients with relapsed acute myeloid leukemia (AML) after hematopoietic cell transplantation, donor-derived memory-like natural killer (ML NK) cells showed significant antileukemic activity, leading to complete remission in 4 out of 8 evaluable patients by day 28.

The ML NK cells expanded and persisted for over 3 months without significant toxicity, suggesting that this approach, combined with donor lymphocyte infusions, could be a promising new immunotherapy for relapsed AML in a post-transplant setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Bednarski, JJ., Zimmerman, C., Berrien-Elliott, MM., et al.[2023]

The study involved 7 pediatric patients with acute myeloid leukemia (AML) who received activated and expanded natural killer (NK) cells as a treatment after chemotherapy, showing that this approach is safe and feasible.

After a median follow-up of 33 months, 85.7% of patients remained in complete remission, and the 3-year overall survival rate was 83.3%, although the small sample size limits definitive conclusions about efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia. Gómez García, LM., Escudero, A., Mestre, C., et al.[2022]

In a study involving 13 high-risk patients with relapsed/refractory acute myeloid leukaemia (AML), repeated infusions of expanded NK cells were safely administered without any dose-limiting toxicities or severe side effects.

The treatment showed promising efficacy, with an overall response rate of 78.6% and a complete response rate of 50%, including successful responses in patients with central nervous system involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy with double-bright (CD56bright /CD16bright ) expanded natural killer cells in patients with relapsed or refractory acute myeloid leukaemia: a proof-of-concept study. Silla, L., Valim, V., Pezzi, A., et al.[2022]

A GMP-compliant method was developed to expand alloreactive NK cells from healthy donors, achieving a 117-fold increase in NK cell numbers over 19 days, which is crucial for effective immunotherapy in acute myeloid leukemia (AML).

The expanded NK cells, particularly those with specific killer immunoglobulin-like receptor (KIR) profiles, demonstrated strong cytotoxicity against AML cells in vitro and reduced tumor load in vivo, indicating their potential for clinical use in NK cell-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Siegler, U., Meyer-Monard, S., Jörger, S., et al.[2020]

The study involved 40 elderly patients with acute myeloid leukemia (AML), showing that donor NK cell infusions are generally safe, with only mild side effects like moderate fever occurring in a few cases after multiple infusions.

High-purity NK cells were successfully expanded and transfused, with no cases of acute graft-versus-host disease (GVHD) observed in elderly AML patients, indicating a promising safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Safety of NK Cell in the Prevention of Leukemia Relapse Post-transplantation and in Treatment of the Elderly Leukemia Patients]. Liu, J., Zheng, XL., Xue, M., et al.[2022]

The phase 1 study involving 7 patients with refractory/relapsed acute myeloid leukemia (AML) demonstrated that adoptive transfer of activated NK cells (aNK) is safe, with no dose-limiting toxicities or severe adverse effects observed during treatment or the 21-day follow-up period.

While the aNK cell therapy showed transient activity in 3 out of 7 patients, the study confirmed the feasibility of using 'off-the-shelf' aNK cells, paving the way for future combination immunotherapy trials to enhance treatment for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial of adoptive immunotherapy using "off-the-shelf" activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia. Boyiadzis, M., Agha, M., Redner, RL., et al.[2018]

Adoptive NK cell infusion using clinical-grade membrane-bound IL-21/4-1BBL-expanded NK cells showed significant antileukemic activity against acute myeloid leukemia (AML) in both laboratory and animal studies, with expanded NK cells persisting in the body for at least 13 days after infusion.

Patients with minimal residual disease (MRD+) who received NK cell treatment experienced better overall survival compared to those undergoing standard consolidation therapy, with no major adverse events reported, indicating a promising safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanded clinical-grade membrane-bound IL-21/4-1BBL NK cell products exhibit activity against acute myeloid leukemia in vivo. Zhao, XY., Jiang, Q., Jiang, H., et al.[2021]

Adoptive cell therapy is emerging as a promising immunotherapy strategy for treating acute myeloid leukemia (AML), particularly for patients with poor prognosis after traditional chemotherapy.

This review highlights various approaches within adoptive cell therapy, including donor lymphocyte infusion, CAR T cell therapy, NK cell therapy, and dendritic cell vaccination, showcasing advancements that could improve clinical outcomes for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cell therapy for acute myeloid leukemia. Ma, H., Padmanabhan Iyer, S., Parmar, S., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Adaptive single-KIR+NKG2C+ NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia. [2023]

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

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. [2023]

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

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy with double-bright (CD56bright /CD16bright ) expanded natural killer cells in patients with relapsed or refractory acute myeloid leukaemia: a proof-of-concept study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. [2020]

6. China pubmed.ncbi.nlm.nih.gov

[Clinical Safety of NK Cell in the Prevention of Leukemia Relapse Post-transplantation and in Treatment of the Elderly Leukemia Patients]. [2022]

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

Phase 1 clinical trial of adoptive immunotherapy using "off-the-shelf" activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Expanded clinical-grade membrane-bound IL-21/4-1BBL NK cell products exhibit activity against acute myeloid leukemia in vivo. [2021]

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

Adoptive cell therapy for acute myeloid leukemia. [2020]