CIML NK Cell Therapy for Acute Myeloid Leukemia

Recruiting in Saint Louis (>99 mi)

Overseen By Amanda Cashen, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Investigational drugs

Disqualifiers: Relapsed post-transplant, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 21

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a standard phase 2 study powered to demonstrate improvement in the 100 day leukemia free survival to 30% from \<10% expected with the use of reduced intensity haplo-HCT in this extremely high-risk patient cohort (based on the institutional experience using non-myeloablative / reduced intensity conditioning in a similar patient cohort). A formal safety evaluation will be done after every 6th patient enrolled and the trial will be stopped if noted to have unusually higher engraftment failure (acute GVHD rates (\>60% any grades or \>30% grade III/IV or ≥ 50% severe cGVHD) or engraftment failure rates (≥15%).

Will I have to stop taking my current medications?

The trial requires that you stop taking corticosteroids and any other immune suppressive medications starting three days before the treatment begins, except for low doses of prednisone or equivalent. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

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

Research shows that Cytokine Induced Memory-like NK cells, which are enhanced natural killer cells, have been effective in treating acute myeloid leukemia (AML). In clinical trials, these cells have shown the ability to reduce leukemia burden and improve patient outcomes, with some patients achieving complete remission. ^{1 2 3 4 5}

Is CIML NK Cell Therapy safe for humans?

Cytokine-induced memory-like (CIML) NK cell therapy has been tested in clinical trials for acute myeloid leukemia (AML) and has shown to be well tolerated in patients, with no significant toxicity reported. In these studies, the therapy was safely administered and led to positive responses in many patients. ^{2 3 4 6 7}

How is CIML NK Cell Therapy different from other treatments for acute myeloid leukemia?

CIML NK Cell Therapy is unique because it uses natural killer (NK) cells that have been 'trained' with specific cytokines (IL-12, IL-15, and IL-18) to develop memory-like features, allowing them to persist longer and enhance their ability to target and destroy cancer cells. This approach offers a novel way to potentially improve outcomes in acute myeloid leukemia by leveraging the body's own immune system. ^{2 5 8 9 10}

Research Team

Amanda Cashen, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with Acute Myeloid Leukemia who haven't responded to at least two cycles of induction therapy or have relapsed after remission. Participants need a matched donor, good overall health, and normal organ function. They must use effective contraception and not be pregnant or breastfeeding.

Inclusion Criteria

Ability to understand and sign an IRB approved informed consent document

My AML did not respond to 2+ induction therapies or has returned after a complete remission.

I have a donor who is a partial genetic match for me.

Exclusion Criteria

I do not have any uncontrolled infections or known HIV, Hepatitis B or C.

Circulating blast count >30,000/uL

My condition worsened after a transplant from another person.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Standard of care reduced conditioning regimen followed by graft cell infusion and post-transplant cyclophosphamide

7 days

Daily visits for conditioning and transplantation procedures

CIML NK Cell Infusion and ALT-803 Administration

Infusion of cytokine-induced memory-like NK cells and administration of ALT-803

4 doses over 63 days

Visits every 21 days for ALT-803 administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Regular follow-up visits

Treatment Details

Interventions

• Cytokine Induced Memory-like NK Cell Adoptive Therapy

Trial Overview The trial is testing the effectiveness of Memory-like Natural Killer (NK) cell therapy following a half-matched bone marrow transplant in high-risk leukemia patients. It aims to improve survival rates by using a combination of treatments including graft cell infusion, immune suppressants, growth factors, and NK cells.

Participant Groups

Group I: Recipient Experimental Treatment 6 Interventions

* Standard of care reduced conditioning regimen on Day -1 * Graft cell infusion on Day 0 * Post-transplant cyclophosphamide on Days +3 and +4 * GvHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF) will start on Day +5. MMF will continue till Day +35 and tacrolimus till Day +180 in the absence of GvHD * G-CSF will start on Day +7 and will continue until neutrophil engraftment as per institutional guidelines * The cytokine-induced memory like natural killer (CIML NK) cells will be infused on Day +7 without a filter or pump, slowly by gravity over at least 15 minutes. * ALT-803 will start approximately 4 hours after the CIML NK cell infusion. ALT-803 will be administered subcutaneously at a dose of 10 mcg/kg subcutaneously beginning Day +7 (on the day of CIML NK cell infusion) and then every 21 days for a total of 4 doses

