Abstract 2723: In vivo activity of combinations of cytotoxic regimens with anti-PD1 and anti-PDL1 in various syngeneic cancer models
Authors: Grasselly Chloé , Denis Morgane , Bourguignon Aurore , Talhi Nolan , Tourette Anne , Mathe Doriane , Serre Laurent , Jordheim Lars Petter , Dumontet Charles 
Published: August 2018

Immune checkpoint inhibitors (ICIs) show impressive response rate in multiple cancer types. Nivolumab and atezolizumab has already been approved by the FDA. However, a large proportion of patients do not show any benefits or will develop acquired resistance phenomenon. In order to increase long term survival, alternative strategies are focused on rationale combination of immunotherapies with well-known therapeutic agents such as chemotherapies. In this present project, we described the impact of various chemotherapies regimen in combination with anti-PD1 and anti-PDL-1 on preclinical bladder, colorectal and metastatic breast cancers models.

We performed a study of PD-1 or PDL-1 blockade in combination with reference chemotherapies in four fully immunocompetent mouse models of cancer: we used the MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) regimen as standard chemotherapy in bladder cancer MBT-2 and MB49, cyclophosphamide and doxorubicin in breast cancer 4T1, and capecitabine with oxaliplatin in colorectal cancer MC38. We analyzed the in vivo antitumor response and collected tumor samples four days after first treatment administration to analyze the immune infiltrate in tumors.

In vivo phenotype study reveals variable responsiveness to ICP blockade. We found strong effects of the combinations in two of the models studied: bladder cancer MB49 and colorectal cancer MC38, a lack of effect in breast cancer 4T1, and an inhibition of immune checkpoint antibody activity in MBT-2 preclinical model. Analysis using flow cytometry showed strong differences both at baseline between mice models as well as after exposure to ICIs, chemotherapy or the combination of both types of treatment. All the preclinical models studied at baseline were highly infiltrated with cells considered as « immunosuppressive », particularly MDSCs. We showed that the balance between antitumor effector cells and immunosuppressive cells could be inverted with some of the treatment combinations. As an example, in the MB49 model the most impressive modifications induced by the combination was an increase of the M1/M2 ratio. However, profound alterations of tumors microenvironment were not systematically correlated with a favorable in vivo phenotype. Indeed, we observed no benefit of the combination in the 4T1 model, although the combination profoundly modified the immune microenvironment with a strong decrease in MDSCs and a large increase in the CD4 and CD8 infiltrates.

Our results suggest that modulation of immune cells infiltrate by cytotoxic agents could impact on the potency of ICIs when these are co-administered, with either an enhance or a reduced antitumor activity of the combination. However this impact appears to be model- and combination-dependent. The present investigations should help to select appropriate chemotherapies to combine with target monoclonal antibodies for clinical trials.

Citation Format: Chloé Grasselly, Morgane Denis, Aurore Bourguignon, Nolan Talhi, Anne Tourette, Doriane Mathe, Laurent Serre, Lars Petter Jordheim, Charles Dumontet. In vivo activity of combinations of cytotoxic regimens with anti-PD1 and anti-PDL1 in various syngeneic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2723.