Abstract 5614: Targeting the radiation-inducible neoantigen GRP78 as a novel strategy for non-small cell lung carcinoma treatment

Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities worldwide. NSCLC immunotherapy has not been successful in the past. Although lung cancer is not typically believed to be an immunogenic malignancy, more and more evidence suggests that immune responses to lung cancer may be important. The objective of this research was to address a critical barrier and develop a new paradigm in the treatment of NSCLC. Development of anticancer antibodies is limited by the scarcity of antigens that are specifically overexpressed in lung cancer, resulting in too few molecular targets and small percentages of patients who can be treated with the therapeutic antibody. We established a platform technology to develop antibodies to radiation-inducible neoantigens. Several radiation-inducible antigens have been identified by our group. Glucose-regulated protein 78 (GRP78), a multifunctional protein folding chaperone and co-receptor that is highly expressed on the surface of NSCLC, holds significant promise as a cancer-specific target. Although the potential of targeting GRP78 has been demonstrated in prostate cancer, melanoma, and breast cancer, there are limited data on the impact of targeting cell surface-associated GRP78 in NSCLC. We show that GRP78 undergoes radiation-induced translocation to the surface of NSCLC cells. We developed several GRP78-targeting monoclonal antibodies. NSCLC-specific antibody binding is achieved for several days by anti-GRP78 monoclonal antibodies after irradiation. Optical imaging and immunohistochemical staining indicated that the GRP78-specific antibodies achieve specific binding to irradiated NSCLC in mouse models. The anti-GRP78 antibodies also have a direct cytotoxic effect on NSCLC cells. The combination of anti-GRP78 antibodies and radiation showed an additive effect. Overall, this study suggests that GRP78 is a promising therapeutic target for the treatment of lung cancer. We propose to harness the physiologic response of cancer to radiotherapy and evolve it for immunotherapy of lung cancer using specific targeting antibodies. Citation Format: Abhay Singh, Vaishali Kapoor, David Dadey, Dinesh Thotala, Dennis Hallahan. Targeting the radiation-inducible neoantigen GRP78 as a novel strategy for non-small cell lung carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl)