Over many centuries, tremendous breakthroughs in cancer therapies have been made beginning with surgery, radiation, and chemotherapy and more recently expanded to include small-molecule drugs, immunotherapies, and oncolytic viruses. While all have had successes, oncolytic viruses are unique in that they are “living drugs” able to replicate within the tumor and are capable of priming an antitumor immune responses in a heterogeneous tumor cell population. Oncolytic virotherapy is the use of replication competent viruses to specifically replicate in and kill malignant cells. Vesicular stomatitis virus (VSV) is one such virus undergoing clinical translation which has an excellent safety record in human trials and observed clinical responses. There is still room for improvement in VSV therapy as responses are not complete. We aim to improve oncolytic VSV therapy by engineering immunomodulatory genes into it to improve intratumoral immune cell infiltration. The oncolytic VSV platform was engineered to encode a variety of murine and human chemokines (CXCL2, CCL2, CXCL10, and CXCL9) and the impact on the tumor microenvironment was evaluated. Amidst the continuing pursuit for enhanced cancer therapeutics, this thesis offers novel oncolytic viruses engineered to express murine and human chemokines.
|Advisor:||Russell, Stephen J|
|Commitee:||Hedin, Karen, Vile, Richard, Windebank, Anthony, Ebihara, Hideki|
|School:||College of Medicine - Mayo Clinic|
|Department:||Clinical and Translational Science|
|School Location:||United States -- Minnesota|
|Source:||DAI-B 81/8(E), Dissertation Abstracts International|
|Subjects:||Immunology, Virology, Oncology|
|Keywords:||Chemokines, CXCL9, Immunotherapy, Oncolytic virotherapy, Tumor microenvironment, Vesicular stomatitis virus|
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