The Dawn of Vaccines for Cancer Prevention

CANCER IMMUNOTHERAPYREVIEWS

The dawn of vaccines for cancer prevention

Olivera J. Finn Abstract | An important role of the immune system is in the surveillance for abnormal or transformed cells, which is known as cancer immunosurveillance. Through this process, the first changes to normal tissue homeostasis caused by infectious or other inflammatory insults can be detected by the immune system through the recognition of antigenic molecules (including tumour antigens) expressed by abnormal cells. However, as they develop, tumour cells can acquire antigenic and other changes that allow them to escape elimination by the immune system. To bias this process towards elimination, immunosurveillance can be improved by the administration of vaccines based on tumour antigens. Therapeutic cancer vaccines have been extensively tested in patients with advanced cancer but have had little clinical success, which has been attributed to the immunosuppressive tumour microenvironment. Thus, the administration of preventive vaccines at pre-malignant stages of the disease holds promise, as they function before tumour-associated immune suppression is established. Accordingly, immunological and clinical studies are yielding impressive results.

Checkpoint inhibitors Treatment without prevention is simply unsustainable. Ribbon Panel included support for basic, translational, Antibodies or other drugs that Bill Gates computational and clinical research in immunotherapy inhibit the function of specific and immunoprevention of all cancers5. The fiscal year molecules (such as cytotoxic T In October 2015, as part of a Grand Challenges initi- 2019 NCI budget proposal for the first time includes vac- lymphocyte antigen 4 (CTLA4), programmed cell death ative, Cancer Research UK (CRUK) published a call cines for cancer prevention as a priority area (see Further protein 1 (PD1) and PD1 ligand for proposals to develop vaccines for the prevention of information). 1 (PDL1)) expressed on the nonviral cancers (see Further information). At the same This push towards cancer prevention and the inclu- surface of immune cells or time, the US National Cancer Institute (NCI) convened sion of immunoprevention by some of the most emi- cancer cells that serve as a Cancer Prevention Think-Tank with research experts nent cancer organizations is a welcome change. Cancer breaks or that keep immune responses in check at in the areas of immunoprevention, precision prevention prevention research has been an active field of investi- 6,7 particular time points and early detection, and surveillance and screening. In gation for many years and has yielded several chemo (checkpoints) in immune cell February 2016, the American Association for Cancer preventive agents that have been approved by the US activation. Blocking the Research (AACR) held a Cancer Prevention Summit Food and Drug Administration (FDA). Nevertheless, function of these molecules releases the breaks and can with immunoprevention prominently represented on cancer prevention research has always taken a back lead to tumour destruction. the agenda (see Further information). Several reports seat to the much larger effort in cancer therapy for the related to these meetings were published, setting the many millions of patients currently living with cancer. course for increased efforts in cancer prevention1–3. Unfortunately, even the most successful cancer thera Among the priority areas identified were molecular and pies, such as the newest immunotherapy approaches immunological studies of pre-malignant states, the gen- with checkpoint inhibitors8 and adoptive transfer of eration of a precancer genome atlas4 for exploring the engineered T cells9, are making a relatively small impact on concept of precision prevention and the identification the large numbers of patients with cancer and are having Department of Immunology, of new targets for prevention, including for immuno- the greatest impact on patients in developed countries. University of Pittsburgh prevention. Also in early 2016, the Blue Ribbon Panel The rationale to increase research on cancer pre- School of Medicine, Pittsburgh, Pennsylvania (see Further information) was appointed by the NCI to vention is supported by not only the need to decrease 15261, USA. highlight priority areas in cancer research and preven- human suffering subsequent to cancer diagnosis but [email protected] tion and to provide funding recommendations to the also economic necessity. In 2010 in the United States, doi:10.1038/nri.2017.140 Cancer Moonshot programme. Recommendations from there were 12.8 million patients with cancer, and that Published online 27 Dec 2017 the Cancer Immunology Working Group to the Blue number is projected to increase to 18.1 million in 2020.

