VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• Oncolytic virus therapy, specifically using oncolytic herpes simplex virus (oHSV), shows promise for cancer treatment.
• Understanding the host's inflammatory response to oHSV is crucial for optimizing its antitumor efficacy.
• Intratumoral injection of oHSV in xenograft models yielded limited antitumor effects, necessitating investigation into the host response.

Purpose of the Study:

• To characterize the host inflammatory response to intratumoral oHSV injection.
• To evaluate the efficacy of anti-VEGF antibodies in combination with oHSV virotherapy.
• To elucidate the mechanisms underlying the combined therapeutic effects.

Main Methods:

• Intratumoral injection of oHSV in xenograft models.
• Analysis of host inflammatory infiltrate (neutrophils, macrophages) post-virotherapy.
• Administration of anti-VEGF antibodies (bevacizumab, r84) in combination with oHSV.
• Assessment of angiogenesis and virus production.
• Systemic depletion of CD11b(+) myeloid cells.

Main Results:

• oHSV induced neutrophilic infiltrate, decreased intratumoral macrophages, and upregulated myeloid cell-derived VEGF.
• Anti-VEGF antibodies enhanced oHSV's antitumor effects by reducing angiogenesis and partially mitigating macrophage depletion.
• Neither antibody increased virus production or affected neutrophilic infiltration.
• The combined therapy's enhancement was largely replicated by depleting CD11b(+) cells.

Conclusions:

• Combined oHSV virotherapy and anti-VEGF antibody treatment modulates the host inflammatory response, leading to enhanced antitumor effects.
• Targeting the host inflammatory reaction, particularly myeloid cell-mediated VEGF production, is a viable strategy to improve oncolytic virotherapy efficacy.
• These findings provide preclinical support for combining oHSV and anti-VEGF antibody therapies to achieve greater antitumor potential.