Adoptive Immunotherapy of High Risk Acute Myeloblastic Leukemia Patients Using Haploidentical Kir Ligand-mismatched Natural Killer Cells

Phase 1

• Conditions: Myeloblastic Leukemia
• Interventions: Biological: NK cells

• Registration Number: NCT00799799
• Lead Sponsor: University of Bologna

Brief Summary

AML patients with de-novo or secondary disease with age greater than 18 years not eligible for stem cell transplantation for medical contraindications, lack of donor or lack of stem cells,are eligible. Leukemias other than AML and M3 FAB subtype will be excluded from the study. Immunosuppressive chemotherapy prior to NK cell infusion will include: fludarabine and cyclophosphamide 4g/m2 (Flu/Cy). The therapy will be administered over 6 days on inpatient basis. Haploidentical NK cells will be selected from a steady-state large volume leukapheresis product from a suitable KIR ligand incompatible donor. Donor-recipients pairs will be selected on the basis of known KIR ligands. In particular, haploidentical donors will be included if present at least one allele mismatch at a class I locus among the following ones: HLA-C alleles with Asn77-Lys80, HLA-C alleles with Ser77-Asn80, HLA-Bw4 alleles. Immunomagnetic enrichment of NK cells will follow two subsequent steps: 1) depletion of CD3+ T cells followed by 2) positive selection of CD56+ NK cells. Contaminating CD3+ T cells will be carefully evaluated.

Detailed Description

When previously cryproserved NK cells are still available, further re-infusions may be performed, according to PI's evaluation. The number of remaining NK cells must be sufficient for the reinfusion of at least the minimum dose of cells (106/kg). At least two months should elapse between two consecutive infusion procedures.

Study Timeline

• Study Start: 2005-10
• Study First Submitted: 2008-11-28
• Study First Submitted QC: 2008-11-28
• Study First Posted: 2008-12-01
• Status Verified: 2009-09
• Last Update Submitted: 2009-09-23
• Last Update Posted: 2009-09-24
• Primary Completion: 2009-12
• Study Completion: 2009-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

• Signed informed consent.
• Performance Status ≥ 70% (Karnofsky score) or ≤ 2 (WHO).
• Age greater than 18 years.
• Availability of a KIR incompatible haploidentical donor.
• Adequate renal (serum creatinine < 2 mg/dl), pulmonary (Sat O2 ≥ 96%) and hepatic (ALT/AST < 2.5 x N) function.
• Patients enrolled in the protocol must have an autologous graft cryopreserved to be reinfused in case of severe myelosuppression induced by haploidentical NK cells. Back-up cells will be reinfused in case of ANC < 0.5 x 109/L at day + 40 from the start of immunosuppressive regimen.

Exclusion Criteria

• Age < 18.
• People unable to give informed consent.
• HIV positivity.
• HCV positivity with high viral load.
• Intercurrent organ damage or medical problems that would interfere with therapy.
• Pregnant or nursing females.
• Current uncontrolled infection.
• No availability of a cryopreserved autologous stem cell graft to be reinfused in case of severe myelosuppression.
• Signs or symptoms of fluid retention (e.g. pleural effusion)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
NK	NK cells	patient treated as per protocol

Primary Outcome Measures

Name	Time	Method
To assess the feasibility of the reinfusion of the minimum accepted cell dose (1x10E6 haploidentical NK cells /Kg) in all patients enrolled into the protocol	every 6 months
To assess the feasibility of the selection and reinfusion of 5x10E6 haploidentical natural killer (NK) cells /Kg of body weight (target cell dose) in at least 40% of adult patients with active acute myeloblastic leukemia (AML) entering the study	every 6 months

Secondary Outcome Measures

Name	Time	Method
To evaluate the microchimerism of AML patients receiving haploidentical human NK cells for adoptive immunotherapy	every 6 months
To evaluate, in vitro and in vivo, the antitumor activity of haploidentical NK cells infused in AML patients	every 6 months
To assess the percentage of patients entering complete remission (CR) after the reinfusion of highly purified haploidentical NK cells	every 6 months
To assess the safety of infusion of haploidentical NK cells, following immunosuppressive chemotherapy, considered as the incidence of adverse event (graded according to WHO) and clinically significant abnormal laboratory values following reinfusion	every 6 months
To assess the disease-free and overall survival of AML patients infused with haploidentical NK cells	every 6 months

Trial Locations

Locations (1)

Institute of Hematology "L. & A. Seragnoli"; 🇮🇹 Bologna, Bo, Italy