Preclinical studies by Belgian researchers suggest it may be possible to use a combination of approved cyclooxygenase-2 (COX-2) inhibitors and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint inhibitors to treat immunosuppressive tumors that constitutively express indoleamine 2,3-dioxygenase (IDO1).

Constitutive IDO1 expression renders tumors intrinsically resistant to attack by the immune system’s T cells, reports a team led by Benoit J. Van den Eynde, M.D., Ph.D., professor at the Ludwig Institute for Cancer Research at de Duve Institute and Université Catholique de Louvain. In a series of studies that investigated the basis of IDO1 expression and potential treatments for IDO1-expressing tumors, the researchers went back to first principles and looked at IDO1 expression in tumor cell lines. “We wanted to understand the molecular mechanisms that make some tumors express IDO1 constitutively,” Prof. Van den Eynde explained.

The researchers initially demonstrated in melanoma, lung, ovarian, and head and neck tumor cell lines that constitutive expression of IDO1 was triggered by COX-2 and its product prostaglandin E2 (PGE2), through the mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and phosphoinositide 3-kinase  (PI3K) cell-signaling pathways. “These data provide evidence that COX-2 drives tumor-induced immunosuppression through constitutive expression of IDO1,” Prof. Van den Eynde stated.

Previous independent research has reported that levels of the inducible enzyme COX-2 are elevated in many human cancers, and studies have also found potential utility for COX-2 inhibitors in cancer therapy.

Prof. Van den Eynde’s team next showed that immunodeficient mice reconstituted with human lymphocytes and carrying human ovarian tumor xenografts that exhibited constitutive IDO1 expression responded equally well to treatment using either the COX-2 inhibitor celecoxib or Incyte’s IDO1 inhibitor candidate epacadostat.

Although Prof. Van den Eynde’s team admitted that this finding was initially something of a surprise, subsequent analysis of transcriptome data from more than 1041 different human tumor cell lines highlighted a correlation between IDO1 expression and activation of the COX2/PGE2 axis in several cancer types. “It is always very useful to have two compounds acting on the same pathway with two different modes of action: in case tumors start resisting one compound, they may still be sensitive to the other,” Prof. Van den Eynde pointed out.

“Our studies provide a clear rationale to test, in the clinics, combinations of anti-PD1 immunotherapy and COX-2 inhibitors. This should be straightforward given the fact that both anti-PD1 and COX-2 inhibitors are already approved for clinical use in different contexts.” The researchers published their research today, in the American Association for Cancer Research journal Cancer Immunology Research. The paper is titled, “Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance.”

Professor Van den Eynde is co-founder and scientific committee chairman of Belgian biotech iTeos Therapeutics, a spin-out from the Ludwig Cancer Research (LICR) and de Duve Institute (UCL), which is developing a pipeline of immunotherapies for cancer, including IDO1 inhibitors. iTeos licensed its lead IDO1 program to Pfizer at the end of 2014. The program is now in Phase I development. Pfizer also has exclusive rights to iTeos’ tryptophan 2,3-dioxygenase (TDO2)-targeting compounds. 

Incyte is evaluating its selective IDO1 enzyme inhibitor epacadostat in combination with Merck’s anti-PD-1 therapy Keytruda® (pembrolizumab) and combined with Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor Opdivo® (nivolumab), against a range of tumor types. Data from a number of studies were presented earlier this year at the American Society of Clinical Oncology (ASCO) meeting in Chicago, IL.

A pivotal Phase III trial evaluating epacadostat combined with Keytruda against melanoma is already ongoing. Incyte and Merck said that this year they also plan to start additional trials epacadostat and Keytruda against other tumor types, including non-small-cell lung cancer (NSCLC), bladder cancer, renal cell carcinoma, and squamous cell carcinoma of the head and neck (SCCHN).

In April, BMS and Incyte separately reported plans to start Phase III studies with epacadostat combined with Opdivo as first-line therapy for NSCLC and head and neck cancers. 

 








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