Combined indoximod–paclitaxel pharmacodynamic interaction

The combined indoximod–paclitaxel pharmacodynamic interaction is a therapeutic strategy that pairs a cytotoxic chemotherapy agent with an immune-checkpoint modifier. Paclitaxel, a taxane, works by binding to the beta-subunit of tubulin, stabilizing microtubules and preventing their disassembly, which leads to cell cycle arrest in the G2/M phase and subsequent apoptosis. Indoximod is a small-molecule tryptophan mimetic that acts downstream of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) to restore mTORC1 signaling and alleviate the immunosuppressive effects of the kynurenine pathway. In combination, paclitaxel is thought to induce immunogenic cell death, releasing tumor antigens, while indoximod prevents the tumor microenvironment from suppressing the resulting T-cell response. This synergistic approach has been primarily evaluated in clinical trials for patients with metastatic breast cancer to improve objective response rates and progression-free survival (ClinicalTrials.gov, NCT01792050).

Other names

Indoximod and Paclitaxel combination therapyIDO pathway inhibition and microtubule stabilization synergyNLG8189 and Paclitaxel interaction

The interaction involves paclitaxel-mediated stabilization of microtubules leading to mitotic arrest and immunogenic cell death, paired with indoximod's role as an IDO pathway modifier that reverses tryptophan-depletion-induced immunosuppression to enhance T-cell proliferation and activation (Soliman et al., 2018, Journal of Clinical Oncology).