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Chemo-immunotherapy by nanoliposomal epacadostat and docetaxel combination to IDO1 inhibition and tumor

Rahimeh Khoshkhabar1, Mona Yazdani2, Seyedeh Hoda Alavizadeh1

  • 1Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

International Immunopharmacology
|June 13, 2024
PubMed

Insights

Combining liposomal epacadostat (Lip-EPA), an IDO1 inhibitor, with docetaxel (DTX) chemotherapy enhances anti-tumor immunity. This combination effectively reduces tumor growth and improves survival by modulating the tumor microenvironment.

Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Overactivation of tryptophan metabolism via Indoleamine 2,3-dioxygenase-1 (IDO1) promotes tumor immune escape and treatment failure.
  • Epacadostat (EPA) is an efficient IDO1 inhibitor, but monotherapy shows insufficient anti-tumor activity.
  • Docetaxel (DTX) acts as a complementary immunogenic cell death (ICD) agent.

Purpose of the Study:

  • To evaluate the efficacy of simultaneous treatment with liposomal epacadostat (Lip-EPA) and docetaxel (DTX) against the B16F10 melanoma model.
  • To assess the impact of this combination therapy on the tumor microenvironment and immune response.

Main Methods:

  • In vitro assessment of the combination index (CI) for epacadostat (EPA) and docetaxel (DTX).
  • In vivo efficacy studies in the B16F10 model.
  • Immune profiling, histopathology analysis, and assessment of tumor growth delay (TGD) and increased lifespan (ILS).

Main Results:

  • Synergistic cytotoxic effects observed in B16F10 cells treated with the combination.
  • Significant increase in T lymphocytes and IFN-γ, decrease in regulatory T cells (Treg) and IL-10 levels.
  • Marked tumor growth delay (69.15%) and increased lifespan (>47.83%) with Lip-EPA + DTX treatment.
  • Increased tryptophan (Trp) and decreased kynurenine (Kyn) levels in tumors post-combination treatment.

Conclusions:

  • Liposomal epacadostat combined with docetaxel chemotherapy significantly enhances anti-tumor immune responses.
  • This combination effectively overcomes the tumor's immunosuppressive microenvironment.
  • The nano-liposomal formulation of IDO1 inhibitors warrants further investigation in combination cancer therapy.
Keywords:
Chemo-immunotherapyDocetaxelIDO1 inhibitorMelanomaTumor microenvironment

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