Abstract B94: Efficacy of PD-1 - PD-L1 pathway disruptors in syngeneic models
Authors: HILLAIRET DE BOISFERON MARC , Bichat Francis , MIGNARD CAROLINE , TIZON XAVIER , FRANCE DAMIEN , MAUBANT SYLVIE , Mirjolet Jean-Francois 
Published: May 2016

Immune checkpoint modulators, such as antibodies targeting CTLA-4 or PD-1, are now being approved for treatment of patients with unresectable or metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC) who have progressed on or after platinum-based chemotherapy. Efficacy was also evidenced on other tumor types (renal cell carcinoma, bladder, Hodgkin lymphoma, colorectal carcinoma (CRC) ⋯). However, there is still needs to identify predictive biomarkers of response in order to select patients who will benefit from treatments. PD-L1 expression was proposed to be a good candidate for NSCLC, even if PD-L1 expression is a difficult parameter due to its expression on both tumor cells and immune cells as well as technical challenges to use immunohistochemical detection. The dynamic of the immune system as well as the site and time where interactions between tumor cells and immune cells take place, increase the complexity of having a solid biomarker identified. In addition, for other pathologies like colorectal carcinoma, genomic biomarkers were evidenced. For example, CRC patients with mismatch repair (MMR) deficiencies have an objective response rate of 62% compared with 0% in patients with MMR-proficient tumors.

We propose here the use of syngeneic models to address mechanism of action and biomarker related questions for agent targeting PD-1 / PD-L1 axis. Syngeneic model systems remain one of the only options to analyse physiologically relevant interactions between tumor and immune cells. Up to now, eight models were characterized for response to either PD-1 and/or PD-L1 targeting antibodies. Among them, 4T1, LLC and Renca were identified as non-responders and B16-F10, CT-26, EMT-6, MBT-2 identified as partial responders. Most of the time, targeting PD-1 is more effective than targeting PD-L1, even if there is exception (e.g. B16-F10). Attempting to identify key parameters that could help us understand efficacy of PD-1 /PD-L1 axis disruptors, intratumoral immune infiltrate was analyzed in depth using flow cytometry: regulatory T cells (Treg), effector T cells (Teff), M-MDSCs, G-MDSCs, TAMs were phenotyped and quantified. In contrast to CTLA-4 targeting therapy, where Teff/Treg ratio was correlated to treatment efficacy, this is not the case for PD-1 or PD-L1 targeting therapies. It is now hypothesized that a more complex signature (e.g. detailed phenotype of CD8 positive T cells, tumor neoantigen expression⋯) will be needed to identify valuable biomarkers of response. Preliminary results using syngeneic models, both subcutaneously or orthotopically engrafted with tumors, will be presented.

Citation Format: MARC HILLAIRET DE BOISFERON, Francis Bichat, CAROLINE MIGNARD, XAVIER TIZON, DAMIEN FRANCE, SYLVIE MAUBANT, Jean-Francois Mirjolet. Efficacy of PD-1 - PD-L1 pathway disruptors in syngeneic models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B94.