Enhanced antitumoral efficacy and immune response following conditionally replicative adenovirus containing constitutive HSF1 delivery to rodent tumors.

Abstract

BACKGROUND:

Oncolytic adenoviruses are promising as anticancer agents but have limited clinical responses. Our previous study showed that heat shock transcription factor 1 (HSF1) overexpression could increase the anti-tumor efficacy of E1B55kD deleted oncolytic adenovirus through increasing the viral burst. Due to the important roles of heat shock proteins (HSPs) in eliciting innate and adaptive immunity, we reasoned that besides increasing the viral burst, HSF1 may also play a role in increasing tumor specific immune response.

METHODS:

In the present study, intra-dermal murine models of melanoma (B16) and colorectal carcinoma (CT26) were treated with E1B55kD deleted oncolytic adenovirus Adel55 or Adel55 incorporated with cHSF1, HSF1i, HSP70, or HSP90 by intra-tumoral injection. Tumors were surgically excised 72 h post injection and animals were analyzed for tumor resistance and survival rate.

RESULTS:

Approximately 95% of animals in the Adel55-cHSF1 treated group showed sustained resistance upon re-challenge with autologous tumor cells, but not in PBS, Adel55, or Adel55-HSF1i treated groups. Only 50-65% animals in the Adel55-HSP70 and Adel55-HSP90 treated group showed tumor resistance. Tumor resistance was associated with development of tumor type specific cellular immune responses. Adel55-cHSF1 treatment also showed higher efficacy in diminishing progression of the secondary tumor focus than Adel55-HSP70 or Adel55-HSP90 treatment.

CONCLUSIONS:

Besides by increasing its burst in tumor cells, cHSF1 could also augment the potential of E1B55kD deleted oncolytic adenovirus by increasing the tumor-specific immune response, which is beneficial to prevent tumor recurrence. cHSF1 is a better gene for neoadjuvant immunotherapy than other heat shock protein genes.

• Authors: Rong Fan, Cheng Wang, Yang Wang, Ping Ren, Pingping Gan, Hui Ji, Zian Xia, Suiyu Hu, Qiongyao Zeng, Wei Huang, Yebin Jiang, Xi Huang
• Journal: Journal of translational medicine (J Transl Med) Vol. 10 Pg. 101 (May 21 2012) ISSN: 1479-5876 [Electronic] England
• PMID: 22613625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• HSF1 protein, human
• Heat Shock Transcription Factors
• Transcription Factors

Topics

• Adenoviridae (physiology)
• Animals
• DNA-Binding Proteins (genetics, therapeutic use)
• Gene Transfer Techniques
• Genetic Therapy
• HEK293 Cells
• Heat Shock Transcription Factors
• Humans
• Immunity
• Immunotherapy
• Kaplan-Meier Estimate
• Mice
• Mice, Inbred C57BL
• Neoadjuvant Therapy
• Neoplasm Micrometastasis
• Neoplasms (immunology, pathology, therapy)
• Spleen (immunology, pathology)
• T-Lymphocytes, Cytotoxic (immunology)
• Transcription Factors (genetics, therapeutic use)
• Treatment Outcome
• Virus Replication (physiology)