Register now After registration you will be able to apply for this opportunity online.
This opportunity is not published. No applications will be accepted.
Immunotherapy of canine brain cancer
We are collaborating with veterinary clinics to launch an interventional trial in dogs bearing spontaneous, naturally occuring gliomas. We plan to combine IL-12Fc with checkpoint blockade. To this end we will test human checkpoint inhibitors for their functionality on canine lymphocytes.
Keywords: Brain Tumors, Glioma, Neuroimmunology, Comparative Oncology, Translational Medicine, Veterinary Immunology, Cancer Immunotherapy, Checkpoint Blockade, Protein Engineering, Protein Purification, Molecular Biology, Primary Cell Culture,
The brain is an immunologically unique site with reduced cellular infiltration and antigen presentation. Gliomblastoma (GB), the most frequent brain cancer, is known to form a highly immunosuppressive microenvironment, suggesting that patients could benefit from immunomodulatory drugs. Multiple therapies focusing on (re-) activating the immune system are currently under development, including application of a potent activator of immune responses, interleukin (IL)-12. This cytokine stimulates the cytotoxic function of lymphocytes and can trigger rejection of gliomas in preclinical studies. The local application of IL-12 Fc-fusion cytokine (IL-12Fc) was an essential prerequisite for effective combination treatments with other immuno-therapeutic regimens, which are already approved for the treatment of metastatic melanoma (CTLA-4 or PD-1 blockade; vom Berg, Vrohlings et al. 2013, vom Berg, Becher unpublished) in extremely late stage tumors. IL-12 therefore represents an ideal candidate to boost other immunotherapeutical approaches in GB and may serve as the prototype for a new class of treatments that are applied intratumorally to break down local GB immunosuppression.
To validate the local immunotherapy with IL-12Fc in a therapeutic setting we are collaborating with veterinary clinics to launch an interventional trial in dogs bearing spontaneous, naturally occuring gliomas. Although the biology of checkpoint receptors is largely shared between humans, dogs and rodents, it has not yet been validated if anti-human checkpoint blocking antibodies are active on canine lymphocytes (Anderson, Modiano 2015). As there is no standard-treatment in dog GB therapy, it is a common practice to repurpose human drugs after dose adjustments (according to dosing recommendations for humans (Furdos et al. 2015)). Using human checkpoint blocking agents in combination with IL-12Fc will facilitate further translation of such combination into human clinics. To this end we plan to test human checkpoint inhibitors for their functionality on canine lymphocytes. Furthermore, the best therapeutic will require optimization for local delivery and validation of its biodistribution in the brain.
The brain is an immunologically unique site with reduced cellular infiltration and antigen presentation. Gliomblastoma (GB), the most frequent brain cancer, is known to form a highly immunosuppressive microenvironment, suggesting that patients could benefit from immunomodulatory drugs. Multiple therapies focusing on (re-) activating the immune system are currently under development, including application of a potent activator of immune responses, interleukin (IL)-12. This cytokine stimulates the cytotoxic function of lymphocytes and can trigger rejection of gliomas in preclinical studies. The local application of IL-12 Fc-fusion cytokine (IL-12Fc) was an essential prerequisite for effective combination treatments with other immuno-therapeutic regimens, which are already approved for the treatment of metastatic melanoma (CTLA-4 or PD-1 blockade; vom Berg, Vrohlings et al. 2013, vom Berg, Becher unpublished) in extremely late stage tumors. IL-12 therefore represents an ideal candidate to boost other immunotherapeutical approaches in GB and may serve as the prototype for a new class of treatments that are applied intratumorally to break down local GB immunosuppression. To validate the local immunotherapy with IL-12Fc in a therapeutic setting we are collaborating with veterinary clinics to launch an interventional trial in dogs bearing spontaneous, naturally occuring gliomas. Although the biology of checkpoint receptors is largely shared between humans, dogs and rodents, it has not yet been validated if anti-human checkpoint blocking antibodies are active on canine lymphocytes (Anderson, Modiano 2015). As there is no standard-treatment in dog GB therapy, it is a common practice to repurpose human drugs after dose adjustments (according to dosing recommendations for humans (Furdos et al. 2015)). Using human checkpoint blocking agents in combination with IL-12Fc will facilitate further translation of such combination into human clinics. To this end we plan to test human checkpoint inhibitors for their functionality on canine lymphocytes. Furthermore, the best therapeutic will require optimization for local delivery and validation of its biodistribution in the brain.
Specific Experiments:
During the stay at the Institute of Laboratory Animals Science at the UZH, successful candidate will be supervised by Prof. Thorsten Buch and Dr. Johannes vom Berg. He will actively pursue:
A) Testing different checkpoint blocking agents for their suitability to be combined with IL-12 on canine lymphocytes (primary cell cultue, flow cytometry, ELISA, flow cytometry)
B) Optimization and upscaling of protein production (cell culture, chromatography, molecular biology)
C) In vivo testing of functionality and body distribution in transgenic mice recapitulating aspects of the human system (animal experimentation, ELISA, flow cytometry)
Specific Experiments: During the stay at the Institute of Laboratory Animals Science at the UZH, successful candidate will be supervised by Prof. Thorsten Buch and Dr. Johannes vom Berg. He will actively pursue:
A) Testing different checkpoint blocking agents for their suitability to be combined with IL-12 on canine lymphocytes (primary cell cultue, flow cytometry, ELISA, flow cytometry) B) Optimization and upscaling of protein production (cell culture, chromatography, molecular biology) C) In vivo testing of functionality and body distribution in transgenic mice recapitulating aspects of the human system (animal experimentation, ELISA, flow cytometry)
Dr. Johannes vom Berg
E-mail: johannes.vomberg@uzh.ch
Tel: +41 44 255 3606
University of Zurich
Transgenic Techniques
Institute of Laboratory Animal Science
Vetsuisse Faculty
Sternwartstr. 6
8091 Zürich
Switzerland
and
University of Zurich
Local Immnotherapy of Glioblastoma Group
Institute of Laboratory Animal Science
Vetsuisse Faculty
Wagistrasse 12
8952 Schlieren
Switzerland
Dr. Johannes vom Berg E-mail: johannes.vomberg@uzh.ch Tel: +41 44 255 3606
University of Zurich Transgenic Techniques Institute of Laboratory Animal Science Vetsuisse Faculty Sternwartstr. 6 8091 Zürich Switzerland
and
University of Zurich Local Immnotherapy of Glioblastoma Group Institute of Laboratory Animal Science Vetsuisse Faculty Wagistrasse 12 8952 Schlieren Switzerland