Synergy between EphA2-ILs-DTXp, a Novel EphA2-Targeted Nanoliposomal Taxane, and PD-1 Inhibitors in Preclinical Tumor Models

Combinations of chemotherapy with immunotherapy have seen recent clinical success, including two approvals of anti-PD-1/L1 agents in combination with taxane-based chemotherapy in non-small cell lung cancer and triple-negative breast cancer. Here, we present a study on the combination activity and me...

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Veröffentlicht in:Molecular cancer therapeutics 2020-01, Vol.19 (1), p.270-281
Hauptverfasser: Kamoun, Walid S, Dugast, Anne-Sophie, Suchy, James J, Grabow, Stephanie, Fulton, Ross B, Sampson, James F, Luus, Lia, Santiago, Michael, Koshkaryev, Alexander, Sun, Gang, Askoxylakis, Vasileios, Tam, Eric, Huang, Zhaohua Richard, Drummond, Daryl C, Sawyer, Andrew J
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Sprache:eng
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Zusammenfassung:Combinations of chemotherapy with immunotherapy have seen recent clinical success, including two approvals of anti-PD-1/L1 agents in combination with taxane-based chemotherapy in non-small cell lung cancer and triple-negative breast cancer. Here, we present a study on the combination activity and mechanistic rationale of a novel EphA2-targeted liposomal taxane (EphA2-ILs-DTXp) and anti-PD-1. This combination was highly active in mouse syngeneic tumor models, with complete responses observed in 3 of 5 models. In the EMT-6 tumor model, combination of EphA2-ILs-DTXp with anti-PD-1 resulted in a 60% complete response rate, with durable responses that were resistant to rechallenge. These responses were not observed in the absence of CD8 T cells. Characterization of the immune infiltrates in EMT-6 tumors reveals increased CD8 T cells, increased CD8 IFNγ CTLs, and an increased CD8/regulatory T-cell (Treg) ratio. These immunomodulatory effects were not observed in mice treated with a combination of docetaxel and anti-PD-1. Pharmacokinetic analysis revealed that the AUC of docetaxel was increased 15 times, from 52.1 to 785 ng/mL/hour, when delivered by EphA2-ILs-DTXp. A dose reduction study of EphA2-ILs-DTXp showed a dose-response relationship for both tumor growth inhibition and the CD8/Treg ratio. Our data indicate that synergism between docetaxel and anti-PD-1 is achievable with nanoliposomal delivery.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.mct-19-0414