Abstract A034: Boosting the efficacy of PD-L1 blockade with oncolytic vaccine for improved antitumor responses in melanoma

Abstract

Immunosuppression of established tumors is a major obstacle hindering the efficacy of anti-tumor T cells. Antagonistic mAbs targeting the PD-1/PD-L1 axis represent an effective way to decrease T cell exhaustion and/or anergy, but the efficacy of such therapies seems to be limited to specific cohorts of patients with ongoing immune responses against the tumor. Thus, we hypothesized that we could boost the efficacy of PD-L1 blockade by using an oncolytic cancer vaccine PeptiCrad, which has previously been shown to elicit potent tumor-specific T cell responses by stimulating antigen-presenting cells. First, we demonstrated that the outcome of therapy may depend on the treatment schedule as mice with high B16.OVA tumor burden were refractory to combination of PD-L1 blockade and oncolytic vaccine PeptiCrad targeting the tumor antigen OVA. In fact, mice receiving combination therapy showed only a modest increase in median survival compared to control groups. However, immunological analyses revealed that combination therapy elicited strong anti-tumor immune responses, observed both by tetramer analysis and IFN γ ELISPOT. Hence, we hypothesized that a different treatment schedule could be beneficial in the case of aggressive melanoma such as B16.OVA. In a subsequent experiment, we started the treatments earlier with an overlapping schedule, allowing the PD-L1 blockade to affect the newly primed T cells induced by PeptiCrad. With this regimen, combination treatment notably inhibited tumor growth and a significant increase in median survival of mice was observed when compared to groups receiving monotherapies. Moreover, 37.5% of combination treated mice were cured, suggesting that PeptiCrad can synergize with PD-L1 blockade. In order to eradicate the residual immunoedited tumors, we utilized the major advantage of PeptiCrad technology by treating the survivor mice with a single PeptiCRAd targeting two endogenous melanoma antigens (TRP-2 and gp100, respectively). As a result, the combination therapy was able to slow down the growth of the residual tumors, suggesting that targeting multiple cancer antigens simultaneously could be a feasible approach also in terms of immune checkpoint blockade. Further analyses on the effect of the combination therapy on antigen-specific T cell subsets and on PD-L1 expressing immune cells (such as MDSCs) are ongoing. Citation Format: Cristian Capasso, Siri Tähtinen, Federica Frascaro, Sara Carpi, Manlio Fusciello, Davide Cardella, Daniela Cropp, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kuryk, Erkko Ylösmäki, Vincenzo Cerullo. Boosting the efficacy of PD-L1 blockade with oncolytic vaccine for improved antitumor responses in melanoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A034.

Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model

“…The oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L showed comparable anti-cancer efficacy to the treatment with AdV5/3-D24 in tested mesothelioma cell lines in vitro . The observed results are in corroboration with the ones reported elsewhere ( 14 , 25 , 36 ). Results suggest that incorporation of ICOSL and CD40L expression cassette into the genome of AdV5/3-D24-ICOSL-CD40L did not impair oncolytic properties of the vector when compared to AdV5/3-D24.…”