title: mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment.
abstract: mTOR is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we had explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here, we report that a combination of αCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic antitumor responses in a model of metastatic renal cell carcinoma. In contrast to the well-established mTOR inhibitor rapamycin, AZD8055 increased the infiltration, activation, and proliferation of CD8(+) T cells and natural killer cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/αCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared with that achieved in mice by αCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFα, which played an indispensable role in activation of the observed antitumor immune response. Levels of Th1 cytokines, including interleukin 12, IFN-γ, TNFα, and the Th1-associated chemokines RANTES, MIG, and IP-10 were each elevated significantly in the livers of mice treated with the combinatorial therapy versus individual treatments. Notably, the AZD8055/αCD40-induced antitumor response was abolished in IFN-γ(-/-) and CD40(-/-) mice, establishing the reliance of the combination therapy on host IFN-γ and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with αCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer.
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, NCI-Frederick, Frederick, Maryland 21702-1201, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Timothy
authors.initials: T
authors.lastname: Back
authors.forename: Tim
authors.initials: T
authors.lastname: Chan
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Sylvie
authors.initials: S
authors.lastname: Guichard
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D009369:Neoplasms / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D009025:Morpholines; D018664:Interleukin-12; D007371:Interferon-gamma; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus