RT Journal Article
SR Electronic
T1 Local Delivery of OncoVEX<sup>mGM-CSF</sup> Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte–Associated Protein Blockade
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 6190
OP 6202
DO 10.1158/1078-0432.CCR-17-0681
VO 23
IS 20
A1 Moesta, Achim K.
A1 Cooke, Keegan
A1 Piasecki, Julia
A1 Mitchell, Petia
A1 Rottman, James B.
A1 Fitzgerald, Karen
A1 Zhan, Jinghui
A1 Yang, Becky
A1 Le, Tiep
A1 Belmontes, Brian
A1 Ikotun, Oluwatayo F.
A1 Merriam, Kim
A1 Glaus, Charles
A1 Ganley, Kenneth
A1 Cordover, David H.
A1 Boden, Andrea M.
A1 Ponce, Rafael
A1 Beers, Courtney
A1 Beltran, Pedro J.
YR 2017
UL http://clincancerres.aacrjournals.org/content/23/20/6190.abstract
AB Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190–202. ©2017 AACR.