Cytokine Induced Memory-like NK Cell Adoptive Therapy for Relapsed AML After Allogeneic Hematopoietic Cell Transplant

NCT03068819 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 202206197P50CA171963
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (8)

• Feasibility of Successfully Generating CIML NK Cells With Standard of Care (SOC) DLI From the Original Stem Cell Donor as Measured by the Number of Participants That Had Successful Doses Infused (Pilot Pediatric/Young Adult Cohort)

  -Feasibility is defined as the ability to generate and successfully infuse CIML NK cells with SOC donor lymphocyte infusion (DLI). Will be considered successful if doses above the minimum can be delivered in at least 18 of 24 patients. Target and minimum CIML doses are maximum capped at 20x10\^6/kg with a minimum dose of 0.5x10\^6 kg.

  Completion of all recipients through Day 0

• Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unexpected Early Mortality (Pilot Pediatric/Young Adult Cohort)

  Unexpected early mortality is defined as deaths that occur through day 100 that are possibly, probably, or definitely related to the study treatment.

  Up to Day 100

• Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unacceptable Graft Versus Host Disease (GVHD) (Pilot Pediatric/Young Adult Cohort)

  Unacceptable GVHD is defined as grade IV acute GVHD as assessed by the Minnesota Grading Scale or grade D acute GVHD as assessed by the CIBMTR Grading Scale.

  From day 14 through month 6

• Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Prolonged Neutropenia (Pilot Pediatric/Young Adult Cohort)

  Prolonged neutropenia is defined as an absolute neutrophil count \<500/μL persisting for \> 2 weeks.

  8 weeks post CIML NK infusion

• Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unexpected Early Mortality (Phase 2 Adult Cohort)

  Unexpected early mortality is defined as deaths that occur through day 100 that are possibly, probably, or definitely related to the study treatment.

  Up to Day 100

• Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Unacceptable GVHD (Phase 2 Adult Cohort)

  Unacceptable GVHD is defined as grade IV acute GVHD as assessed by the Minnesota Grading Scale or grade D acute GVHD as assessed by the CIBMTR Grading Scale.

  From day 14 through month 6

• Safety of Administering CIML NK Cells Plus T Cell DLI as Measured by Number of Recipients With Prolonged Neutropenia (Phase 2 Adult Cohort)

  Prolonged neutropenia is defined as an absolute neutrophil count \<500/μL persisting for \> 2 weeks.

  8 weeks post CIML NK infusion

• Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Phase 2 Adult Cohort)

  -LFS is defined as the time from achievement of CR/CRi to the time of relapse, death in remission, or last follow-up.

  6 months

Secondary Outcomes (16)

• Complete Remission Rate (CR/CRi) (Pilot Pediatric/Young Adult Cohort)

  Day 30

• Complete Remission Rate (CR/CRi) (Phase 2 Adult Cohort)

  Day 30

• Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Pilot Pediatric/Young Adult Cohort)

  100 days post CIML NK cell infusion

• Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Pilot Pediatric/Young Adult Cohort)

  1 year post CIML NK cell infusion

• Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Phase 2 Adult Cohort)

  100 days post CIML NK cell infusion

Study Arms (3)

CIML NK cell after T cell DLI (Pilot Pediatric/Young Adult Cohort)

EXPERIMENTAL

* Recipients will receive standard of care salvage chemotherapy with FLAG (fludarabine, ara-C and G-CSF) or decitabine 2-4 weeks prior to receiving the DLI on day -1 and CIML NK cell infusion on day 0. * 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.

Drug: CIML NK Cell Infusion; Procedure: CD3+ T Cell Product Infusion; Procedure: Leukapheresis

CIML NK cell after T cell DLI (Phase 2 Adult Cohort)

EXPERIMENTAL

* Recipients will receive lymphodepleting therapy with fludarabine and cyclophosphamide on days -7 through -3 prior to receiving CIML NK cell infusion on day 0. DLI will be given on day 30. rh IL-2 will be administered beginning on Day 0, continuing every other day through Day + 12. Note that the addition of IL-2 started with the 7th recipient treated. * A 2nd cycle of therapy may be administered \> 30 days after the administration of the 1st course of protocol therapy to maintain response or to treat persistent/relapsed AML, if a patient continues to meet the eligibility criteria. Chemotherapy may be omitted before a second infusion of DLI and CIML NK cells. In the setting of GVHD following the 1st cycle of therapy, the T cell DLI may be omitted, and ML NK cells administered. The date of the 2nd NK cell infusion will be considered a 2nd Day 0.

