Cancer Research in Switzerland - Krebsliga Schweiz

centre of a new study, based on the same data and also
supported by the Foundation Cancer Research Switzerland
(CRS) and the Swiss Cancer League (SCL).
Project coordinator
PD Dr Nicolas von der Weid
Service de pédiatrie
Centre hospitalier universitaire vaudois (CHUV)
Rue du Bugnon 46
CH-1011 Lausanne
Phone +41 (0)21 314 13 34
Fax +41 (0)21 314 33 32
nicolas.von-der-weid@chuv.ch
Wodnar-Filipowicz Aleksandra | Immunotherapy of
human leukemia with natural killer cells: From bench
to bedside (OCS 02175-02-2008)
Acute leukaemias are rapidly progressing blood cell malignancies
with poor prognosis. Front-line therapies with
high doses of cytostatic agents and transplantation of
allogeneic stem cells from the healthy bone marrow of
donors offer the best chance of cure, but relapses are
frequent and often fatal. This study aims at increasing the
cure rate of patients with acute leukaemia by developing
clinically-suitable approaches to immunotherapy with
natural killer (NK) cells, a subpopulation of white blood
cells capable of recognizing and eliminating malignant
cells.
The following goals have been achieved:
1) The protocol of large-scale clinical-grade in vitro expansion
of highly purified human NK cell products, which
was developed at the Laboratory of Experimental Haematology,
was adapted to rigorous good manufacturing
practice (GMP)-compliant conditions suitable for clinical
implementation. NK cells were purified from the peripheral
blood of 6 healthy blood donors, and cultured in
closed air-permeable culture bags with certified culture
medium and components approved for human use. NK
cell numbers increased 117.0±20.0 fold in 19 days.
2) GMP-certified cell sorting was introduced to obtain
cells with a high anti-leukaemic potential, called “single
KIR NK cells”. The subsequent GMP-compliant expansion
of cells was 268.3±66.8 fold, with a contaminating T cell
content of only 0.006 %±0.002 %. The cell sorting step
preceding the expansion step offered important advantages
of increased tumour specificity with reduced culture
volume, as well as lowered the costs of NK cell expansion.
3) To implement our project in clinical practice, the GMP
Laboratory was designed and built in 2010 at the Division
of Diagnostic Hematology of University Hospital Basel.
The construction and infrastructure conform to current
regulations in Switzerland. The personnel, including academics
and technicians, were trained, and the standard
operating procedures were established. After the final
certification of the GMP laboratory by Swissmedic, the
feasibility, safety and efficacy of administration of expanded
NK cells will be evaluated in phase I/II trials in the
following clinical settings: a) in patients with leukaemia,
after haploidentical stem cell transplantation; b) in patients
with multiple myeloma, after autologous transplantation;
and c) in elderly leukaemia patients not eligible for
intensive chemotherapy and stem cell transplant.
4) Our experimental studies designed to characterize the
efficacy of alloreactive NK cells against leukaemia demonstrated
that NK cells generated ex vivo with a GMP-compatible
expansion protocol specifically recognize and destroy
primary leukaemic blasts.
We provided the first evidence that expanded “single-KIR
NK” cells had a significant tumour-reducing effect in vivo
in mice inoculated with human leukaemic cells. We also
showed that NK cells are active against leukaemic stem
cells, a small cell population responsible for both the initiation
and recurrence of the malignancy, and therefore
representing an important target for immunotherapy.
The preclinical studies described in this project delivered
important information as to the anti-leukaemic potential
of high dose of activated NK cells, and the obtained results
are contributing to the development of novel immunotherapeutic
approaches increasing the chances of leukaemia
cure. Our translational project combines the
expertise of the Laboratory of Experimental Hematology
in the Department of Biomedicine and the Stem Cell
Transplant Team at the Hematology Clinic in the University
Hospital Basel.
Project coordinator
Prof. Dr. Aleksandra Wodnar-Filipowicz
Basel Stem Cell Center of Competence
Medizinische Fakultät
Universität Basel
Klingelbergstrasse 61
CH-4056 Basel
Phone +41 (0)61 265 33 87
aleksandra.wodnar-filipowicz@unibas.ch
Wodnar-Filipowicz Aleksandra | Role of the natural
killer cell receptors NCR and KIR in immune defence
against human leukemia (OCS 01664-02-2005)
Acute leukaemias are rapidly progressing blood cell malignancies
with poor prognosis. Therapies with high dose of
cytostatic agents and transplantation of stem cells offer
the best chance of cure, but relapses are frequent and often
fatal. Immunotherapy with natural killer (NK) cells
represents a novel strategy to eliminate the residual malignant
clones and prevent recurrence of the disease.
This research project addressed the mechanisms of antileukaemic
function of human NK cells. In a collaborative
effort with the clinics of haematology in Basel and Aarau
and in Warsaw, Poland, we were able to acquire a large
number of leukaemia patient-derived blood and bone
marrow samples. We demonstrated that expression of cell
surface molecules serving as ligands for activating and inhibitory
NK cell receptors defines the recognition and
elimination of tumour cells by the cytotoxic function of
NK cells. Therefore, our next goal was to design experimental
approaches to enhance the leukaemia recognition
process by means of selecting the anti-leukaemic, alloreactive
NK cell populations. To strengthen the activating
interactions between NK cells and leukaemic targets, we
developed pharmacological treatments that enhanced the
expression of cell surface ligand molecules specific for NK
cells. To optimize the NK cell-mediated immunity against
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