Entolimod, a clinical stage flagellin derivative, improves clinically relevant chemo-immunotherapy responses in pre-clinical triple negative breast cancer

Chemotherapy+anti-PD-1 is FDA approved and has improved outcomes for locally advanced and metastatic PD-L1+ triple negative breast cancer (TNBC). Unfortunately, a need still exists to improve this chemo-immunotherapy (CTx-I) platform especially in advanced disease. Entolimod, an agonist of the TLR5 and NAIP5 receptors, is our flagellin derivative which has successfully completed Phase I safety trials. We previously showed that systemically administered entolimod enhances durable antitumor immunity against metastasis of 4T1, a preclinical PD-L1+ TNBC model. However, the antimetastatic activity of single-agent entolimod was not completely effective, highlighting the need to combine entolimod with additional immune-based modalities such as CTx-I to further improve tumor control. Here, we used Paclitaxel+anti-PD-1 as a clinically oriented CTx-I platform in pre-clinical metastatic TNBC models. CTx-I+entolimod effectively controlled primary tumors and reduced lung metastatic burden more so than the single or double agent treatments. Consistent with our prior work that neutrophils express functional TLR5, depletion abrogated CTx-I+entolimod efficacy. Collectively, the immune enhancing effects of entolimod can be leveraged to boost urgently needed CTx-I outcomes in TNBC. Because entolimod has successfully completed Phase I clinical trials, this preclinical work supports the rationale design of a clinical trial that combines CTx-I with entolimod as an effective immunotherapy platform.