Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

Zuzana Berrong, Mikayel Mkrtichyan, Shamim Ahmad, Mason Webb, Eslam Mohamed, Grigori Okoev, Adelaida Matevosyan, Rajeev Shrimali, Rasha Abu Eid, Scott Hammond, John E Janik, Samir N Khleif

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Abstract

Although an immune response to tumors may be generated using vaccines, so far, this approach has only shown minimal clinical success. This is attributed to the tendency of cancer to escape immune surveillance via multiple immune suppressive mechanisms. Successful cancer immunotherapy requires targeting these inhibitory mechanisms along with enhancement of antigen-specific immune responses to promote sustained tumor-specific immunity. Here we evaluated the effect of indoximod, an inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway, on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the IDO- TC-1 tumor model. We demonstrate that although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice. We show that the mechanisms by which the IDO inhibitor leads to this therapeutic potency include (i) an increment of vaccine-induced tumor-infiltrating effector T cells that is facilitated by anti-OX40, and (ii) a decrease of IDO enzyme activity produced by non-tumor cells within the tumor microenvironment that results in enhancement of the specificity and the functionality of vaccine-induced effector T cells. Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy.

Original languageEnglish
Pages (from-to)201-208
Number of pages8
JournalCancer immunology research
Volume6
Issue number2
Early online date5 Jan 2018
DOIs
Publication statusPublished - Feb 2018

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  • Journal Article

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    Berrong, Z., Mkrtichyan, M., Ahmad, S., Webb, M., Mohamed, E., Okoev, G., Matevosyan, A., Shrimali, R., Abu Eid, R., Hammond, S., Janik, J. E., & Khleif, S. N. (2018). Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod. Cancer immunology research, 6(2), 201-208. https://doi.org/10.1158/2326-6066.CIR-17-0223