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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment that combines Universal Donor Natural Killer (UD-NK) cells with chemotherapy for acute myeloid leukemia (AML), particularly when the cancer has returned or resisted other treatments. The main goal is to assess the treatment's safety and determine the best dose for future studies. Researchers aim to evaluate the effectiveness of this combination in treating AML. This trial may suit individuals aged 1 to 24 whose AML has returned or not responded to previous treatments. As a Phase 1/Phase 2 trial, it focuses on understanding the treatment's effects and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that donor-derived natural killer (NK) cells are generally safe for patients with relapsed or hard-to-treat acute myeloid leukemia (AML). Several studies have found that cancer patients tolerate these cells well. For example, trials reported that NK cells from donors did not cause severe side effects and showed promise in treating AML that is difficult to treat or has returned.

In one study, patients received NK cells that were further cultivated in the lab to enhance effectiveness. These patients did not experience major safety issues. Another study demonstrated that NK cells, especially those boosted with IL-21 (a protein that enhances the immune response), offer potential benefits without significant safety concerns.

While these studies provide a positive outlook on safety, it is important to remember that this treatment is still being tested. So far, the evidence suggests that universal donor NK cells are a safe option for those considering participating in this clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for acute myeloid leukemia?

Unlike the standard treatments for acute myeloid leukemia, which often include chemotherapy and targeted therapies, this new approach uses Universal Donor Natural Killer (UD-NK) cells. These NK cells are a type of immune cell that can be expanded and activated to specifically target and destroy cancer cells. This treatment is particularly exciting because it leverages the body's own immune system to fight the cancer, potentially offering a more targeted and less toxic alternative to traditional chemotherapy. Furthermore, the use of universal donor cells means that they can be used for any patient without the need for a perfect match, potentially speeding up the treatment process. Researchers are hopeful that this innovative approach could lead to more effective and rapid responses in patients with acute myeloid leukemia.

What evidence suggests that this treatment might be an effective treatment for acute myeloid leukemia?

Research has shown that natural killer (NK) cells can effectively fight tumors, particularly in treating acute myeloid leukemia (AML) that has returned or not responded to other treatments. In this trial, participants will receive Universal Donor NK Cells, which studies have found to be safe and beneficial for patients with relapsed and hard-to-treat AML. Patients who received these donor NK cells demonstrated better outcomes, which is promising given the lack of progress in this area over the past 30 years. This approach, known as adoptive NK cell therapy, is being explored as a new way to help the immune system fight cancer cells. Overall, these findings suggest that NK cells could be an effective treatment for challenging AML cases. ^{1 4 5 6 7}

Who Is on the Research Team?

Margaret Lamb, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT07026942

Phase I/II Clinical Trial of Universal Donor CD33 CAR ... This phase 1/2 study is testing a new treatment for acute myeloid leukemia (AML) that has come back or has not responded to other treatments.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38444268/

Results of a phase I trial with Haploidentical mbIL-21 ex ... Natural killer (NK)-cells have potent anti-tumor effects, yet it remains unclear if they are effective for patients with relapsed acute myeloid leukemia (AML).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11748472/

Adoptive NK cell therapy in AML: progress and challenges Adoptive cell therapy (ACT) using natural killer (NK) cells has emerged as a promising therapeutic strategy for acute myeloid leukemia (AML) ...

4. asco.org asco.org/abstracts-presentations/ABSTRACT411662

Clinical-grade natural killer cells expanded from donor ... It has been reported that allogeneic NK cell therapy has good safety and curative effect in patients with refractory and relapsed acute myeloid leukemia (AML).

5. pediatricsnationwide.org pediatricsnationwide.org/2024/04/30/donor-derived-nk-cells-safe-and-efficacious-in-relapsed-and-refractory-aml/

Donor-Derived NK Cells Safe and Efficacious in Relapsed ... Outcomes for patients with relapsed and refractory acute myeloid leukemia (R/R AML) have not significantly improved over the last 30 years.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11694373/

Safety and efficacy of CD33-targeted CAR-NK cell therapy ... CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S000649712103696X

A Phase I Clinical Trial Testing the Safety of IL-21 ... Several studies have shown therapeutic potential for related donor NK cells expanded and/or activated ex vivo when administered to cancer patients, including ...