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The associated treatment costs are projected to increase antigens that resulted from mutations in the newly dis- from US$124.57 billion in 2010 to $157.77 billion in covered cancer-causing genes (known as oncogenes; 2020. With a projected annual increase of 2% in the cost such as those of the RAS family), tumour suppressor of medical care, the real cost in 2020 may be closer to genes (such as TP53) and other common mutations $173 billion10. There is also a discrepancy in the human (such as gene fusions exemplified by BCR–ABL1). and economic burden of cancer between developed and Vaccines based on these mutations showed immuno- developing countries, as people in developing countries genicity and antitumour efficacy in mouse models and suffer and die in greater numbers without the benefit of were promptly moved to clinical testing (TABLE 1). effective but expensive cancer therapies and preventive Another set of antigens that were expected to elicit measures, such as clinical surveillance and early detec- strong antitumour responses are the products of onco- tion. The desire to make cancer care a universal human genic viruses such as HPV, HBV and Epstein–Barr right11,12 supports an increased effort in developing more virus (EBV). Low frequencies of T cells against such cost-effective cancer prevention approaches. antigens could be detected in patients with cancer13,14. One such disease prevention approach is vaccination. Various vaccines were generated to elicit or boost these It is clear that vaccines against cancer-causing viruses, responses. These vaccines were immunogenic and pro- such as human papillomavirus (HPV) and hepatitis B tective in mouse models, but when they were tested in virus (HBV), are very effective in preventing the initial patients with advanced cervical cancer (HPV vaccines)15, infection and therefore in markedly reducing the risk of hepatocellular carcinoma (HCC; HBV vaccines)13 and cancers caused by these viruses. However, for the major- oropharyngeal carcinomas and Hodgkin disease (EBV ity of cancers, infectious aetiology is either unknown or vaccines)14, they showed little or no clinical efficacy. nonexistent, so other targets must be evaluated as can- By far the largest number of tumour antigens didate antigens for preventive vaccines. Because most detected by T cells and antibodies from patients with tumour antigens are derived from self-molecules, gener cancer are derived from nonmutated cellular proteins ating a strong immune response against them has been that are differentially expressed between normal and considered to be breaking tolerance to self and to carry tumour cells. Many of these tumour-associated antigens the risk of autoimmunity. For this reason, most cancer (TAAs) had been previously characterized as targets of vaccine efforts have focused on developing vaccines to tumour-specific monoclonal antibodies that were gen- treat advanced cancer, for which the risks inherent in the erated in mice against human tumours. Some of the target antigen choice have been more acceptable. The well-known examples are carcinoembryonic antigen results have been disappointing in the therapeutic set- (CEA; also known as CEACAM5) and other oncofetal ting and have greatly under-represented the full poten- antigens, melanocytic antigens, the mucin family of tial of these vaccines. Nevertheless, we have gained great molecules and various tumour-specific carbohydrates. insight from trying to understand the failures of various Molecular and biochemical characterization of many cancer vaccine approaches. TAAs revealed the basis of their tumour-specific In this Review, I discuss the probably enormous expression and triggered the field of therapeutic cancer but still untested potential of vaccines for cancer pre- vaccines16–19. vention instead of cancer therapy and the path to their development. I review how lessons learnt from work on The vaccine effort. The period from 1990 to 2010 therapeutic cancer vaccines provide a strong basis for was characterized by a gold rush of effort to discover developing preventive vaccines, describe the past suc- more TAAs and combine them with various adjuvants cesses and current efforts in developing vaccines for the and delivery systems to achieve the greatest possible prevention of cancers with an infectious origin, propose immunogenicity and hoped-for clinical effective- that pre-malignant lesions should be the first targets for ness17,20. New developments and new knowledge in preventive vaccines and review a small but increasing immunology and molecular biology were promptly number of clinical efforts to test vaccines for cancer pre- incorporated into vaccine designs16,21 (FIG. 1). The first vention. Examples will be limited to studies in humans. clinical trials either tested peptide-based vaccines using TAAs such as the epithelial tumour antigen Therapeutic cancer vaccines mucin 1 (MUC1)22, melanoma-associated antigen 3 (MAGEA3)23 and the breast cancer antigen human epi- If people are constantly falling off a cliff, you could dermal growth factor receptor 2 (HER2; also known place ambulances under the cliff or build a fence on the as ERBB2 and NEU)24, or tested vaccines composed of Engineered T cells top of the cliff. We are placing all too many ambulances whole tumour cells or cell lysates that contained some T cells that have been modified under the cliff. Denis Burkitt of the known TAAs as well as potentially many others ex vivo through gene transfer 25 to assume new functions. For not yet identified . When the importance of dendritic 26 example, T cells can be Identifying antigens. In the late 1970s and early 1980s, cells (DCs) as professional antigen-presenting cells transduced either with some researchers considered cancer to be a strictly was established, in vitro-generated and fully activated chimeric antigen receptors or genetic disease, whereas others considered it to be pri- DCs became a delivery vehicle for TAAs, and hundreds with T cell receptors, which marily due to a failure of immunosurveillance. It proved of DC‑based vaccine trials were carried out in differ- endows them with different 27 antigen specificity from that of to be both, and this was reflected in the first attempts at ent cancer types . There were also vaccines developed 28 29 their endogenous T cell active specific immunotherapy of cancer. These initial based on viral or bacterial vectors or virus-like receptors. approaches involved identifying and targeting cancer particles30 that were engineered to express TAAs in

