Epacadostat/ Nivolumab Combo Active in Melanoma, Head and Neck Cancer

Excerpt:

“Combining the IDO inhibitor epacadostat with nivolumab (Opdivo) demonstrated promising signs of activity for patients with squamous cell carcinoma of the head and neck (SCCHC) and those with melanoma, according to findings from the phase I/II ECHO-204 study presented at the 2017 ASCO Annual Meeting.

“The combination demonstrated an objective response rate (ORR) of 63% and a complete response (CR) rate of 5% for patients with treatment-naive melanoma, in the multi-arm, open-label trial. In those with SCCHC, the ORR was 23% and the CR rate was 3%. The combination was not effective in unselected patients with ovarian cancer and colorectal cancer (CRC).”

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Innovative Immunotherapy Combo Tests IDO Inhibitor in Melanoma Trial

Excerpt:

“Investigators are looking into a novel immunotherapy combination that pairs the first-in-class IDO1 inhibitor epacadostat (INCB024360) with the checkpoint blockade agent pembrolizumab (Keytruda) in patients with unresectable or metastatic melanoma.

“The phase III KEYNOTE-252/ECHO-301 trial, which is enrolling at more than 120 locations, will randomize 600 patients in a 1:1 ratio to either epacadostat combined with pembrolizumab or pembrolizumab plus placebo (NCT02752074).”

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Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells

“Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8+ T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell–inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3+ regulatory T cells (Tregs), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8+ T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of Tregs, in the tumor microenvironment depended on the presence of CD8+ T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell–inflamed tumor microenvironment.”