Project

Back to overview

Immunotherapy with NK cells: adoptive transfer of ex vivo expanded and activated NK cells in elderly patients with acute myeloid leukemia

English title Immunotherapy with NK cells: adoptive transfer of ex vivo expanded and activated NK cells in elderly patients with acute myeloid leukemia
Applicant Passweg Jakob
Number 149647
Funding scheme Project funding (Div. I-III)
Research institution Abteilung für Hämatologie Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Internal Medicine
Start/End 01.01.2015 - 31.12.2017
Approved amount 300'318.00
Show all

Keywords (5)

NK cell; in vitro expansion and activation; adoptive immunotherapy; acute myeloid leukemia; cell therapy

Lay Summary (German)

Lead
Immun-Therapie bei älteren Menschen mit akuter myeloischer Leukämie mit Hilfe von in vitro expandierten und aktivierten natürlichen Killerzellen.Die akute myeloische Leukämie hat bei Patienten über 65 Jahren eine ungünstig Prognose . Das Ziel dieses Projektes ist, mit Hilfe zellulärer Therapien Rückfälle nach Chemotherapie zu verhindern. Natürliche Killerzellen (NK-Zellen) sind Teil der menschlichen Abwehr und können Tumorzellen zerstören.
Lay summary

Vorgehen des Forschungsprojektes

Die Technologie der besten Expansion wird in 3 Gruppen mit 5 Spender-Empfängerpaaren getestet.  Der Teil des Projektes, welcher sich mit der Optimierung der Expansion der NK-Zellen befasst, untersucht Expansion in Kulturbeuteln mit einem Bioreaktor, in dem je hälftig die eine oder andere Methode angewendet wird (Teil I). Dann soll die Expansion von herkömmlichen NK-Zell-Präparaten verglichen werden mit der Expansion nach einer durchflusszytometrie-basierten Selektion von Zellen. Dies definiert die beste Strategie für Expansion und Aktivierung (Teil II).

Teil III dient die Resultate zu bestätigen. Vor der NK-Zell-Übertragung erhalten die Patienten eine Therapie, welche die Abwehr hemmt, um das Überleben der NK Zellen zu erleichtern. Mit dem gleichen Ziel erhalten sie niedrig dosiertes Interleukin-2, ein Gewebehormon, welches Angehen und Überleben der NK-Zellen fördert. Auch wird ein Medikament verabreicht, welches auf Leukämiezellen Eiweisse aufreguliert, welche von NK-Zellen erkannt werden. Die Übertragung von NK-Zellen ist begleitet von Untersuchungen über die Wirksamkeit und das Überleben der Zellen im Empfänger.

Als Ganzes wird dieses Projekt erlauben die beste Strategie der natürliche Killer-Zell Expansion und Aktivierung zu definieren und die Durchführbarkeit und die Sicherheit dieses Vorgehens beim Patienten zu bestätigen. Auch können erste Daten zur Wirksamkeit bei Patienten gewonnen werden.

Wissenschaftliche und Medizinische Bedeutung

Nach Jahren der Therapieoptimierung mit immer neuen Chemotherapie-Kombinationen ohne durchschlagenden Erfolg erscheint es sinnvoll, andere Vorgehensweisen zu erforschen, welche die Chemotherapie mit immun-therapeutischen Ansätzen kombinieren. Die NK-Zellen sind auf Grund bisheriger Ergebnisse geeignet, hier eine Rolle zu spielen.

