DHA-SBT-1214 taxoid nanoemulsion and anti–PD-L1 antibody combination therapy enhances antitumor efficacy in a syngeneic pancreatic adenocarcinoma model

Gulzar Ahmad, Gerardo G. Mackenzie, James Egan, Mansoor M. Amiji

Research output: Contribution to journalArticle

Abstract

The goal of this study was to evaluate combination of a novel taxoid, DHA-SBT-1214 chemotherapy, in modulating immune checkpoint marker expression and ultimately in improving antibody-based checkpoint blockade therapy in pancreatic adenocarcinoma (PDAC). DHA-SBT-1214 was encapsulated in an oil-in-water nanoemulsion and administered systemically in Panc02 syngeneic PDAC-bearing C57BL/ 6 mice. Following treatment with DHA-SBT-1214, expression levels of PD-L1 were measured and anti–PD-L1 antibody was administered in combination. The effects of combination therapy on efficacy and the molecular basis of synergistic effects were evaluated. PD-L1 expression was lower on Panc02 pancreatic tumor cells in vitro, which significantly increased after exposure to different chemotherapy drugs. Administration of DHA-SBT-1214, gemcitabine, and PD-L1 antibody alone failed to increase CD8þ T-cell infiltration inside tumors. However, combination of anti–PD-L1 therapy with a novel chemotherapy drug DHA-SBT-1214 in nanoemulsion (NE-DHA-SBT-1214) significantly enhanced CD8þ T-cell infiltration and the therapeutic effects of the anti–PD-L1 antibody. Furthermore, in the Panc02 syngeneic model, the NE-DHA-SBT-1214 combination therapy group reduced tumor growth to a higher extend than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti–PD-L1 antibody therapy groups. Our results indicate that NE-DHA-SBT-1214 stimulated immunogenic potential of PDAC and provided an enhanced therapeutic effect with immune checkpoint blockade therapy, which warrants further evaluation.

Original languageEnglish (US)
Pages (from-to)1961-1972
Number of pages12
JournalMolecular Cancer Therapeutics
Volume18
Issue number11
DOIs
StatePublished - Jan 1 2019

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Taxoids
Adenocarcinoma
Antibodies
gemcitabine
Therapeutic Uses
Therapeutics
Group Psychotherapy
Drug Therapy
T-Lymphocytes
Neoplasms
SB T-1214
Paclitaxel
Inbred C57BL Mouse
Pharmaceutical Preparations
Oils
Biomarkers
Water
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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DHA-SBT-1214 taxoid nanoemulsion and anti–PD-L1 antibody combination therapy enhances antitumor efficacy in a syngeneic pancreatic adenocarcinoma model. / Ahmad, Gulzar; Mackenzie, Gerardo G.; Egan, James; Amiji, Mansoor M.

In: Molecular Cancer Therapeutics, Vol. 18, No. 11, 01.01.2019, p. 1961-1972.

Research output: Contribution to journalArticle

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abstract = "The goal of this study was to evaluate combination of a novel taxoid, DHA-SBT-1214 chemotherapy, in modulating immune checkpoint marker expression and ultimately in improving antibody-based checkpoint blockade therapy in pancreatic adenocarcinoma (PDAC). DHA-SBT-1214 was encapsulated in an oil-in-water nanoemulsion and administered systemically in Panc02 syngeneic PDAC-bearing C57BL/ 6 mice. Following treatment with DHA-SBT-1214, expression levels of PD-L1 were measured and anti–PD-L1 antibody was administered in combination. The effects of combination therapy on efficacy and the molecular basis of synergistic effects were evaluated. PD-L1 expression was lower on Panc02 pancreatic tumor cells in vitro, which significantly increased after exposure to different chemotherapy drugs. Administration of DHA-SBT-1214, gemcitabine, and PD-L1 antibody alone failed to increase CD8{\th} T-cell infiltration inside tumors. However, combination of anti–PD-L1 therapy with a novel chemotherapy drug DHA-SBT-1214 in nanoemulsion (NE-DHA-SBT-1214) significantly enhanced CD8{\th} T-cell infiltration and the therapeutic effects of the anti–PD-L1 antibody. Furthermore, in the Panc02 syngeneic model, the NE-DHA-SBT-1214 combination therapy group reduced tumor growth to a higher extend than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti–PD-L1 antibody therapy groups. Our results indicate that NE-DHA-SBT-1214 stimulated immunogenic potential of PDAC and provided an enhanced therapeutic effect with immune checkpoint blockade therapy, which warrants further evaluation.",
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