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

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.

Study Overview

• Status: Unknown
• Conditions: Myeloblastic Leukemia
• Intervention / Treatment: Biological: NK cells

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 Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Roberto M Lemoli, MD; Phone Number: 3680 +39 051 636; Email: roberto.lemoli@unibo.it
• Study Contact Backup: Name: Antonio Curti, MD; Phone Number: 3680 +39 051 636; Email: antonio.curti2@unibo.it

Study Locations

• Italy
  • Bo
    • Bologna, Bo, Italy, 40138
      • Recruiting
      • Institute of Hematology "L. & A. Seragnoli"

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NK; patient treated as per protocol	Biological: NK cells; NK cells infusion after immunosuppressive chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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
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

Secondary Outcome Measures

Outcome Measure	Time Frame
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 disease-free and overall survival of AML patients infused with 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

Collaborators and Investigators

• Sponsor: University of Bologna

Publications and helpful links

General Publications

• Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002 Mar 15;295(5562):2097-100. doi: 10.1126/science.1068440.
• Curti A, Ruggeri L, D'Addio A, Bontadini A, Dan E, Motta MR, Trabanelli S, Giudice V, Urbani E, Martinelli G, Paolini S, Fruet F, Isidori A, Parisi S, Bandini G, Baccarani M, Velardi A, Lemoli RM. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood. 2011 Sep 22;118(12):3273-9. doi: 10.1182/blood-2011-01-329508. Epub 2011 Jul 25.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Anticipated): December 1, 2009
• Study Completion (Anticipated): December 1, 2009

Study Registration Dates

• First Submitted: November 28, 2008
• First Submitted That Met QC Criteria: November 28, 2008
• First Posted (Estimate): December 1, 2008

Study Record Updates

• Last Update Posted (Estimate): September 24, 2009
• Last Update Submitted That Met QC Criteria: September 23, 2009
• Last Verified: September 1, 2009

More Information

Terms related to this study

• Keywords: Nk cells infusion; minimal residual disease in AML patients; trafficking of NK cells after infusion; cytolytic effects on leukemic cells
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
• Other Study ID Numbers: NK TRIAL