Memory-like NK Cell Therapy for Acute Myeloid Leukemia

Overseen By Amanda Cashen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Washington University School of Medicine

Must not be taking: Systemic corticosteroids, Immunosuppressants

Disqualifiers: GvHD, High blast count, Infections, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

62 Participants Needed

Trial Summary

What is the purpose of this trial?

Donor Lymphocyte Infusion (DLI) following salvage chemotherapy is the one of the most widely used treatment approaches in patients who relapse after allogeneic hematopoietic cell transplant (allo-HCT). However, the complete remission (CR) rates and long term survival remain very poor in these patients and, therefore, there is an unmet need to develop more effective treatment approaches in patients who relapse after allo-HCT. Based on the initial promising results with our ongoing cytokine-induced memory-like (CIML) natural killer (NK) cell trial, the investigators hypothesize that combining the CIML NK cells with DLI approach will significantly enhance the graft versus leukemia and therefore potentially provide potentially curative therapy for these patients with otherwise extremely poor prognosis. Combining CIML NK cells with the DLI platform will also potentially allow these adoptively transferred cells to persist for longer duration as they should not be rejected by donor T cells as the CIML NK cells are derived from the same donor. The use of CIML NK cells is unlikely to lead to excessive graft versus host disease (GVHD) as previous studies have not been associated with excessive GVHD rates.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on systemic corticosteroid therapy above 10 mg of prednisone or equivalent, or any other immune suppressive medications. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Memory-like NK Cell Therapy for Acute Myeloid Leukemia?

Research shows that memory-like NK cells, which are enhanced by cytokines like IL-12, IL-15, and IL-18, have been effective in treating acute myeloid leukemia (AML). In clinical trials, these cells have shown strong anti-leukemia activity, with some patients achieving complete remission and improved survival rates. ^{1 2 3 4 5}

Is Memory-like NK Cell Therapy safe for humans?

Memory-like NK Cell Therapy has been tested in clinical trials for acute myeloid leukemia and has been generally well tolerated, with no significant toxicity reported. Patients have shown good responses, and the therapy is considered safe in the studies conducted so far. ^{1 2 3 4 5}

How is the Memory-like NK Cell Therapy different from other treatments for acute myeloid leukemia?

Memory-like NK Cell Therapy is unique because it uses natural killer (NK) cells that have been preactivated with specific cytokines (proteins that help cells communicate) like IL-12, IL-15, and IL-18, which enhances their ability to fight leukemia cells. This therapy shows promise as it can lead to complete remissions in some patients and the NK cells can persist and remain active for a long time, offering a novel approach compared to traditional treatments. ^{1 3 4 5 6}

Research Team

Amanda Cashen, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults who have relapsed Acute Myeloid Leukemia after a stem cell transplant from a matched donor. They must be in good health, with normal organ function and no active infections or uncontrolled heart conditions. Pregnant women or those on systemic steroids/high blast counts are excluded.

Inclusion Criteria

My original stem cell donor is available and willing to donate again without mobilization.

Adequate organ function as defined below: Total bilirubin < 2 mg/dL, AST(SGOT)/ALT(SGPT) < 3.0 x IULN, Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2 by Cockcroft-Gault Formula, Oxygen saturation ≥90% on room air, Not currently requiring systemic corticosteroid therapy (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) or any other immune suppressive medications, Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration. Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study including throughout the initial evaluation period (100 days after CIML NK cell infusion), Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)

I can care for myself but may not be able to do active work.

Exclusion Criteria

I do not have severe heart issues like uncontrolled chest pain or irregular heartbeats.

Pregnant and/or breastfeeding

Known hypersensitivity to one or more of the study agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive standard of care salvage chemotherapy consisting of fludarabine (or cladribine if shortage), cytarabine, and G-CSF (FLAG) or 5-day decitabine as an alternative

2-4 weeks

CIML NK Cell Infusion

Participants receive cytokine-induced memory-like NK cell infusion following chemotherapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for GVHD and leukemia-free survival

12 months

Treatment Details

Interventions

• Cytokine Induced Memory-like NK Cell Adoptive Therapy

Trial Overview The study tests combining Cytokine Induced Memory-like Natural Killer (CIML NK) cells with Donor Lymphocyte Infusion (DLI) to improve treatment outcomes in relapsed AML patients post-transplant. It aims to enhance graft versus leukemia effects without excessive Graft versus Host Disease.