Drug: CIML NK Cell Infusion; Procedure: CD3+ T Cell Product Infusion; Procedure: Leukapheresis

Donors

OTHER

On Day -2 or -1, peripheral blood mononuclear cells will be collected by a standard apheresis over 4-5 hours (with a target volume of at least 20 L for patients ≥ 18 years of age) from the same donor that provided the HCT graft. For related local donors, apheresis will occur on Day -1. For unrelated donors, apheresis will occur on Day -2 or -1, with the goal of processing the product into T cell and NK cells on Day -1. The dose of the DLI will be 1x106 CD3+/kg the first cycle in the pediatric cohort, and follow institutional practices for the adult cohort and for subsequent cycles in the pediatric cohort.

Procedure: Leukapheresis

Interventions

CIML NK Cell Infusion DRUG

Day 0 and possible second cycle \> 30 days after the first course

CIML NK cell after T cell DLI (Phase 2 Adult Cohort); CIML NK cell after T cell DLI (Pilot Pediatric/Young Adult Cohort)

CD3+ T Cell Product Infusion PROCEDURE

Day -1 and possible second cycle \> 30 days after the first course (Pilot Pediatric/Young Adult Cohort). Day 30 and possible second cycle \>30 days after the first course (Phase 2 Adult Cohort)

Also known as: DLI

CIML NK cell after T cell DLI (Phase 2 Adult Cohort); CIML NK cell after T cell DLI (Pilot Pediatric/Young Adult Cohort)

Leukapheresis PROCEDURE

On Day -2 or -1

CIML NK cell after T cell DLI (Phase 2 Adult Cohort); CIML NK cell after T cell DLI (Pilot Pediatric/Young Adult Cohort); Donors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Relapsed AML after HLA-matched related or unrelated allogeneic hematopoietic cell transplant
• For pilot pediatric/young adult patient cohort ≥1 and \<18 years of age
• For phase 2 adult patient cohort ≥18 years of age
• Available original donor (same donor as used for the initial stem cell transplant) that is willing and eligible for non-mobilized collection
• Patients with known central nervous system (CNS) involvement with AML are eligible provided that they have been treated and cerebrospinal fluid (CSF) is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.
• Karnofsky performance status \> 60 %
• 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).

You may not qualify if:

• Acute or chronic GvHD with ongoing active systemic treatment.
• Circulating blast count \>10,000/uL by morphology or flow cytometry (cyto-reductive therapies, including salvage chemotherapy, is encouraged prior to study enrollment)
• Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B, or Hepatitis C infection.
• Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.
• New or progressive pulmonary infiltrates concerning for new or uncontrolled infectious process.
• Known hypersensitivity to one or more of the study agents
• Received any investigational drugs within the 14 days prior to CIML NK cell infusion date
• Pregnant and/or breastfeeding
• At least 18 years of age
• Same donor as used for the allo-HCT
• In general good health, and medically able to tolerate leukapheresis
• Ability to understand and willingness to sign an IRB approved written informed consent document
• Active hepatitis, positive for HTLV, or HIV on donor viral screen
• Pregnant

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Cancer Institute (NCI): collaborator
• Wugen, Inc.: collaborator
• Children's Discovery Institute: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Bednarski JJ, Zimmerman C, Berrien-Elliott MM, Foltz JA, Becker-Hapak M, Neal CC, Foster M, Schappe T, McClain E, Pence PP, Desai S, Kersting-Schadek S, Wong P, Russler-Germain DA, Fisk B, Lie WR, Eisele J, Hyde S, Bhatt ST, Griffith OL, Griffith M, Petti AA, Cashen AF, Fehniger TA. Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Blood. 2022 Mar 17;139(11):1670-1683. doi: 10.1182/blood.2021013972.

  PMID: 34871371 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Leukapheresis

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques

Results Point of Contact

• Title: Dr. Amanda Cashen
• Organization: Washington University School of Medicine

acashen@wustl.edu

314-454-8323

Study Officials

• Amanda Cashen, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 27, 2017
• First Posted: March 3, 2017
• Study Start: October 23, 2017
• Primary Completion: June 15, 2025
• Study Completion: June 15, 2025
• Last Updated: April 24, 2026
• Results First Posted: April 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)