Synergy between EphA2-ILs-DTXp, a Novel EphA2-Targeted Nanoliposomal Taxane, and PD-1 Inhibitors in Preclinical Tumor Models
| Autor: | Alexander Koshkaryev, Walid S. Kamoun, Gang Sun, Vasileios Askoxylakis, Lia Luus, Ross B. Fulton, James F. Sampson, Eric M. Tam, Andrew J. Sawyer, Zhaohua Richard Huang, Daryl C. Drummond, Anne-Sophie Dugast, Michael Santiago, James Suchy, Stephanie Grabow |
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| Rok vydání: | 2020 |
| Předmět: |
Bridged-Ring Compounds
0301 basic medicine Cancer Research medicine.medical_treatment Programmed Cell Death 1 Receptor Mice 03 medical and health sciences 0302 clinical medicine Immune system Breast cancer Neoplasms medicine Animals Humans Chemotherapy Taxane business.industry Receptor EphA2 Immunotherapy EPH receptor A2 medicine.disease Disease Models Animal 030104 developmental biology Oncology Docetaxel 030220 oncology & carcinogenesis Cancer research Female Taxoids business CD8 medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 19:270-281 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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