CANCER IMMUNOTHERAPYREVIEWS

Table 1 | Important tumour antigens for vaccines Antigen category Antigens Tumour targets for Tested in Suitable for Setting for preventive therapeutic vaccines therapeutic preventive vaccines vaccines? vaccines? Cancer–testis: expressed in CT83, MAGEA1–4, Bladder, breast, lung, Yes Yes • Genetic risk (for example, normal testis and no other NY‑ESO‑1, PRAME melanoma, myeloma and BRCA1 and BRCA2 mutations) healthy tissue and SSX2 ovarian • Pre-malignant precursor lesions (for example, DCIS, MGUS, colonic polyps and bronchial neoplasia) Differentiation-specific or CD19, GP100, B cell lymphoma, Yes No None lineage-specific: expressed MART1, PSA, PSMA melanoma and prostate by normal and tumour cells of and tyrosinase the same organ or tissue type Overexpressed: expressed CEA, cyclin B1, Bladder, breast, cervical, Yes Yes • Genetic risk (for example, at markedly higher levels EGFR, EPHA2, colon, glioblastoma, BRCA1 and BRCA2 mutations) on tumours compared HER2, mesothelin, hereditary nonpolyposis • Pre-malignant precursor lesions with normal tissue and MUC1, survivin and colon cancer, lung, (for example, DCIS, MGUS, preferentially targeted on telomerase myeloma, oesophageal, colonic polyps, bronchial tumours by the immune ovarian, pancreas and neoplasia, Barrett oesophagus, system prostate pancreatic intraepithelial neoplasias, IPMNs and cervical intraepithelial neoplasias) Post-translationally modified: Glycopeptides (for All tumours Yes Yes Pre-malignant precursor lesions products of tumour-specific example, MUC1T (for example, DCIS, MGUS, changes in glycosylation and and MUC1Tn), colonic polyps, bronchial other modifications phosphopeptides neoplasia, Barrett oesophagus, (for example, LSP1 pancreatic intraepithelial and NCOA1) and neoplasias, IPMNs and cervical citrullinated peptides intraepithelial neoplasias) Mutated oncogenes: products BCR–ABL1, EGFR Acute lymphoblastic Yes Yes Pre-malignant precursor of common somatic mutations variant III, HRAS and leukaemia, acute lesions (for example, pancreatic or gene translocations KRAS myeloid leukaemia, intraepithelial neoplasias and chronic myeloid IPMNs) leukaemia, glioblastoma, lung and pancreas Mutated neoantigens: Unique to each All tumours No No None peptides encompassing tumour random somatic mutations in individual tumours BCR–ABL1, fusion between breakpoint cluster region protein and ABL1; CEA, carcinoembryonic antigen; CT83, cancer–testis antigen 83; DCIS, ductal carcinomas in situ; EGFR, epidermal growth factor receptor; EPHA2, ephrin type A receptor 2; HER2, human epidermal growth factor receptor 2; IPMNs, intraductal papillary mucinous neoplasms; LSP1, lymphocyte-specific protein 1; MAGEA, melanoma-associated antigen; MART1, melanoma antigen recognized by T cells 1; MGUS, monoclonal gammopathy of undetermined significance; MUC1, mucin 1; NCOA1, nuclear receptor coactivator 1; PRAME, melanoma antigen preferentially expressed in tumours; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen.

