AbstractThe use of Fas ligand (FasL) gene therapy for cancer has shown promise in laboratory animals. The mechanism by which this treatment works appears to be through induction of tumor inflammation and anti-tumor immunity. However, the efficacy of FasL to treat spontaneous tumors is unknown. To investigate this, we used the intratumoral FasL gene delivered in an adenovirus vector as neoadjuvant to standard of care in 56 dogs with naturally occurring appendicular osteosarcoma. Tumors from dogs treated with FasL had greater inflammation, necrosis, apoptosis, and fibrosis at day-10 (amputation) than tumors from controls dogs that did not receive FasL. These parameters also were increased when compared to pre-treatment biopsy samples (day-0). Survival improvement was apparent in dogs with greater inflammation or lymphocyte infiltration scores and in the top 50th percentile of apoptosis, whereas it was no different than standard of care alone in dogs with lower inflammation scores and the bottom 50th percentile of apoptosis. Reduced Fas expression in tumor cells was the only variable associated with prognostically advantageous inflammation; this relationship was not seen in dogs that did not receive FasL therapy. Together, the data suggest that FasL gene therapy can improve survival in naturally occurring tumors of large animals, and may be most effective when tumors fail to express Fas receptor, thus allowing FasL to exert its pro-inflammatory effects on the tumor microenvironment.
