Our overall goal is to develop protocols by which oncolytic viruses can be systemically delivered in patients leading to treatment of metastatic tumors. Based upon our pre-clinical experiments showing that intravenous (i.v.) delivery of oncolytic reovirus can have significant anti tumor activity in animal models, we have completed Phase I/II clinical trials, confirming that i.v. reovirus is safe in humans. Using data from these trials, our additional pre-clinical experiments showed that tumor vasculature can be conditioned for increased reovirus replication following i.v. delivery by carefully timed combination of paclitaxel chemotherapy and reovirus virotherapy, leading to a Phase I trial of carboplatin/paclitaxel and reovirus for relapsed/metastatic cancers. During the course of this trial, we observed very encouraging suggestions of possible clinical effects, as well as the emergence of aggressive recurrences in some patients who initially responded very well following the therapy. In the current proposal, we will build further on these pre-clinical and clinical data, which have, cumulatively, shown that PAC/Reo is a well tolerated, and potentially efficacious, method of deliverying oncolytic virotherapy to tumor bearing patients. Therefore, the overall hypothesis of the current proposal is that it will be possible to develop novel treatments which both improve initial tumor responses to i.v. reovirus and either prevent, or treat, aggressive tumor recurrences. To test this hypothesis, we will improve initial anti tumor responses following i.v. reovirus, in virus immune/ non-immune mice, by conditioning the host with cytokines, chemo- or radio-therapy (Aim 1) and/or chaperoning, and protecting, i.v. administered reovirus using immune cell carriers (Aim 2), in order to enhance levels, and immune consequences, of virus delivered to the tumor and/or its vasculature. In addition, we will treat recurrent tumors, which fail initial systemic virotherapy, with rational, mechanism-based 2nd line therapies by targeting the predictable recurrent tumor phenotype which emerges upon treatment failure with front line chemo-/virotherapy (Aim 3). Overall these experiments will lead to new clinical trials for i.v. delivery of reovirus and should also be directly applicable to a rage of both different tumor types and oncolytic viruses.
The experiments in this grant aim to improve upon the efficiency, and efficacy, by which oncolytic reovirus can be delivered to established melanomas in both mice and patients. The proposal builds upon a series of clinical trials which we have already completed which have shown that intravenous delivery of reovirus to tumor bearing patients is safe and in which there have been encouraging suggestions of clinical benefits. We will now use these clinical experiences to return to our pre- clinical models to develop further methods to combine conventional therapies with systemic delivery of reovirus to treat metastic disease. In addition, having observed aggressive tumor recurrences in several patients treated in our most recent clinical trial, we have developed a pre-clinical model of tumor treatment and recurrence. Experiments in this proposal will characterize the properties of recurrent tumors which fail initial virotherapy and will use those properties to generate rational mechanism-based second line therapies to treat clinical recurrences. If successful, our studies will 1) lead directy to implementation of the next generation of clinical trials to test both the safety, and efficacy, f systemic virotherapy and 2) will develop new clinical regimens for the targeted treatment of recurrent tumors which emerge following frontline viro-/chemo-therapy.
|Ilett, E; Kottke, T; Thompson, J et al. (2017) Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy. Gene Ther 24:21-30|
|Shim, Kevin G; Zaidi, Shane; Thompson, Jill et al. (2017) Inhibitory Receptors Induced by VSV Viroimmunotherapy Are Not Necessarily Targets for Improving Treatment Efficacy. Mol Ther 25:962-975|
|Kottke, Tim; Shim, Kevin G; Alonso-Camino, Vanesa et al. (2016) Immunogenicity of self tumor associated proteins is enhanced through protein truncation. Mol Ther Oncolytics 3:16030|
|Rajani, Karishma; Parrish, Christopher; Kottke, Timothy et al. (2016) Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses. Mol Ther 24:166-74|
|Cockle, Julia V; Rajani, Karishma; Zaidi, Shane et al. (2016) Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling. Neuro Oncol 18:518-27|
|Blanchard, Miran; Shim, Kevin G; Grams, Michael P et al. (2015) Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. Int J Radiat Oncol Biol Phys 93:577-87|
|Zaidi, Shane; Blanchard, Miran; Shim, Kevin et al. (2015) Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents. Mol Ther 23:845-856|
|Roulstone, Victoria; Khan, Khurum; Pandha, Hardev S et al. (2015) Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. Clin Cancer Res 21:1305-12|
|Roulstone, Victoria; Pedersen, Malin; Kyula, Joan et al. (2015) BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic Reovirus Through ER Stress. Mol Ther 23:931-942|
|Rajani, Karishma R; Vile, Richard G (2015) Harnessing the Power of Onco-Immunotherapy with Checkpoint Inhibitors. Viruses 7:5889-901|
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