Natural Killer Cells in Acute Leukaemia and Myelodysplastic Syndrome

NCT02123836 | Unknown Phase 1

• 1 other identifier: NKEXPSIN-2013/01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

A novel method has been developed to expand natural (NK) cells and enhance their cytotoxicity against cancer cells while maintaining low killing capacity against non-transformed cells. In this method, donor NK cells are expanded by co-culture with the irradiated K562 cell line modified to express membrane bound IL-15 and 41BB ligand (K562-mb15-41BBL). Expression of these proteins in conjunction with unknown stimuli provided by K562 cells promotes selective growth of NK cells. Then, the expanded NK cell population is depleted of T cells to prevent graft versus host disease (GVHD). Expanded and activated NK cells showed powerful anti-leukemic activity against acute myeloid leukemia (AML) cells in vitro and in animal models of leukemia.Unpublished laboratory results also demonstrated that T-cell acute lymphoblastic leukaemia (T-ALL) is extremely sensitive to the cytotoxicity exerted by the expanded and activated NK cells. The present study represents the translation of the laboratory findings into clinical application. The study proposes to determine the feasibility, safety and efficacy of infusing expanded NK cells into patients who have AML or T-lineage ALL which is resistant to standard therapy as demonstrated by persistent minimal residual disease (MRD). Patients with myelodysplastic syndrome (MDS), who are at high risk to develop AML will also be eligible for the study. In this patient cohort, the study will also investigate the in vivo lifespan and phenotype of the expanded NK cells. The main hypothesis to be tested in this study is that infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML or T-ALL.

Conditions

Acute Leukaemia; Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Minimal Residual Disease (MRD) levels

  MRD blood levels will be tested at baseline, weekly during the first 2 months and monthly thereafter

  1 year

Study Arms (1)

NK cells

EXPERIMENTAL

Peripheral blood cell will be collected by apheresis from donors. Peripheral blood mononucleated cells will be cultured with irradiated K562-mb15-41BBL cells and low dose (10 IU/mL) IL-2 for 10 days. After T-cell depletion, expanded activated NK cells will be infused. Before infusion, patients will receive immunosuppressive therapy to promote temporary engraftment of NK cells. After infusion, they will receive IL-2 to support NK cell viability and expansion in vivo. The effects of NK cell infusion will be determine by comparing MRD levels before and after treatment.

Biological: NK cells

Interventions

NK cells BIOLOGICAL

7 days of preparatory treatment are given before the NK cell infusion. Chemotherapy will be given over 6 days. This chemotherapy will promote donor NK cells engraftment. After which, a drug called Interleukin-2 (IL-2) will be given as an injection just under the skin three times per week for at least 2 weeks (total of 6 doses). This treatment is used to help keep the donor NK cells alive. Blood cells will be collected from an eligible and suitable family donor 10 days before infusion. The collection sample will be processed to remove red blood cells and as many T-cells as possible. T-cells from the donor might cause these donor cells to attack the body, usually the skin, liver, and intestines. NK cells will be activated in the National University Hospital lab and ready for infusion on Day 0. The NK cells will then be infused into the vein, through a peripheral catheter.

NK cells

Eligibility Criteria

• Age: 6 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• From 6 to 80 years old at time of consent.
• Patients with the following haematological diseases:
• Acute myeloid leukaemia (de novo or secondary)
• Myelodysplastic syndromes (RAEB I/II)
• T-cell acute lymphoblastic leukaemia (T-ALL)
• Patients must have been treated with prior standard intensive chemotherapy upfront, which will be defined according to institutional practice for each respective disease, and may include allogeneic haematopoietic stem cell transplantation.
• Patients must have persistent detectable residual leukaemia following initial treatment with intensive chemotherapy. Residual leukaemia is defined as the presence of \>=0.01%-20% blasts in the bone marrow by flow cytometry.
• High risk AML patients with either High risk cytogenetics or FLT3-ITD mutation or Acute megakaryoblastic leukaemia in non-Down's Therapy related leukaemia or Myelodysplastic syndrome
• will qualify for NKEXPSIN either after Induction I chemotherapy or Induction II chemotherapy regardless of residual disease.
• At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation therapy.
• Shortening fraction greater than or equal to 25%.
• Glomerular filtration rate greater than or equal to 60ml/min.
• Pulse oximetry greater than or equal to 92% on room air.
• Direct bilirubin less than or equal to 3x Upper Limit of Normal (ULN).
• Karnofsky performance score of greater than or equal to 50.

You may not qualify if:

• Currently has pleural or pericardial effusion.
• Receiving more than the equivalent of prednisone 10 mg daily.
• Lactating or pregnant. Negative serum or urine pregnancy test result must be within 7 days prior to enrolment.
• HIV positive. Negative results must be within 60 days prior to enrolment.
• Lactating or pregnant. Negative serum or urine pregnancy test result must be within 7 days prior to enrolment.

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital

Singapore, 119074, Singapore

RECRUITING

Related Publications (3)

• Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009 May 1;69(9):4010-7. doi: 10.1158/0008-5472.CAN-08-3712. Epub 2009 Apr 21.

  PMID: 19383914 BACKGROUND

• Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005 Jul 1;106(1):376-83. doi: 10.1182/blood-2004-12-4797. Epub 2005 Mar 8.

  PMID: 15755898 BACKGROUND

• Fujisaki H, Kakuda H, Imai C, Mullighan CG, Campana D. Replicative potential of human natural killer cells. Br J Haematol. 2009 Jun;145(5):606-13. doi: 10.1111/j.1365-2141.2009.07667.x. Epub 2009 Mar 26.

  PMID: 19344420 BACKGROUND

Related Links

• National University Cancer Institute, Singapore

MeSH Terms

Conditions

Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Frances Yeap, MBBS

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Frances Yeap, MBBS

CONTACT

(65) 6779 5555; frances_yeap@nuhs.edu.sg

Dario Campana, MBBS

CONTACT

(65) 6601 2666; paedc@nus.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2014
• First Posted: April 28, 2014
• Study Start: April 1, 2014
• Primary Completion: September 1, 2020
• Study Completion: October 1, 2020
• Last Updated: April 16, 2019

Record last verified: 2019-04

Locations

SG (1)