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[Abstract] How PDX models could help the development of immuno-oncology therapies?

Caroline Mignard1, Jean-François Mirjolet1, Josselin Caradec1, Valentin Derangere2, François Ghiringhelli2, Laurent Arnould2, Séverine Tabone-Eglinger3, Pauline Wajda3,4, Bertrand Dubois4, Fabrice Lavial4, Isabelle Treilleux3, Olivier Duchamp1

1 Oncodesign, Dijon, France - 2 Centre Georges François Leclerc, Dijon, France - 3 Centre Léon Bérard, Lyon, France - 4 Cancer Research Center of Lyon, France

Immunotherapy is one of the most exiting recent breakthroughs in the field of cancer treatment. Different approaches are developed such as cancer vaccines, adoptive cellular immunotherapy or immune checkpoint blockade, and a number have been regulatory approved or are currently investigated in clinic.

Effective immunity against cancer involves complex interaction between the tumor, the host and the environment. The assessment of cancer immunotherapy requires the use of appropriate preclinical animal models that sufficiently reflect the physiological situation in humans and that must be chosen carefully to address a specific scientific question.

Patient-derived xenograft (PDX) models have been developed from different tumor types and are used for the pre-clinical drug evaluation and for the predictive results of clinical outcomes because they conserve original tumor characteristics such as heterogeneity and molecular diversity. Nevertheless, they have limited utility for therapies that target the human immune system. This limitation has been partially overcome by the development of humanized mice meaning co-transplantation of human tumor and human immune or hematopoietic progenitor cells.

Humanized models were then used for in vivo evaluation of immunomodulatory agents with mice xenografted with cell lines or patient-derived xenografts. Therapeutic efficiency was assessed by following mice survival and tumor growth. The impact of therapeutics on tumors and immune cells was also assessed by flow cytometry and immunohistochemistry analyses.

We developed a large panel of humanized models that are available for the investigation of the mechanism of action of novel immuno-oncology therapies. Nevertheless challenges are still remaining, for the development of immune checkpoint-based therapy, in particular, to identify and validate predictive models and biomarkers.