NK cell research – translational and clinical trials

NK Cell Research – Translational and Clinical Trials

Translational NK cell projects

Cytokines are small secreted or membrane bound proteins used by immune cells to communicate. NK cells express a number of cytokine receptors, that upon exposure to their specific cytokine signal, result in changes in the NK cell functional status. One recent and paradigm changing development in NK cell biology is the discovery of innate immune memory, whereby the NK cell undergoes a pre-activation event, and later has an enhanced responsiveness when re-simulated. First identified in mice by the Yokoyama/Cooper (cytokine-induced memory-like NK cells), Lanier/Sun (memory NK cells in the context of MCMV infection), and von Andrian labs (memory NK cells in the context of hapten-induced hypersensitivity), our laboratory has collaborated with the Cooper lab to investigate human cytokine-induced memory-like (CIML) NK cells. Human NK cells pre-activated overnight with combinations of IL-12, IL-15, and IL-18, that are then rested in vitro for 1-6 weeks, exhibit enhanced recall functional responses to cytokines, activating receptors, and tumor targets (Romee R et al, Blood, 2012, focus of Inside Blood comment.) Human CIML NK cells are induced to express CD25, which results in a functional high affinity IL-2αβγ expression, and responsiveness to low dose IL-2 (Leong R et al, BMT, 2014). Ongoing work in our laboratory involves the functional characterization of human CIML NK cells, their potential as anti-leukemia effectors, and translating this approach for preparing NK cells for adoptive immunotherapy for patients with acute myeloid leukemia.

FUNDING:

The following grants or awards support (or have supported) this research:
K08 Award form the NIH/NHLBI
V Scholar Award from the V Foundation for Cancer Research
BRIGHT Institute / P50 Molecular Imaging Center Pilot Award, Washington University
Translational Oncology Group Pilot Award, Division of Oncology, Washington University

Correlative studies for clinical trials

We have led or collaborated on a number of clinical trials using agents that may modulate NK cell functionality for cancer immunotherapy. This includes immunomudulatory agents in both acute myeloid leukemia (AML) (Fehniger et al., Blood, 2009 and 2011) and relapsed/refractory Hodgkin lymphoma (Fehniger et al., Blood, 2011). Ongoing research is examining the impact of these agents on NK cells and other lymphocytes, and correlating with clinical responses on these trials. We also are evaluating NK cell number and function in several ongoing clinical trials in relapsed/refractory Hodgkin lymphoma, and maintenance therapy after autologous hematopoietic stem cell transplantation.

FUNDING:

The following grants or awards support (or have supported) this research:

American Society of Clinical Oncology Young Investigator Award

NK cell immunotherapy

One approach to utilize NK cells as cancer therapeutics is to transfer allogeneic NK cells as a cellular therapy. We are currently participating in multi-center clinical studies evaluating NK cell adoptive immunotherapy. In other collaborative studies, hematopoietic stem cell donors are chosen in an attempt to maximize NK cell responses to leukemia by analyzing the killer-cell immunoglobulin-like receptors (KIR) repertoire, and NK cells are used as immunotherapy prior to MHC-haploidentical allogeneic hematopoietic stem cell transplantation. In addition, our laboratory seeks to translate novel findings in NK cell biology into new immunotherapy strategies for cancer patients.