Direct link to Lay Summary Last update: 16.10.2014

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
152992 Killer cell Immunoglobulin-like Receptors (KIR) in the recognition of tumor- and virus-transformed target cells 01.10.2014 SNSF Professorships
128461 Killer cell Immunoglobulin-like Receptors (KIR) in the recognition of tumor- and virus-transformed target cells 01.10.2010 SNSF Professorships

Abstract

Immunotherapy with NK cells: Adoptive Transfer of ex vivo Expanded and Activated NK Cells in Elderly Patients with Acute Myeloid LeukemiaAcute myeloid leukemia (AML) is the most common acute leukemia in adults and incidence is increasing as the population ages. More than 75% of AML patients are older than 65 years of age. These patients have worse prognosis, for reasons of unfavorable complex cytogenetic abnormalities, poor drug tolerance, concurrent medical conditions, and reduced performance status. Despite recent diagnostic and therapeutic advances, the cure rates in elderly with AML do not exceed 10%, an outlook that has not improved in 3 decades.Once diagnosis of AML is made, the primary treatment objective is to induce remission and thereafter to prevent relapse. In elderly patients this intensive treatment plan often cannot be carried out. With this project, we propose to improve the outlook in elderly AML patients by introducing anti-tumor immunotherapy with natural killer (NK) cells to patients with otherwise no curative options. Our strategy will offer a 2-phase treatment, with induction chemotherapy applied first to reduce the tumor load, to be followed by multiple infusions of alloreactive NK cells from haploidentical family donors to prevent disease recurrence.This translational project represents a committed continuation of our 10-year experience in NK cell research and clinical application. The therapeutic strategies investigated here will explore molecular mechanisms of receptor-regulated NK cell alloreactivity to enhance antitumor efficacy of high doses of ex vivo expanded and activated NK cells in a clinical setting. The proposed trial will include patients with AML older than 65 years and will be conducted with the following aims: Aim (I): Infuse high doses of alloreactive NK cells against AML NK cell products obtained from haploidentical donors, will be expanded ex vivo under Good Manufacturing Practice (GMP) conditions and used to treat patients with AML with multiple NK cell infusions. The strategy of cell expansion is defined in Aim II, and will be performed in 3 steps, each involving 5 donors. Consequently, the treatment will include fifteen patients. Transfer of NK cells will be preceded by lymphodepleting treatment with fludarabine and cyclophosphamide, and followed by subcutaneous administration of low-dose interleukin-2, to promote NK cell engraftment and survival. In addition, valproic acid, an inhibitor of histone deacetylase, will be administered during the lymphodepleting treatment with the aim to up-regulate the expression of ligands for activating NK cell receptors on residual AML blast cells, thus enhancing the recognition of AML blasts by infused NK cells. The immunotherapy trial will be supported by follow-up studies to correlate clinical parameters with NK cell dose, timing and characteristics. The details of the trial are given in the attached clinical phase I/II protocol.Aim (II): Define optimal GMP laboratory procedures to expand alloreactive NK cellsIn the current trial, two novel GMP expansion strategies will be assessed: A) expansion in a bioreactor providing constant medium exchange, allowing for increased cell density; B) flow-sorting of alloreactive NK cell subsets expressing single inhibitory NK cell receptors (KIR), with the aim of reducing culture volume, and eliminating contaminating T cells and nonreactive NK cell subsets. To evaluate these novel strategies, 3 consecutive steps, each involving 5 haploidentical NK cell donors, will be applied. In step one, purified NK cells will be split into equal portions half to be expanded in the standard culture bags and CO2 incubators and half in the bioreactor. In step two, expansions will apply the better technology defined in step one, and compare equally split portions of purified NK cells cultured as bulk or as flow-sorted alloreactive cell subsets. In step three, expansions will combine the knowledge obtained in steps one and two to confirm the methodology of generating the optimal NK cell product in a GMP setting. Paired comparisons of cell products will include NK cell expansion rate, T-cell contamination, cell viability, and cytotoxic function.The primary short-term goal of the proposed study is feasibility and safety of novel NK cell-based immunotherapy strategies. In the long-term, our goal is to improve clinical parameters, which prolong patients’ survival. This project will strengthen the expertise of the Stem Cell Transplant Team at the University Hospital Basel as a leading center in treatment of hematological malignancies in Europe.
-