addition to ‘naked’ DNA-based31 or RNA-based vac- with chemotherapy, radiation, surgery, antibody ther- cines32. Increasing knowledge of the importance of apy, hormone therapy or other therapy, and the other activating antigen-presenting cells through Toll-like 266 trials applied the vaccine alone. Vaccine-only trials receptors (TLRs) led to the development of many TLR were more common in the first decade covered by the ligands that were added to the vaccines as adjuvants to meta-analysis, with the combination trials dominating properly activate the immune system. However, despite the second decade. Although the number of patients applying the latest and best immunological knowledge in phase III trials was relatively large compared with to the design and testing of therapeutic cancer vac- those in phase II trials, the number of phase III trials cines, the overall impact of vaccines on disease-free compared with phase II was very small. This indicates survival, overall survival and cancer recurrence has that the data from the numerous phase II trials were not been minimal21. strong enough to support further development. As a Several meta-analyses have been carried out on the result, only one therapeutic vaccine, Sipuleucel‑T, has therapeutic cancer vaccine effort over the past two dec- been approved to date by the FDA for the treatment ades to extract some commonalities characterizing the of prostate cancer on the basis of a 4.1‑month increase successes and failures that could inform future direc- in median survival34. Another retrospective cross-sec- tions for vaccine efforts. One study evaluated 451 trials tional and longitudinal study analysed 995 trials carried (phases II and III only) carried out in more than 25 dif- out between 1991 and 2013 (REF. 35). In this study, it ferent cancer types from 1999 to 2015 (REF. 33). Of those was noted that the peak number of trials was in 2008 evaluated, 185 trials tested a vaccine in combination and has declined since. Of the 995 trials, only 40 (4%)

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Development of antigen- nonspeciﬁc vaccines, such as Mycobacterium bovis, bacillus Calmette–Guérin and Molecular characterization Cryptosporidium parvum of human shared tumour (2010) FDA approval of antigens17,18,136 (2006 and 2009) the therapeutic vaccine Sipuleucel-T34 (1975) Development of US Food and Drug hybridoma technology133 Administration (1997) Discovery of Toll-like (FDA) approval of receptors137 Development of mutated the human neoantigens as Identiﬁcation of human papillomavirus personalized therapeutic tumour antigens with mouse Clinical trials of therapeutic vaccines Gardasil vaccines111 monoclonal antibodies cancer vaccines138,139 (Merck) and Cervarix (GlaxoSmithKline) Phase I/II trials of shared Discovery of antitumour (1975) Discovery and Clinical trials of DNA-based as preventive antigen preventive immunity in mice128,129 ascension of dendritic cells26 vaccines31 cancer vaccines66 vaccines122

1950s 1960s 1970s 1980s 1990s 2000s 2010s Ongoing

Burnet and Thomas Development of vaccines based on Phase I/II trials of shared ‘immunosurveillance tumour cells, tumour lysates, tumour antigens as hypothesis’ (REFS 130,131) genetically modiﬁed tumour cells and preventive vaccines103 heat shock proteins21 Development of mouse Renaissance of tumour models132 (1980) Discovery of the T cell growth immunosurveillance140 factor IL-2 (REF. 134)

