Project Details
Projekt
Imaging NK cell reactivity in cancer immunotherapy
Applicant
Dr. Stefanie Maurer
Subject Area
Hematology, Oncology
Term
from 2019 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 432642091
The introduction of therapeutic antibodies (mAb) has largely improved the treatment options for cancer patients. Induction of antibody-dependent cellular cytotoxicity (ADCC) of NK cells is a major mechanism by which antitumor mAb mediate their efficacy in hematological malignancies; in solid tumors, mAb are less effective so far. Accordingly, many efforts presently aim to improve induction of ADCC as important mAb function. Imaging modalities which allow for detection of tumor-infiltrating immune cells and their antitumor effects upon therapeutic intervention would improve our understanding of the mechanisms underlying host-tumor interaction. Notably, they may also be able to predict therapy response and thus serve as marker to guide treatment and predict treatment success in patients. In the proposed project, we plan to establish a multireporter-based model to non-invasively image induction of NK cell tumoricidal effects against solid tumors upon application of two exemplary antibody-like molecules containing engineered Fc domains to bolster ADCC. The first is termed NKG2D-Fc-ADCC and targets ligands of the immunoreceptor NKG2D (NKG2DL) which are widely expressed on malignant cells but generally absent on healthy tissue. The second, termed 293C3-SDIE, targets CD133 (Prominin-1) which is expressed in several tumor entities and associated with so called cancer stemness in solid tumors. To allow for concurrent imaging of NK cell infiltration and their specific tumoricidal effects, NK cells as well as tumor cells will be genetically engineered to express a distinct combination of fluorescent protein and luciferase. The resulting model will constitute a valuable “toolbox” to study NK cell mediated specific lysis of fluorescent target cells in vitro as well as tumor infiltration / eradication in vivo by measuring distinct luciferase-activity using optical imaging. This will allow to monitor tumor infiltration by NK cells and the induction of ADCC by the Fc engineered NKG2DL- or CD133-targeting compounds. Finally, we will determine whether the combination of both therapeutic compounds achieves additive effects superior to treatment with either compound alone, in particular with regard to elimination of tumor stem cells.Altogether, the envisaged project employs cost-effective imaging modalities for imaging of cytotoxic lymphocytes and monitoring of their antitumor reactivity upon immunotherapeutic intervention. Besides improving our understanding of the mechanisms underlying therapeutically induced antitumor immunity, it may ultimately serve to develop a valuable marker for predicting treatment response in cancer patients. The latter could then be readily translated to clinical trials evaluating future nuclear reporter-based investigations.
DFG Programme
Research Fellowships
International Connection
USA
