Final Report Summary - TRASTUZUCRAD (Oncolytic adenoviruses expressing monoclonal antibody trastuzumab for treatment of Her-2+ cancer)
Purpose: Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing cancer. Nevertheless, systemic antibody therapy is expensive and carries the risk of severe side-effects such as cardiomyopathy. Oncolytic viruses can kill infected cancer cells per se, mount anti-tumor immune responses, and show promising efficacy in combination treatments. We hypothesized we could arm an oncolytic adenovirus with trastuzumab to combine local antibody production with oncolytic efficacy.
Experimental design: We constructed a chimeric serotype 5 oncolytic adenovirus Ad5/3-∆24-tras coding for human trastuzumab antibody heavy and light chain genes, connected by an internal ribosome entry site. We studied antibody production from cancer cells, anti-cancer activity in vitro, and evaluated efficacy and mechanism of action in vivo.
Results: Infected cancer cells were able to produce full-length assembled antibody, as confirmed by Western blot and ELISA, which was released to supernatant and could induce antibody-dependent cell-mediated cytotoxicity (ADCC) via immune cells. Ad5/3-∆24-tras showed in vitro cytotoxicity and enhanced anti-tumor efficacy over oncolytic control virus Ad5/3-∆24 or commercial trastuzumab in HER2-positive gastric cancer in nude mice (P < 0.05 both). Moreover, higher local and lower systemic concentrations of trastuzumab were detected after Ad5/3-∆24-tras treatment as compared to controls. Flow cytometry analysis suggested dendritic and natural killer cell induction in draining lymph nodes following Ad5/3-∆24-tras treatment.
Conclusions: Ad5/3-∆24-tras is an attractive anticancer approach combining oncolytic potency with local trastuzumab production, resulting in improved in vivo efficacy in HER2-positive cancer. Antibody-mediated immune cell activation may further potentiate the effects of oncolytic immunotherapy.
Experimental design: We constructed a chimeric serotype 5 oncolytic adenovirus Ad5/3-∆24-tras coding for human trastuzumab antibody heavy and light chain genes, connected by an internal ribosome entry site. We studied antibody production from cancer cells, anti-cancer activity in vitro, and evaluated efficacy and mechanism of action in vivo.
Results: Infected cancer cells were able to produce full-length assembled antibody, as confirmed by Western blot and ELISA, which was released to supernatant and could induce antibody-dependent cell-mediated cytotoxicity (ADCC) via immune cells. Ad5/3-∆24-tras showed in vitro cytotoxicity and enhanced anti-tumor efficacy over oncolytic control virus Ad5/3-∆24 or commercial trastuzumab in HER2-positive gastric cancer in nude mice (P < 0.05 both). Moreover, higher local and lower systemic concentrations of trastuzumab were detected after Ad5/3-∆24-tras treatment as compared to controls. Flow cytometry analysis suggested dendritic and natural killer cell induction in draining lymph nodes following Ad5/3-∆24-tras treatment.
Conclusions: Ad5/3-∆24-tras is an attractive anticancer approach combining oncolytic potency with local trastuzumab production, resulting in improved in vivo efficacy in HER2-positive cancer. Antibody-mediated immune cell activation may further potentiate the effects of oncolytic immunotherapy.