neoadjuvant celecoxib in newly diagnosed patients with endometrial carcinoma

Conditions: Endometrium Cancer

Summary: indoleamine 2,3 dioxygenase 1 (ido 1) is the major enzyme catabolising the tryptophan outside the liver. it has been shown that its plays a important role in generating a immunosuppressive micro-environment in tumors. ido expression has been shown by hennequart et al. to be driven by cyclooxygenase-2 (cox-2) expression. the investigator's team also shown that anti-cox2, celecoxib, can in a xenograft models of ovarian cancer decrease ido1 expression and result in an infiltration of the tumor by t cells. the investigator proposed then to conduct a proof of concept study to evaluate the effect of pre-operative short administration of celecoxib on ido expression and immune cells tumors infiltration, in patients with endometrial cancer. indeed, this tumor type is well known to express frequently a high level of ido.

indoleamine 2,3-dioxygenase 1 (ido1) is an enzyme that regulates immune responses by degrading tryptophan, which is required for efficient t-cell activation. ido1 expression is limited in normal tissues but is induced by ifn-gamma in inflammatory tissues, to prevent excessive t-cell activity. the investigator's collaborators previously reported that ido1 is expressed in many human tumours, and that pharmacological inhibition of ido1 leads to immune rejection of ido1+ mouse tumours. based on these results, ido1 inhibitors are now in clinical development. a first inhibitor, epacadostat, showed encouraging results combined with anti- programmed cell death -1 (pd-1) antibodies. tumoural expression of ido1 can be induced by ifn-gamma, which is produced by tumour-infiltrating lymphocytes (til), and represents a mechanism of adaptive immune resistance. however, other tumours express ido1 in the absence of til and interferon-gamma (inf gamma). this seems to be particularly frequent in endometrial carcinoma. this constitutive ido1 expression prevents t-cell infiltration and represents a mechanism of intrinsic immune resistance. the investigator's collaborators recently showed that constitutive tumoural expression of ido1 was triggered by cyclooxygenase-2 (cox-2) and mediated by autocrine prostaglandin-e2 (pge2) signaling via the protein kinase c (pkc) and phosphoinositide 3-kinase (pi3k) pathways. constitutive ido1 expression was reduced by cox-2 inhibitors in vitro. celecoxib is a well-known and widely used anti-inflammatory drug. it is a specific inhibitor of cox-2. in vivo, celecoxib induced immune rejection of ido1-expressing human tumour xenografts, while reducing ido1 expression and promoting t-cell infiltration. these preclinical results suggest that cox-2 inhibition in patients carrying tumours expressing ido1 constitutively will decrease ido1 expression, increase t-cell infiltration and might increase responsiveness to anti-pd-1/ programmed cell death ligand-1(pd-l1) therapy and thereby exert enhanced anti-tumour activity. the investigators wish to obtain clinical evidence that celecoxib can induce these first two effects

Eligibility criteria:
key inclusion criteria: * women \> 18 years of age. * eastern cooperative oncology group (ecog) performance status of 0-2 * adequate renal, hepatic and haematologic functions as defined by laboratory parameters. * agrees to undergo additional endometrial biopsies for scientific purposes. key exclusion criteria: * known hypersensitivity or intolerance to celecoxib * active, known or suspected autoimmune disease. vitiligo, type i diabetes mellitus, residual hypothyroidism controlled by hormone substitution therapy, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are allowed. * positive hepatitis b or c, hiv, and pregnancy tests. * immunosuppressive treatment