Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC
Status:
Unknown status
Trial end date:
2020-08-29
Target enrollment:
Participant gender:
Summary
Colo-rectal cancer is still one of the leading causes of cancer death worldwide. In France,
approximately 40 500 new cases are diagnosed each year. With more than 17 500 deaths in
France in 2011, colo-rectal cancer is responsible for more than 12% of all cancer deaths, the
overwhelming of deaths occurring in patients with metastatic disease.
Many studies highlight the fact that colo-rectal cancer has immunogenic properties and that
host immune responses can influence survival. Recent data have provided a clearer
understanding of the factors limiting the antitumor immune response in colo-rectal cancer.
One of the most critical checkpoint pathways responsible for mediating tumor-induced immune
suppression is the programmed death-1 (PD-1) and PD ligand 1 (PD-L1) pathway.
PD-1 is expressed on activated immune cells and can link to PD-L1 express on
Antigen-Presenting-Cell. Usually, this pathway is involved in promoting T-cells tolerance and
preventing tissue damage in settings of chronic inflammation. In pathological context, the
PD-1/PD-L1 pathway contributes to immune suppression and evasion. Many human solid tumors
including colo-rectal cancer express PD-L1, and this expression is associated with a worse
prognosis. The interaction of PD-1 with the ligand PD-L1 inhibits T-cell proliferation,
survival, and effectors functions; induces apoptosis of tumor-specific T cells; promotes the
differentiation of CD4+ T cells into immunosuppressive regulatory T cells; and increases the
resistance of tumor cells to cytotoxic T lymphocytes attack. Thus, the blockage of the
PD-1/PD-L1 interactions represents a logical target for cancer immunotherapy and in
particular colo rectal cancer immunotherapy strategy.
Preclinical studies have shown that PD-L1 blockade improves the immune response by restoring
T-cell effectors functions. Recent work in two in vivo tumor models shows a strong interest
in using an anti-PD-L1 in combination with standard treatment of colo-rectal cancer (FOLFOX).
In these models, the survival of mice that are treated with the combination therapy reached
40% when no mice were alive with FOLFOX treatment alone. This result may be explained, in one
hand by cytotoxicity of 5FU and in the other hand by the restoration of anti-tumor immune
activity of anti-PD-L1. These results suggest that the combination of chemotherapy with
immunotherapy would act synergistically in patients with colo-rectal cancer.
Research Hypothesis: Combination of chemotherapy (FOLFOX) with immunotherapy association
(anti-PD-L1 + anti-CTLA-4) would act synergistically in patients with colo-rectal cancer.