Palladini et al. BMC Immunology (2018) 19:16 https://doi.org/10.1186/s12865-018-0253-0 REVIEW Open Access Cancer immunoprevention: from mice to early clinical trials Arianna Palladini1, Lorena Landuzzi2, Pier-Luigi Lollini1* and Patrizia Nanni1 Abstract Cancer immunoprevention is based on the fact that a functioning immune system controls tumor onset and development in humans and animals, thus leading to the idea that the enhancement of immune responses in healthy individuals could effectively reduce cancer risk later in life. Successful primary immunoprevention of tumors caused by hepatitis B and papilloma viruses is already implemented at the population level with specific vaccines. The immunoprevention of human tumors unrelated to infectious agents is an outstanding challenge. Proof-of- principle preclinical studies in genetically-modified or in carcinogen-exposed mice clearly demonstrated that vaccines and other immunological treatments induce host immune responses that effectively control tumor onset and progression, eventually resulting in cancer prevention. While a straightforward translation to healthy humans is currently unfeasible, a number of pioneering clinical trials showed that cancer immunoprevention can be effectively implemented in human cohorts affected by specific cancer risks, such as preneoplastic/early neoplastic lesions. Future developments will see the implementation of cancer immunoprevention in a wider range of conditions at risk of tumor development, such as the exposure to known carcinogens and genetic predispositions. Keywords: Cancer immunoprevention, Cancer vaccines, Genetically-modified mouse models, HER-2, Oncoantigens Background After 50 years of intense research, we have reached The immune system is a major player in the prevention of general conclusions that apply to humans and mice: any diseases. Immunity is best known for the prevention of severe, congenital immune deficiency exposes the adult infectious diseases, however it plays an equally important host to a high risk of tumor onset involving all tumor role in the prevention of tumors. Such a role was first hy- types. Partial or transient immune deficiencies entail a pothesized half a century ago, but a definitive demonstra- correspondingly reduced tumor risk, possibly limited to tion came only at the beginning of this century, when it specific tumor types, such as highly immunogenic viral was shown that severely immunodeficient mice invariably tumors [4]. Under non-sterile conditions, severe primary develop tumors over time, whereas immunocompetent immune deficiencies expose the host to an early septic mice of the same age are tumor-free [1, 2]. death, well before the age when the tumor risk would While mouse immunologists were struggling to devise become manifest, hence human cancer risk related to appropriate genetically-modified immunodeficient immune deficiency is mostly confined to secondary im- mouse models, human immunologists accumulated mune deficiencies and viral tumors [5]. evidence on transplant recipients and AIDS patients, Just as it happens with infectious diseases, the tumor showing that, in both cases, human immunodeficiency preventive efficacy of the immune system is far from brought about a strong increase in the risk of complete and declines with age, thus contributing to the virus-related tumors, such as Kaposi sarcoma, caused by age-related risk of cancer [6]. From a preventive point of human herpesvirus 8, or carcinomas caused by human view, this leads to the concept of cancer immunopreven- papilloma viruses [3]. tion, i.e. the opportunity to further decrease tumor risk through the stimulation of immune defenses [7, 8]. * Correspondence: [email protected] 1Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126 Bologna, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Palladini et al. BMC Immunology (2018) 19:16 Page 2 of 6 Immunoprevention of viral and non-viral tumors conceptual perspective, and we will consider as second- Human cancer immunoprevention is clearly divided in ary prevention any intervention taking place after the two: on the one hand are tumors related to infectious start of the carcinogenic process, regardless of whether agents, for which some effective vaccines are already im- the underlying abnormal tissue is formally labeled as plemented at the population level, even though some preneoplastic or as early neoplastic. difficulties remain, as we shall see. On the other hand are all tumors unrelated to infectious agents (here re- Prevention of infection-related tumors ferred to as noninfectious tumors), which represent the Outside of the laboratory, the first successful application bulk of human tumor burden [9], for which we are of vaccines to the prevention of cancer was in the late beginning to see some early clinical application, after 1960s to Marek’s disease, an avian leucosis that affected two decades of tantalizing preclinical results in mouse poultry farms, caused by the eponymous herpesvirus models [10, 11]. MDV [14]. One issue that must be clarified in advance is that the The first human cancer preventive vaccine was against notion of cancer prevention, and by extension of cancer hepatitis B virus (HBV), which in a minority of infected immunoprevention, encompasses conceptually different individuals could result in chronic hepatitis, hepatic approaches (see [12] for a more formal definition of the cirrhosis and eventually hepatocellular carcinoma. The various types of prevention). Primary prevention aims at earliest confirmation of the tumor preventive activity of removing cancer risk factors to reduce tumor incidence. anti-HBV vaccines came from a pediatric Taiwanese A classic example in the field of chemical carcinogenesis cohort, which showed a 70% overall reduction of liver is the avoidance of cigarette smoke, to prevent the onset cancer risk, further confirmed in a subsequent of lung cancer and many other tobacco-related tumors. long-term re-evaluation [15]. Vaccines against oncogenic viruses are a typical example Worldwide implementation of HBV vaccination pro- of primary cancer immunoprevention. In the field of pri- grams in the 1980s thus represents the first instance of mary cancer prevention, the use of drugs that reduce the mass cancer immunoprevention. It might be objected risk of cancer, for example by preventing exposure to that prevention of acute HBV infection is the raison carcinogenic agents, is labeled as chemoprevention. d’être of the HBV vaccine, and that cancer prevention is Given that vaccines are drugs, immunoprevention can just a nice, but secondary, side effect. The point is well be also defined as a type of chemoprevention that acts taken, but certainly it does not apply to the second wave through the immune system [13]. Secondary prevention of cancer preventive vaccines, directed against human aims at limiting cancer progression toward malignancy, papillomaviruses (HPV), which are essentially oncogenic through interventions targeted at early stages of tumor viruses [16], hence any HPV vaccine is by definition onset. Early diagnosis is the classic human application aimed at cancer prevention. labeled as secondary prevention, implemented through Mass vaccination against HPV begun in the late 2000s, mass screenings, for example using mammography. thus long-term results for what concerns cancer preven- However, it must be considered that early diagnosis is tion at the population level are not yet available, but the only the beginning of secondary prevention, and an early results of approval trials, which involved tens of thou- therapeutic intervention is needed to actually avoid pro- sands of women worldwide, showed near 100% preven- gression to malignancy. Thus, immunological treatments tion of neoplastic lesions caused by the viral genotypes applied after an early diagnosis, to prevent tumor pro- included in each vaccine [17]. Furthermore, early ana- gression, are instances of secondary cancer immunopre- lyses of national vaccination programs confirm sizeable vention [12]. reductions in HPV prevalence [18], foreboding corre- When one considers that the carcinogenic process is a sponding reductions in cancer incidence. continuum that goes from a normal tissue to a highly In principle, cervical carcinoma could become the first malignant tumor, in some instances it is a matter of human cancer eradicated by immunoprevention, much definition whether a given intervention should be labeled as it happened with smallpox in the late 1970s. However, as primary or secondary prevention. From a practical major obstacles must be overcome before this happens. perspective this can result either in the reduction of The major one is that in most countries the proportion incident tumors, through the discovery of lesions labeled of subjects vaccinated each year is low, even down