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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: CIML NK Cell Infusion; Procedure: CD3+ T Cell Product Infusion; Procedure: Leukapheresis

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Recipient Inclusion Criteria:

• 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).

Recipient Exclusion Criteria:

• 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

Donor Inclusion Criteria:

• 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

Donor Exclusion Criteria:

• Active hepatitis, positive for HTLV, or HIV on donor viral screen
• Pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CIML NK cell after T cell DLI (Pilot Pediatric/Young Adult Cohort); 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; Day 0 and possible second cycle > 30 days after the first course; Procedure: CD3+ T Cell Product Infusion; 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); Other Names: DLI; Procedure: Leukapheresis; On Day -2 or -1
Experimental: CIML NK cell after T cell DLI (Phase 2 Adult Cohort); 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; Day 0 and possible second cycle > 30 days after the first course; Procedure: CD3+ T Cell Product Infusion; 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); Other Names: DLI; Procedure: Leukapheresis; On Day -2 or -1
Other: Donors; 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; On Day -2 or -1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission Rate (CR/CRi) (Pilot Pediatric/Young Adult Cohort)	Complete remission (CR):Morphologically leukemia free state (i.e. bone marrow with <5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions; Complete remission with incomplete blood count recover (CRi): All of the above criteria for CR must be met, except that absolute neutrophils <1000 /μL or platelets <100,000 /μL in the blood.	Day 30
Complete Remission Rate (CR/CRi) (Phase 2 Adult Cohort)	Complete remission (CR):Morphologically leukemia free state (i.e. bone marrow with <5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions; Complete remission with incomplete blood count recover (CRi): All of the above criteria for CR must be met, except that absolute neutrophils <1000 /μL or platelets <100,000 /μL in the blood.	Day 30
Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Pilot Pediatric/Young 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.	100 days post CIML NK cell infusion
Kaplan-Meier Estimate of Percentage of Participants With Leukemia-Free Survival (LFS) (Pilot Pediatric/Young 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.	1 year post CIML NK cell 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.	100 days post CIML NK cell 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.	1 year post CIML NK cell infusion
Kaplan-Meier Estimate of Percentage of Participants With Overall Survival (OS) (Pilot Pediatric/Young Adult Cohort)	-OS is defined as the time from the date of Day 0 until death from any cause.	100 days post CIML NK cell infusion
Kaplan-Meier Estimate of Percentage of Participants With Overall Survival (OS) (Pilot Pediatric/Young Adult Cohort)	-OS is defined as the time from the date of Day 0 until death from any cause.	1 year post CIML NK cell infusion
Kaplan-Meier Estimate of Percentage of Participants With Overall Survival (OS) (Phase 2 Adult Cohort)	-OS is defined as the time from the date of Day 0 until death from any cause.	100 days post CIML NK cell infusion
Kaplan-Meier Estimate of Percentage of Participants With Overall Survival (OS) (Phase 2 Adult Cohort)	-OS is defined as the time from the date of Day 0 until death from any cause.	1 year post CIML NK cell infusion
Incidence and Severity of Acute GVHD Rates as Assessed on the Minnesota Grading Scale (Pilot Pediatric/Young Adult Cohort)	Incidence and severity of acute GVHD will be assessed based on the Minnesota grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).; The Minnesota Grading scale is graded with I, II, III, IV. Grade I is the least severe and Grade IV is the most severe.	Day 14 through 6 months
Incidence and Severity of Acute GVHD Rates as Assessed on the CIBMTR Grading Scale (Pilot Pediatric/Young Adult Cohort)	Incidence and severity of acute GVHD will be assessed based on the CIBMTR grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).; The CIBMTR grading scale is graded with A, B, C, or D. Grade A is considered the least severe with Grade D being the most severe.	Day 14 through 6 months
Incidence and Severity of Chronic GVHD Rates (Pilot Pediatric/Young Adult Cohort)	Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).; Severity is graded with mild, moderate, or severe chronic GVHD.	Day 100 through 12 months
Incidence and Severity of Acute GVHD Rates as Assessed on the Minnesota Grading Scale (Phase 2 Adult Cohort)	Incidence and severity of acute GVHD will be assessed based on the CIBMTR grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).; The Minnesota Grading scale is graded with I, II, III, IV. Grade I is the least severe and Grade IV is the most severe.	Day 14 through 6 months
Incidence and Severity of Acute GVHD Rates as Assessed on the CIBMTR Grading Scale (Phase 2 Adult Cohort)	Incidence and severity of acute GVHD will be assessed based on the CIBMTR grading scale. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).; The CIBMTR grading scale is graded with A, B, C, or D. Grade A is considered the least severe with Grade D being the most severe.	Day 14 through 6 months
Incidence and Severity of Chronic GVHD Rates (Phase 2 Adult Cohort)	Incidence and severity of chronic GVHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).; Severity is graded with mild, moderate, or severe chronic GVHD.	Day 100 through 12 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); Wugen, Inc.; Children's Discovery Institute
• Investigators: Principal Investigator: Amanda Cashen, M.D., Washington University School of Medicine

Publications and helpful links

General Publications

• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2017
• Primary Completion (Actual): June 15, 2025
• Study Completion (Actual): June 15, 2025

Study Registration Dates

• First Submitted: February 27, 2017
• First Submitted That Met QC Criteria: February 27, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Cytological Techniques; Biological Therapy; Cytapheresis; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Leukapheresis
• Other Study ID Numbers: 202206197; P50CA171963 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No