Session 3:  Cancer therapeutic innovations

Oxaliplatin, ATR inhibitor and anti-PD1 combinaison leads to colon cancer eradication through immune system activation

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, but its treatment is limited by the emergence of resistance, including to oxaliplatin. In this context, we recently showed that the combination of oxaliplatin and ATR inhibition (VE-822) (Vox combination) is synergistic and may have a potential therapeutic effect in metastatic CRC. Here, using organoids and orthotopic syngeneic mouse models we showed that the Vox + anti-PD-1 antibody combination completely cured tumor-bearing mice and protected them from a rechallenge. Vox was associated with a reduction of tumor-infiltrated neutrophils, CD206+ macrophages and regulatory T cells. Vox also induced a deep depletion of blood neutrophils and led to the emergence of a Ly6C+ PD-1+ CD8+ T cell population in the blood and spleen of tumor-harboring mice. These cells were proliferating and expressed IFN-g, CD62L, CXCR3 and Eomes. Moreover, the proportions of tumor antigen-specific T cells and of CD122+ BCL6+ T cells, which shared phenotypic characteristics with stem-like CD8+ T cells, were increased in treated mice. Altogether, our findings suggest that the Vox + anti-PD-1 antibody combination might improve survival in patients with metastatic and treatment-refractory CRC by acting both on cancer cells and CD8+ T cells.