Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo

Oncoimmunology. 2019 Aug 28;8(11):e1649971. doi: 10.1080/2162402X.2019.1649971. eCollection 2019.

Abstract

Epithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required. Adoptive transfer(s) of immune effector cells, including allogeneic human Vγ9Vδ2 T lymphocytes, represent attractive targets for efficiently and safely tracking tissue-invading tumor cells and controlling tumor dissemination in the organism. Our study describes the establishment of robust and physiological orthotopic model of human EOC in mouse, that includes surgical resection (ovariectomy) and chemotherapy, which are ineluctably accompanied by a fatal peritoneal carcinosis recurrence. Through a complementary set of in vitro and in vivo experiments, we provide here a preclinical proof of interest of the antitumor efficiency of adoptive transfers of allogeneic human Vγ9Vδ2 T lymphocytes against EOC, in association with surgical debulking and standard chemotherapies (i.e., taxanes and platinum salts). Moreover, our results indicate that chemo- and immunotherapies can be combined to improve the antitumor efficiency of immunotherapeutic lines. Altogether, these results further pave the way for next-generation antitumor immunotherapies, based on local administrations of human allogeneic human Vγ9Vδ2 T lymphocytes, in association with standard treatments.

Keywords: Human Vγ9Vδ2 T lymphocytes; chemotherapy; epithelial ovarian cancer; immunotherapy; orthotopic xenograft mouse model; zoledronate.

Publication types

  • Research Support, Non-U.S. Gov't

Grants and funding

This study was supported by INSERM, CNRS, Université de Nantes, Association pour la Recherche contre le Cancer (R10139NN), Institut National du Cancer (INCa, PLBio2013-201, PLBio2014-155), Ligue Nationale contre le Cancer (AO InterRegional 2012). This work was realized in the context of the LabEX IGO and the IHU-Cesti programs, supported by the National Research Agency Investissements d’Avenir via the programs ANR-11-LABX-0016-01 and ANR-10-IBHU-005, respectively. The IHU-Cesti project is also supported by Nantes Metropole and the Pays de la Loire Region.