Cancer Res. 2011 May 3. [Epub ahead of print]
mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment.
Jiang Q, Weiss JM, Back T, Chan T, Ortaldo JR, Guichard S, Wiltrout RH.
CCR,LEI,CIP, NCI-Frederick.
Abstract
Mammalian target of rapamycin (mTOR) is a central mediator of cancer cell growth, but it also directs immune cell differentiation and function. On this basis, we have explored the hypothesis that mTOR inhibition can enhance cancer immunotherapy. Here we report that a combination of aCD40 agonistic antibody and the ATP-competitive mTOR kinase inhibitory drug AZD8055 elicited synergistic anti-tumor 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 NK cells in liver metastatic foci when combined with the CD40 agonist. AZD8055/ aCD40-treated mice also display an increased incidence of matured macrophages and dendritic cells compared to that achieved in mice by aCD40 or AZD8055 treatment alone. We found that the combination treatment also increased macrophage production of TNFa; which played an indispensable role in activation of the observed anti-tumor immune response. Levels of Th1 cytokines, including IL-12, IFN-?, TNFa, 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/aCD40-induced anti-tumor response was abolished in IFN-? -/- and CD40 -/- mice, establishing the reliance of the combination therapy on host IFN-? and CD40 expression. Our findings offer a preclinical proof of concept that, unlike rapamycin, the ATP-competitive mTOR kinase inhibitor AZD8055 can contribute with aCD40 treatment to trigger a restructuring of the tumor immune microenvironment to trigger regressions of an established metastatic cancer. |
