Beyond Neoantigens: Antigens Derived from Tumor Drivers as Cancer Vaccine Targets

Abstract

A vaccine targeting HER2, a nonmutated but overexpressed tumor antigen, readily primed T cells for ex vivo expansion and adoptive transfer with minimal toxicity. This regimen led to intramolecular epitope spreading in a majority of patients and offers a treatment modality that may improve outcomes for patients with metastatic breast cancer expressing HER2. See related article by Disis et al., p. 3362.

Figure 1.

Cancer vaccine target types. Targets for tumor vaccines fall into two classes: tumor-associated antigens (TAA) and tumor-specific antigens (TSA) and may represent antigens from proteins essential for the malignant phenotype (drivers) or antigens that are noncritical (passengers). TSAs can be derived from cancer mutations or viral oncogenes. The majority of passenger neoantigens are unique to individual patients’ tumors (private neoantigens), are unpredictable, and have low evolutionary pressure to generate or sustain expression. Neoantigens encoded by oncogenic driver mutations may be prevalent across patients and tumor types with evolutionary pressure to maintain expression. TAAs are self-antigens that are preferentially or abnormally expressed in tumor cells but may be expressed at some level in normal cells as well. A tumor-associated driver antigen (such as HER2) has evolutionary pressure to maintain expression while a passenger TAA does not. Therapy-induced TAAs or TSAs can be highly specific for expression in the tumor, appear in resistant clones, and are immunogenic, especially when neoantigens. There is high evolutionary pressure during therapy to select for expression of these antigens, and their onset can be predicted. [Figure adapted from Hollingsworth RE, Jansen K. Turning the corner on therapeutic cancer vaccines. npj Vaccines 2019:4 (7). CC-BY-4.0. http://creativecommons.org/licenses/by/4.0/]