Isolation of human tumour-speciﬁc T cells and antibodies16,135

Introduction of hepatitis B virus vaccine for prevention of liver cancer61

| Figure 1 Timeline of cancer vaccine development. Milestones in the development of cancerNature vaccines Reviews are |indicated Immunology by the decade from which they were first reported.

were phase III trials, which tested 15 different vaccines have given a different outcome. They also credit the vac- and 8 different adjuvants. This again indicated that the cine failure to the paucity of good adjuvants. However, other 96% of trials did not show positive data to support there is another way to interpret the data. The fact that progression to phase III trials. a wide variety of antigens, adjuvants and delivery sys- Myeloid-derived suppressor The trials reviewed in these two studies did not tems all gave the same lacklustre results suggests that cells have long-term follow‑up data; thus, the efficacy of the common denominator of vaccine failure was not the (MDSCs). A group of immature myeloid cells (including the vaccines may have been underestimated. A recent antigen, the adjuvant or the delivery vector but rather precursors of macrophages, report reviewed the 12‑year survival of patients with the advanced disease suppressing the patient’s response granulocytes and dendritic nonresectable metastatic melanoma who received a to the vaccine. cells) that are produced in vaccine composed of monocyte-derived DCs matured response to various tumour-derived cytokines. with tumour necrosis factor (TNF), IL‑1β, IL‑6 and Impact of the tumour microenvironment. In the first These cells have been shown to prostaglandin E2 loaded with four MHC class I-binding decade of therapeutic vaccine development and testing, induce tumour-associated and six MHC class II‑binding melanoma-derived pep- not much was known about systemic and intratumoural antigen-specific CD8+ T cell tides, which was injected intradermally over a period immunosuppression. A few early reports of the compro- tolerance and to suppress of 2 years36. An impressive 19% of these patients are mised function of T cells and natural killer (NK) cells in other immune effector cells. still alive, which compares well with the results of treat- patients with cancer38–40 were not immediately appreci- Tumour-associated ment of melanoma using checkpoint blockade against ated. Many different mechanisms of immune suppres- macrophages cytotoxic T lymphocyte antigen 4 (CTLA4)37. sion in cancer have since been identified, including the Cells that are an important Most therapeutic vaccine trials included in the retro expansion of myeloid-derived suppressor cells (MDSCs)41, component of the tumour tumour-associated macrophages 42 microenvironment. They spective analyses were carried out in an adjuvant set- and other myeloid cells 43 differentiate from circulating ting (using a wide variety of adjuvants) and were mostly and regulatory T cells in addition to the perturbation blood monocytes that have composed of single antigens (which were mutated, of cytokine networks44, changes in host metabolism45 infiltrated tumours. They can nonmutated or viral antigens). The authors suggest that and the production of amino acid-degrading enzymes have positive or negative the weak or absent therapeutic efficacy was due to sub and indoleamine 2,3‑dioxygenase 1 (IDO1)46,47 (FIG. 2). effects on tumorigenesis (that is, tumour promotion or optimal vaccine design and that more complex vaccines In addition, a recent report reveals an unexpected sup- immunosurveillance, using a wider range of tumour antigens and antigen pressive activity of oxygen and potassium in the tumour respectively). combinations and viral vectors for their delivery would microenviroment42.

CANCER IMMUNOTHERAPYREVIEWS

Early pre-malignant lesion Advanced pre-malignant lesion Cancer

IFNγ +++ IFNγ ++ IFNγ +++ TNF + TNF ++ TNF +++ IL-6 + IL-6 ++ IL-6 +++ Arginase + Arginase +++ IDO1 +++

Tumour-associated Cytotoxic T cell T helper cell Macrophage macrophage DC

Treg cell B cell MDSC NK cell

Figure 2 | Progressive stages of cancer development are accompanied by changes in the local immune microenvironment. Early pre-malignant lesions are infiltrated by both adaptive immune cellsNature (T cells Reviews and B cells) | Immunology and innate immune cells (natural killer (NK) cells and macrophages) that have an activated phenotype and produce effector

cytokines (such as interferon‑γ (IFNγ)), suggesting an ongoing antitumour response. Immunosuppressive regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs) are rare. Advanced pre-malignant lesions contain fewer T and B cells

and many more Treg cells and MDSCs and produce higher levels of pro-inflammatory cytokines (such as tumour necrosis factor (TNF) and IL‑6), suggesting the transition from antitumour to pro-tumour immune responses. The cancer immune

microenvironment is characterized by a predominance of immunosuppressive Treg cells and MDSCs, as well as by the conversion of macrophages into immunosuppressive tumour-associated macrophages (TAMs). DC, dendritic cell; IDO1, indoleamine 2,3‑dioxygenase 1.

