Despite oncolytic adenoviruses emerging as promising new therapeutics for patients with glioblastoma (GBM), there are no translational mammalian models in an immune competent animal that are permissive to adenoviral infection and that allow for integration of both the oncolytic and immune effects of these viruses. The overall objectives of this proposal are to develop and characterize a Golden hamster model of GBM that addresses the limitations of existing murine models with respect to pre-clinical testing of oncolytic adenoviral therapy. The central hypothesis is that hamster GBM models will provide reliable pre-clinical data to decipher oncolytic adenoviral therapeutic mechanisms and to evaluate preclinical strategies for translation to patients. The rationale for the proposed research is that understanding the interactions between viral oncolysis and the immune system will uncover mechanisms of therapeutic efficacy, identify which patients might respond best, and reveal new combinatorial therapeutic approaches. The central hypothesis will be tested in three specific aims: 1) Develop hamster glioma stem cell (hamGSC) lines that reflect common molecular alteration in human glioma, 2) Characterize the hamster immune response to oncolytic adenovirus, and 3) Evaluate the effects of pharmacological manipulation of the immune system on the efficacy of Delta-24-RGD.
In Aim 1, CRISPR gene targeting will be used to create hamGSC lines driven by specific driver alterations to reflect human GBM molecular subtypes.
In Aim 2, the immune response to oncolytic adenovirus will be characterized. Using T-cell depletions strategies, the contributions of immune effector cells to oncolytic virus efficacy and long-term immune memory and the impacts of pre-existing exposure to adenovirus will be evaluated.
Aim 3 will evaluate the effects of immune function via either corticosteroids or immune checkpoint inhibitors on oncolytic adenovirus therapeutic efficacy. Collectively, the studies proposed in this application will result in the development and characterization of a novel mammalian model for translational evaluation of oncolytic adenovirus in the treatment of GBM. This contribution is significant because it will overcome many limitations of mouse glioma models and for the first time provide a platform for pre-clinical studies to evaluate the efficacy and mechanisms of oncolytic adenoviral therapy against GBM. The proposed research is innovative because this is the first hamster glioma model that is intracranial, immune competent, and adenoviral replication permissive. This represents a distinct advantage over traditional murine models, particularly in the setting of evaluating immune-modulating therapies such as oncolytic adenoviral therapy.
The proposed studies in this research project are relevant to public health because the translational mammalian models such as those developed in this proposal are crucial for evaluating the efficacy of oncolytic virotherapy for cancer. This is particularly important for GBM, a disease for which few therapeutic strategies exist. These models will provide a much-needed platform for determining appropriate patient populations and evaluating effective single and combination immunotherapy treatment strategies.
