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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
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Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally

Diane Evrard1, Clément Dumont2, Michel Gatineau3

  • 1Department of Otorhinolaryngology, Bichat University Hospital, Université Paris Cité, 75018 Paris, France.

Cancers
|September 23, 2022
PubMed

Insights

This study shows that combining everolimus with chemotherapy is safe and effective for head and neck cancer, leading to significant tumor reduction and favorable changes in the tumor microenvironment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The PI3K-AKT-mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), correlating with poor patient prognosis.
  • The mammalian target of rapamycin (mTOR) pathway plays a crucial role in regulating cellular functions and responding to the tumor microenvironment (TME).

Purpose of the Study:

  • To investigate the safety and antitumor activity of everolimus, an mTOR inhibitor, combined with induction chemotherapy in treatment-naïve patients with locally advanced HNSCC.
  • To evaluate molecular biomarkers in tumor tissue and blood to understand the treatment's impact on the TME.

Main Methods:

  • A phase I-II clinical trial involving patients with locally advanced HNSCC receiving weekly everolimus (30 mg or 50 mg) plus carboplatin and paclitaxel for 9 cycles.
  • Assessment of safety, overall response rate (ORR), major responses, and analysis of p-S6K, Ki67 expression, and cytokine profiles in peripheral blood.

Main Results:

  • The recommended dose of 50 mg weekly everolimus showed good tolerance.
  • An overall response rate of 75.6% was observed in evaluable patients, with 20 major responses (≥50% tumor reduction).
  • Significant decreases in p-S6K and Ki67 expression were noted in post-treatment tumor tissue, alongside increased pro-immunogenic Th1 cytokine release in peripheral blood.

Conclusions:

  • The combination of everolimus and chemotherapy is a safe and effective neoadjuvant strategy for locally advanced HNSCC, achieving substantial tumor responses.
  • This combination therapy positively modulates the tumor microenvironment and suggests potential for combination with immunotherapy agents.
Keywords:
PI3K-AKT-mTOR pathwayhead and neck carcinomainterferon gammamTOR inhibitiontumor microenvironment

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