Stereotactic body radiation therapy (SBRT) uses image guidance to deliver very high doses of radiation, in no more than 5 fractions, to tumors. SBRT has shown remarkable benefit in patients with peripheral lung tumors but can cause severe toxicity to central organs when the tumor is proximally located if full potency doses are used (18 Gy x 3 fractions, for example). Bavituximab, a therapeutic monoclonal antibody in Phase III clinical testing in non-small cell lung cancer (NSCLC) patients, recognizes the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on blood vessels and cells in tumors subjected to SBRT. Using orthotopic rat models, we hypothesized that treatment with the antibody 2aG4 (a murine version of bavituximab) would synergize with SBRT and allow tolerable doses of radiation to be used to treat centrally-located NSCLC without sacrificing efficacy.
Immunodeficient nude rats bearing established orthotopic A549-luciferase NSCLC tumors were enrolled in a therapy study after the bioluminescence signal of their tumor was greater than 10 million photons per second (typically 2-3 weeks post implantation of tumor cells). These animals were treated with 3x12 Gy of radiation alone (n=10), 2aG4 alone (n=8; 4 mg/kg, twice per week), or with a combination of radiation and 2aG4 (n=11). Tumor growth was monitored by bioluminescence weekly. Rats treated with radiation and 2aG4 had a 100% survival rate 185 days after implantation and tumors were completely eradicated in 73% of these animals. In contrast, rats treated with radiation had a survival rate of 60%, those treated with 2aG4 had a 62.5% survival rate, while only 18% of untreated rats (n=16) survived after 185 days. Additionally, we confirmed that exposure of PS was induced by intense radiation in orthotopic lung tumors . These survival experiments are being validated with H460-luciferase NSCLC tumors resulting from an improved lung implantation technique. Current preliminary results from the ongoing experiments show a similar benefit of radiation + 2aG4 in rats bearing H460-luciferase tumors. Additionally, we performed endpoint experiments with the same treatment arms and are evaluating immune cell infiltration in lung tumors after radiation therapy +/- antibody-mediated PS blockade.
Toxicity studies were conducted in which 3x12 Gy of radiation was delivered to central organs of tumor-free rats in presence or absence of 2aG4. The presence of 2aG4 did not significantly prevent or exacerbate normal radiation-induced toxicity as measured by lung fibrosis, thickness of esophageal tissues, or bronchus integrity.
These results indicate that administration of bavituximab in combination with radiation should be explored in patients with centrally-located NSCLC.
Citation Format: Olivier Belzile, Zhang Zhang, Xianming Huang, Debabrata Saha, Rolf A. Brekken. Antibody-mediated blockade of phosphatidylserine combined with intense radiation improves survival and tumor eradication in rat models of non-small cell lung cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B116.
- ©2016 American Association for Cancer Research.