Oncolytic Tanapoxvirus recombinants expressing mIL-2, Flagellin-C, and mCCL2 regress human cancer xenografts in immune deficient nude mice and immune cell reconstituted BALB/c nude mice.
Date of Award
Doctor of Philosophy
Karim Essani, Ph.D.
Richard Van Enk, Ph.D.
Robert Eversole, Ph.D.
Silvia Rossbach, Ph.D.
Immune reconstitution, melanoma, oncolytic virus, pancreatic cancer, tanapoxvirus, triple negative breast cancer
Tanapoxvirus (TPV) is a double stranded DNA virus from the genus Yatapoxvirus which has been engineered for the purpose of potentially treating a number of human cancers. Previous studies have shown TPV recombinants are capable of inducing tumor inhibition and even regression in athymic nude mice bearing human cancer xenografts of colorectal, melanoma and triple negative breast cancer (TNBC). However, TPV is host-restricted to humans and monkeys, including cancerous cells, which has provided a unique obstacle in its development as an oncolytic virus (OV). Namely, standard syngeneic mouse models cannot be used as test systems to evaluate TPV’s efficacy against cancer as it does not replicate in mouse tumor cells. Therefore, a new model system needed to be made in order to continue the evaluation and development of TPV against human cancer beyond immune deficient, athymic nude mice. Here, three tumor model studies are described where TPV recombinants are tested against the following human cancers in xenograft models within nude mice: TNBC, melanoma, and pancreatic ductal adenocarcinoma (PDAC). In two of those three studies (TNBC and melanoma), BALB/c nude mice are used as hosts for the tumor xenografts and 4 days following treatment, are reconstituted with splenocytes from normal, immune competent BALB/c donors via adoptive transfer injections. Data presented in these experiments suggest that not only are the mice effectively made immunocompetent through the adoptive transfers via the presence of neutralizing antibodies against TPV in collected serum and histopathological observations of plasma cells in treated tumors, but that recombinant TPV expressing flagellin C (TPV/Δ2L/Δ66R/FliC) significantly regresses TNBC tumors compared to the reconstituted control animals (no virotherapy, but adoptive transfer occurs, RC) when injected intratumorally (IT), and a TPV recombinant expressing mouse interleukin-2 (TPV/Δ66R/mIL-2) significantly regresses melanoma tumors compared to RC when injected IT, intramuscularly (IM) or intravenously (IV). In the third experimental model, TPV recombinants were evaluated in athymic nude mice against PDAC xenografts when delivered IT or IV. A recombinant TPV expressing mCCL2 (mouse monocyte chemoattractant protein-1, TPV/Δ66R/mCCL2) demonstrated significant tumor inhibition when delivered IT compared to control in both a directly injected tumor and a non-treated secondary tumor. TPV/Δ66R/mIL-2 also demonstrated significant tumor inhibition of the secondary tumor when delivered IV via the tail vein. Taken collectively, these results suggest that TPV and various recombinant viruses should be further developed for the treatment of human TNBC, melanoma, and PDAC and additionally, that the reconstituted BALB/c nude mouse model is a suitable new system to study OVs that are capable of replicating only in xenograft models.
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Monaco, Michael Leonard, "Oncolytic Tanapoxvirus recombinants expressing mIL-2, Flagellin-C, and mCCL2 regress human cancer xenografts in immune deficient nude mice and immune cell reconstituted BALB/c nude mice." (2023). Dissertations. 4038.