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E1A-expressing adenoviral E3B mutants act synergistically with chemotherapeutics in immunocompetent tumor models

S C Cheong1, Y Wang, J-H Meng

  • 1Centre for Molecular Oncology, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Cancer Gene Therapy
|November 24, 2007
PubMed

Insights

Oncolytic adenovirus therapy efficacy is improved when combined with chemotherapy, especially for mutants lacking E3B genes. An intact immune system is crucial for this enhanced tumor inhibition, highlighting T-cell roles.

Area of Science:

  • Oncolytic virotherapy
  • Cancer immunology
  • Viral gene therapy

Background:

  • Replication-selective oncolytic adenoviruses often have deleted immunomodulatory E3B genes, potentially reducing efficacy.
  • The role of an intact immune response in enhancing oncolytic adenovirus efficacy, particularly in combination with chemotherapy, requires further investigation.

Purpose of the Study:

  • To evaluate the synergistic effects of combining oncolytic adenovirus mutants with chemotherapeutics on cancer cell death.
  • To assess the in vivo tumor growth inhibition achieved by combining different oncolytic adenovirus mutants with cisplatin and paclitaxel.
  • To determine the impact of an intact immune response on the efficacy of oncolytic adenovirus-chemotherapy combinations.

Main Methods:

  • Cultured seven carcinoma cell lines with viral mutants (wild-type Ad5, dl309 (DeltaE3B), dl704 (DeltaE3gp19K), dl312 (DeltaE1A)) and chemotherapeutics (cisplatin, paclitaxel).
  • Determined synergistic effects on cell death using combination indexes.
  • Evaluated in vivo tumor growth inhibition in immunocompetent and immunodeficient models.

Main Results:

  • Virotherapy alone inhibited tumor growth, with wild-type virus being most efficacious and the DeltaE3B mutant least efficacious.
  • Combining viruses with drugs significantly enhanced tumor inhibition.
  • The DeltaE3B mutant showed the greatest enhancement when combined with drugs, restoring potency to wild-type levels, but only in animals with intact immune responses.
  • Increased infectivity, viral gene expression, and replication were identified as potential synergistic mechanisms.

Conclusions:

  • The attenuation of DeltaE3B oncolytic adenovirus mutants can be overcome by low-dose chemotherapy in the presence of an intact immune response.
  • T-cell-mediated immune functions play a critical role in the enhanced efficacy of oncolytic adenovirus-chemotherapy combinations.
  • Optimizing oncolytic adenovirus therapy may involve strategies that leverage or restore immune function.

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