Participant Groups

Group I: CIML NK cell after T cell DLT (Pilot Pediatric/Young Adult Cohort) Experimental Treatment 2 Interventions

* The recipient will receive standard of care salvage chemotherapy consisting of fludarabine (or cladribine if shortage), cytarabine, and G-CSF (FLAG) to be started 2 to 4 weeks prior to the CIML NK cell infusion. 5-day decitabine is an acceptable alternative for FLAG, and another standard of care salvage chemotherapy regimen, if clinically appropriate and approved by the study PI, may be used. * The donor will undergo non-mobilized leukapheresis on Day -2 or -1. Standard of care DLI (1 x 10\^6 CD3+ cells/kg) will be given fresh on day -1. * A second cycle of therapy may be administered \> 30 days after the administration of the first course of protocol therapy to maintain response or to treat persistent/relapsed AML, if a patient continues to meet the inclusion/exclusion criteria. Chemotherapy may be omitted before a second infusion of DLI and CIML NK cells. In the setting of GVHD following the first cycle of therapy, the T cell DLI may be omitted, and ML NK cells administered.

Group II: CIML NK cell after T cell DLT (Phase 2 Adult Cohort) Experimental Treatment 2 Interventions

* The recipient will receive lymphodepleting chemotherapy with fludarabine (or cladribine if shortage) and cyclophosphamide beginning on day -7. * The donor will undergo non-mobilized leukapheresis on Day -2 or -1. T cell dose per standard of care institutional practices and physician discretion will be given frozen for administration on day 30. * A second cycle of therapy may be administered \> 30 days after the administration of the first course of protocol therapy to maintain response or to treat persistent/relapsed AML, if a patient continues to meet the inclusion/exclusion criteria. Chemotherapy may be omitted before a second infusion of DLI and CIML NK cells. In the setting of GVHD following the first cycle of therapy, the T cell DLI may be omitted, and ML NK cells administered. The date of the second NK cell infusion will be considered a second Day 0.

Cytokine Induced Memory-like NK Cell Adoptive Therapy is already approved in United States for the following indications:

Approved in United States as Cytokine Induced Memory-like NK Cell Therapy for:

• Acute Myeloid Leukemia (AML)
• Relapsed/Refractory AML

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Wugen, Inc.

Industry Sponsor

Trials

8

Recruited

400+

Children's Discovery Institute

Collaborator

Trials

6

Recruited

540+

Findings from Research

Cytokine-induced memory-like NK cells show enhanced ability to produce interferon-γ and kill leukemia cells, making them a promising option for treating acute myeloid leukemia (AML).

In a first-in-human phase 1 clinical trial, memory-like NK cells were successfully expanded in AML patients, leading to clinical responses in five out of nine patients, including four complete remissions, indicating their potential effectiveness as an immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Romee, R., Rosario, M., Berrien-Elliott, MM., et al.[2021]

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]

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]

In a clinical trial involving 15 patients with relapsed/refractory acute myeloid leukemia (AML), the use of donor-derived memory-like (ML) NK cells combined with N-803 (an IL-15 superagonist) was well tolerated and resulted in an impressive 87% of patients achieving a composite complete response within 28 days.

The ML NK cells showed significant expansion and persistence, remaining the dominant lymphocyte population for over 2 months post-transplant, and exhibited enhanced antitumor functions compared to conventional NK cells, indicating their potential as an effective immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. Berrien-Elliott, MM., Foltz, JA., Russler-Germain, DA., et al.[2023]

Cytokine-induced memory-like (CIML) NK cells, which are generated through brief stimulation with IL-12, IL-15, and IL-18, show enhanced effector functions and long-term persistence, making them promising candidates for cancer immunotherapy.

Clinical trials have demonstrated that infusions of CIML NK cells are safe and have led to complete clinical remissions in patients with relapse/refractory acute myeloid leukemia (AML).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications. Terrén, I., Orrantia, A., Astarloa-Pando, G., et al.[2022]

Cytokine-induced memory-like (ML) NK cell therapy is safe and shows promise in inducing remissions in patients with acute myeloid leukemia (AML), with a unique NK cell phenotype identified through mass cytometry.

The inhibitory receptor NKG2A plays a crucial role in the response of ML NK cells to cancer, while a higher frequency of CD8α+ donor NK cells is linked to poorer patient outcomes, suggesting new strategies to improve NK cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia. Berrien-Elliott, MM., Cashen, AF., Cubitt, CC., et al.[2022]

References

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

Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. [2021]

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. 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]

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

Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications. [2022]

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

Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia. [2022]