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

The Washington University

Status and phase: Completed; Phase 2; Phase 1

Conditions: Acute Myeloid Leukemia

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

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT03068819

202206197

P50CA171963 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Enrollment: 62 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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62 participants in 2 patient groups

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

Experimental group

Description:

* 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.

Treatment:

Procedure: CD3+ T Cell Product Infusion

Drug: CIML NK Cell Infusion

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

Experimental group

Description:

* 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.

Treatment:

Procedure: CD3+ T Cell Product Infusion

Drug: CIML NK Cell Infusion