Published OnlineFirst January 26, 2015; DOI: 10.1158/1078-0432.CCR-14-1186 Review Clinical Cancer Research Nonviral Oncogenic Antigens and the Inflammatory Signals Driving Early Cancer Development as Targets for Cancer Immunoprevention Nina J. Chu1,2, Todd D. Armstrong1, and Elizabeth M. Jaffee1,2 Abstract Cancer immunoprevention is an emerging field that holds monocytogenes–based vaccine expressing mutant oncogene much promise. Within the past 20 years, prophylactic vaccines KrasG12D (LM-Kras) effective in a pancreatic cancer model. A have been implemented on the population level for the immu- novel chimeric human/rat HER-2 plasmid vaccine (HuRT-DNA noprevention of carcinomas induced by viruses, specifically vaccine) effective in a breast cancer model is also discussed. In hepatitis B virus (HBV) and human papillomavirus (HPV) addition to prophylactic vaccine developments, this review infection. Armed with the success of prophylactic vaccines that highlights the potential use of classic drugs, such as aspirin prevent viral-induced tumors, the field must overcome its next and metformin, as chemopreventive agents that can potentially hurdle: to develop robust prophylactic vaccines that prevent the be used as adjuvants to enhance the anticancer immunogenicity remaining >80% of human cancers not induced by viral infec- and efficacy of noninfectious prophylactic vaccines by modu- tion. In this review, we discuss some of the most promising lating the inflammatory pathways within the early tumor micro- non–virus-associated prophylactic vaccines that target endoge- environment (TME) that propels tumorigenesis. Finally, timing nous neoantigens, including the earliest oncogene products, of prophylactic vaccine administration is critical to its immu- altered mucin 1 (MUC1) and a-enolase (ENO1), all of which nopreventive efficacy, providing a necessary role of current and produce new targets in the earliest stages of nonviral-induced emerging biomarkers for cancer screening and early cancer tumorigenesis. We also highlight a novel attenuated Listeria detection. Clin Cancer Res; 21(7); 1549–57. Ó2015 AACR. Introduction the first "pure" implementation of human cancer immunopre- vention (1). The recent population-based data indicating the In the past two decades, significant progress has occurred in efficacy of the HPV vaccine in Australia following the imple- the field of cancer immunoprevention as evidenced by the mentation of Australia's National HPV Vaccination Program in success of prophylactic vaccines in preventing cancers caused 2007 is very promising, and represents the first fully govern- by viral infection, so-called "infectious tumors," which account ment-funded HPV vaccination program using the prophylactic for 10% to 20% of all human tumors (1, 2). The most successful quadrivalent HPV vaccine Gardasil (Merck; 4–6). In 2011, the prophylactic vaccines targeting infectious tumors are effective prevalence of vaccine-targeted HPV genotypes in women of against hepatitis B virus (HBV) and human papillomavirus ages 18 to 24 years was significantly lower in postvaccinated (HPV; refs. 1–3). The HBV-specific prophylactic vaccine, ini- womenthaninprevaccinatedwomen(6.7%vs.28.7%;ref.4), tially developed to prevent chronic acute hepatitis, had the while in 2014, the prevalence of HPV genotypes in postvacci- unintentional favorable effect of dramatically reducing the nated women further declined to 1.6% (5). Such significant incidence of post-hepatitis hepatocellular carcinoma (HCC; reductions in HPV prevalence should be indicative of an refs. 1, 2). Conversely, the original intention for developing eventual decrease in HPV-related cervical cancer incidence. the prophylactic HPV vaccine was to prevent cervical cancer Although the long-term efficacy of the HPV vaccine in prevent- caused by persistent HPV infection. Hence, the HPV vaccine was ing cervical cancer has not yet been determined because of its recent worldwide administration, the results of clinical trials predict a near complete prevention of cancer occurrence (1). 1Department of Oncology,The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Mary- Because most human cancers are not induced by viral infection, land. 2Department of Pharmacology and Molecular Sciences, Johns and are therefore termed "noninfectious tumors," the current Hopkins University School of Medicine, Baltimore, Maryland. goal of cancer immunoprevention is to translate the successes Corresponding Author: Elizabeth M. Jaffee, Sidney Kimmel Cancer Center, of prophylactic vaccine development from infectious tumor Johns Hopkins University School of Medicine, Room 4M07, Bunting Blaustein models to noninfectious tumors (2). Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410- There are two reasons for the success of prophylactic vaccines 955-2957; Fax: 410-614-8216; E-mail: [email protected] that combat infectious tumors. First, these vaccines target known doi: 10.1158/1078-0432.CCR-14-1186 viral antigens involved in the tumorigenesis process (1). Second, Ó2015 American Association for Cancer Research. they work when given to those at risk before exposure (1). Also www.aacrjournals.org 1549 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst January 26, 2015; DOI: 10.1158/1078-0432.CCR-14-1186 Chu et al. critical is the fact that, in the case of HPV vaccine administration Antigen Targets for Prophylactic Vaccine for the prevention of cervical cancer, the at-risk group is essentially Development all young adults, which alleviates the need for developing screen- ing methods to identify a small at-risk population who would The first step toward the design of effective vaccines for cancer benefit most (6). In contrast, a number of additional challenges prevention is the selection of the antigen target. An optimal must be addressed to successfully develop prophylactic vaccines antigen target should be an early alteration in a normal gene that that target noninfectious tumors. The first is the need to identify is likely an initiator (driver) or facilitator of tumor development to the optimal tumor antigens that can serve as vaccine targets. ensure that the immune response is directed toward a "causative" Currently, most antigens that have been identified are not unique signal without which the developing tumor cannot survive. Vac- to the cancer, but are instead variations of or differentially cination of such a target is likely to produce an immunopreventive expressed endogenous self-antigens (1, 2, 7, 8). Although these response that is both efficacious and the least toxic, mounting a antigens may serve as targets for primary cancer prevention, they focused and concerted immune response to early neoplasms may also increase the risk of autoimmune responses to similar (1, 8). The difficulty lies in predicting the earliest antigenic profile antigens expressed on normal tissue (1). Second, emerging data in of developing tumors and discovering such antigens that are animal models suggest that immune escape in the form of dysregulated in the earliest stages of tumorigenesis, along with immune editing and immune tolerance mechanisms begins early their differential expression among other cell types. However, the in cancer development, at the time of the first genetic alteration rapidly progressing field of cancer genetics is uncovering the that initiates the cascade of genetic and inflammatory changes that earliest cancer driver genes and their expressed neoantigens asso- eventually lead to cancer development (9–11). Thus, it is likely ciated with the development of different cancers. The various that any vaccine that targets a noninfectious tumor-promoting methods used to discover potential cancer driver genes and their antigen will likely need to be given with other agents that expressed antigenic targets are discussed in detail elsewhere modulate the early inflammatory tumor microenvironment (12–14). Currently, there are sets of known driver gene antigens (TME) and precancerous mechanisms of immune evasion (9). for some cancers that are classified according to their tumor/ This challenge raises the need for biomarkers that can identify normal tissue exclusivity and cellular localization (Table 1). populations at risk for a given cancer type and who will benefit Tumor-specific antigens (TSA) are antigens that are exclusively most from early immune-based interventions. However, with expressed on tumor cells and not on any other cells (8). TSAs are G12D careful selection of oncogenic antigen targets that are specific often mutated proteins, such as Kras and p53 (3). Tumor- "driver" gene products that arise early in a particular cancer's associated antigens (TAA) are endogenous antigens present on development, adjuvant regulation of the inflammatory TME, both tumor and normal cells but are dysregulated in their expres- and robust diagnostic and prognostic screening for the early sion or cellular localization. The HER-2/neu receptor is one detection of cancer, there is great potential for the successful example of a TAA (3, 8). As progress in cancer immunotherapy development of prophylactic vaccines that prevent nonvirally and immunoprevention has greatly accelerated in the past two induced tumorigenesis. decades, a novel class of antigens, oncoantigens, has been defined Table 1. Select driver antigens and their antigenic classifications Driver antigen Oncogenic state Cellular location Type of antigen