Augmenting Effector Function And Abrogating Treg Function By Ox40 Costimulation Enhances Adoptive Transfer Tumor-Specific Ctl Response

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC We have recently shown that OX40 (CD134) costimulation provided with GM-CSF-secreting vaccine can bypass CD8+ T cell tolerance. OX40 costimulation can also abrogate Foxp3+ regulatory T cell (Treg)-mediated suppression of antitumor immunity by reducing Foxp3 expression on Tregs. In addition, OX40 costimulation can directly augment tumor-specific CTL function without CD4+ T cell help in vivo. Here we show that pre-treatment with agonistic anti-OX40 mAb augments the antitumor immune effects of adoptive CD8+ T cell therapy in the clinically relevant wild-type model, not TCR-transgenic, mouse model. CD8+ T cells stimulated with tumor antigen (HER2/neu immunodominant peptide and T2 cells), including a small number of tumor antigen-specific effector CD8+ T cells, were transferred into tumor-bearing FVB/N mice. We could detect the response of tumor antigen-specific CD8+ T cells that were adoptively transferred into the recipient mice, however, the response was not sufficient to eradicate an established tumor. In addition, we showed that pre-treatment with OX40 costimulation in tumor-bearing recipient in order to inhibit the Treg-mediated suppressive function enhanced tumor specific immune response of adoptively transferred CD8+ T cells in the recipients, thus resulting in the eradication of an established tumor. Moreover, adoptively transferred CTLs, with OX40 costimulation in vitro before transfer, significantly enhanced a tumor-specific immune response in the tumor-bearing recipient. Furthermore, when tumor antigen-specific CTLs costimulated through OX40 in vitro were adoptively transferred into the tumor-bearing recipients that had been pre-treated with OX40 costimulation to inhibit Treg function, transferred tumor-specific CTLs were effectively maintained in this recipient 7 times more than in the recipient with CTL transfer alone without OX40 treatment, and about 3 times more than in the recipient with a single treatment of OX40 costimulation. These findings therefore suggest that both direct enhancement of adoptive transfer CTL function and pre-inhibition of Treg-mediated suppressive function in recipients with OX40 costimulation are useful strategy for antitumor adoptive CTL therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1939.