Reprogramming tumor immune microenvironment by milbemycin oxime results in pancreatic tumor growth suppression and...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with limited treatment options.
• Existing anti-PD-1 immunotherapies have shown limited efficacy in PDAC clinical trials.
• There is a critical need for novel therapeutic strategies to improve PDAC patient outcomes.

Purpose of the Study:

• To investigate the potential of milbemycin oxime (MBO), an antiparasitic drug, as an immunomodulatory agent for PDAC treatment.
• To evaluate the efficacy of MBO as a monotherapy and in combination with anti-PD-1 therapy in preclinical PDAC models.
• To assess the safety and tolerability of MBO in relevant toxicological studies.

Main Methods:

• In vitro assessment of MBO's effect on PDAC cell line proliferation and apoptosis.
• In vivo evaluation of MBO's anti-tumor activity in subcutaneous and orthotopic PDAC mouse models.
• Analysis of tumor immune microenvironment changes, including CD8+ T cell infiltration, following MBO treatment.
• Assessment of MBO's impact on the efficacy of combination therapy with anti-PD-1 antibodies.
• Preclinical toxicological studies to determine MBO's safety profile.

Main Results:

• Milbemycin oxime (MBO) demonstrated direct anti-proliferative and pro-apoptotic effects on multiple PDAC cell lines.
• Oral administration of MBO significantly inhibited PDAC tumor growth by 49% (subcutaneous) and 56% (orthotopic) in vivo.
• MBO treatment led to a 27-day increase in median survival for tumor-bearing mice.
• MBO therapy significantly increased the infiltration of CD8+ T cells within the tumor microenvironment.
• CD8+ T cell depletion abrogated the anti-tumor efficacy of MBO, confirming their crucial role.
• MBO significantly enhanced the efficacy of anti-PD-1 therapy, leading to increased active cytotoxic T cells.
• MBO exhibited a favorable safety profile in preclinical toxicological assessments.

Conclusions:

• Milbemycin oxime (MBO) exhibits significant anti-PDAC activity through apoptosis induction and immune modulation, particularly by enhancing CD8+ T cell responses.
• MBO demonstrates potent anti-tumor efficacy as a monotherapy and synergistically enhances the effectiveness of anti-PD-1 immunotherapy in PDAC.
• Repurposing MBO presents a promising novel therapeutic strategy for pancreatic ductal adenocarcinoma, potentially improving outcomes when combined with checkpoint inhibitors.