Group II: Donor Experimental Treatment 1 Intervention

* Donors will receive subcutaneous G-CSF from Day -4 till Day 0 and undergo 20L apheresis per institutional guidelines. * Two consecutive days for collection are allowed in case of the target CD34+ cell dose being less than the target 4 x106/kg-bw from the first day of collection. * On Day +6 (one day before the planned CIML NK cell infusion), peripheral blood mononuclear cells will be collected by a single standard 20-L apheresis over 4-5 hours from the same haploidentical related donor that provided the HCT graft.

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+

ImmunityBio, Inc.

Industry Sponsor

Trials

75

Recruited

5,000+

Richard Adcock

ImmunityBio, Inc.

Chief Executive Officer since 2024

Information not available

Dr. Patrick Soon-Shiong

ImmunityBio, Inc.

Chief Medical Officer since 2021

MD

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

The V Foundation for Cancer Research

Collaborator

Trials

21

Recruited

1,300+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

NK cells can develop a memory-like phenotype with strong anti-leukemic properties after being co-cultured with irradiated leukemia cells for 7 days, suggesting potential for enhanced cancer treatment.

The study introduces a specialized antibody panel to identify and analyze the activation and maturation changes in tumor-induced memory-like NK cells, which can help optimize future clinical trials involving NK cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimized flow cytometry panel for the detection and analysis of human tumor-induced memory-like NK cells. Schwab, L., Bühler, S., Biedritzky, A., 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 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]

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]

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]

Cytokine-induced killer (CIK) cells, derived from patients or healthy donors, show strong potential in targeting leukemia cells without harming normal hematopoietic stem cells, making them a promising option for leukemia treatment.

CIK cells can generate a graft versus tumor response while minimizing graft versus host disease, suggesting they could effectively prevent leukemia relapse after hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-induced killer cells: A novel immunotherapy strategy for leukemia. Yang, XY., Zeng, H., Chen, FP.[2020]

Natural killer (NK) cell-based immunotherapy shows promise in treating acute myeloid leukemia (AML) by targeting cancer cells and enhancing the immune response, particularly through the use of cytokine-induced memory-like (CIML) NK cells.

CIML-NK cells, which are pre-activated with specific cytokines, demonstrate a longer lifespan and adaptive immunity characteristics, making them a potentially effective and safe treatment option for AML, addressing the limitations of traditional NK cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-Induced Memory-Like NK Cells: Emerging strategy for AML immunotherapy. Bakhtiyaridovvombaygi, M., Yazdanparast, S., Mikanik, F., et al.[2023]

Expanding lymphokine activated natural killer cells and cytokine induced killer T cells using high-quality manufacturing processes is crucial for effectively treating acute myeloid leukemia in patients undergoing stem cell transplantation.

Understanding how these killer cells identify and target leukemia stem cells is essential for improving their therapeutic effectiveness in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LAK cell therapy of AML: not to be lost in translation. Takei, F.[2013]

In a study involving 24 patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), the infusion of autologous cytokine-induced killer (CIK) cells did not show a survival benefit for AML patients post-transplant, nor did it significantly reduce detectable disease in CML patients.

The treatment was found to be safe, with only mild adverse reactions like fever reported, but the results suggest that further modifications to enhance the effectiveness of CIK cells are necessary for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. Linn, YC., Yong, HX., Niam, M., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Optimized flow cytometry panel for the detection and analysis of human tumor-induced memory-like NK cells. [2023]

2. 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]

3. 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]

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

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

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

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

7. Greece pubmed.ncbi.nlm.nih.gov

Cytokine-induced killer cells: A novel immunotherapy strategy for leukemia. [2020]

8. France pubmed.ncbi.nlm.nih.gov

Cytokine-Induced Memory-Like NK Cells: Emerging strategy for AML immunotherapy. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

LAK cell therapy of AML: not to be lost in translation. [2013]

10. England pubmed.ncbi.nlm.nih.gov

A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. [2022]