In attempts to overcome immunosuppression, mouse models are showing encouraging results in which pharmaceutical companies are developing specific vaccines, checkpoint blockade and inhibition of one of reagents, such as IDO1 inhibitors48, and various ways the other immunosuppressive mechanisms are not effec- to inhibit MDSCs either by blocking their growth fac- tive when used alone, but a combination of two or three tor receptors49 or by reprogramming their metabolism50. of these therapies results in an antitumour effect56. There is accumulating evidence that standard treatments such as chemotherapy and radiation, if used appropriately, Combination approaches. High volumes of new data might also reverse immunosuppression51,52. from immunotherapy trials with checkpoint inhibitors These efforts to inhibit the suppressors and modulate have suggested that including cancer vaccines as part of the tumour microenvironment in favour of antitumour combination immunotherapy will increase the efficacy immunity underlie the so far unprecedented successes of checkpoint inhibitors as well as overall therapeutic of checkpoint blockade immunotherapy achieved efficacy57–59. This has brought a renewed enthusiasm for through targeting negative regulators of effector T cell the therapeutic cancer vaccines field. Exhausted phenotype function, such as CTLA4, programmed cell death pro- Many cancer vaccines have already been tested in The condition of functionally tein 1 (PD1) and PD1 ligand 1 (PDL1)53. Inhibition of clinical trials and so could be immediately used in com- impaired antigen-specific T cells, typified by increased additional inhibitors is considered to be a good way to bination with checkpoint inhibitors or other immuno- surface expression of increase the success of this particular therapy as well as modulators of the tumour microenvironment. However, programmed cell death other forms of immunotherapy, including therapeutic there is a perception that many elements of therapeutic protein 1 (PD1), which occurs vaccines. The extent to which this will be successful is vaccines should be revisited: the choice and prioritiza- in the context of persistent high antigen load. The defects likely to vary greatly. There is strong evidence that T cells tion of tumour antigens to include new mutated neo in effector T cell function can be profoundly affected by the long-term stay in the antigens; antigen-delivery methods to include new include a progressive decrease tumour microenvironment and exhibit an exhausted oncolytic and other viral vectors, nanoparticles and in their ability to produce phenotype that may not be fully reversible54. These in vivo DC targeting; vaccine formulations that will tar- cytokines, loss of proliferative exhausted T cells do not respond well to checkpoint get exhausted memory T cells and trial designs to take capacity and decreased cytotoxicity, and these defects inhibitors, and if they do respond, the effect is tran- into account immunological fitness of the patients. Some 55 can result in apoptotic cell sient . They are also unlikely to greatly increase in num- of this work is planned as an organized international death. ber in response to a vaccine. Combination therapies in collaboration between academic and industry scientists

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known as The Human Vaccine Project60. Although new 90%63. This would prevent an estimated 7.3 million knowledge needs to be incorporated into (not so) old deaths between now and 2030, 1.5 million of which vaccines, there is no need to start with a blank slate. would probably be due to HCC63. Several vaccines based on shared TAAs that are clearly A more recent successful prevention story is that of immunogenic and not subject to self-tolerance, such HPV vaccines for the prevention of cervical and HPV- as the cancer–testis antigen NY‑ESO‑1 (also known as positive oral cancers. Like HBV, HPV can establish a CTAG1A), telomerase reverse transcriptase (TERT), chronic infection in approximately 20% of infected MUC1 and HER2, or based on viral antigens, such as individuals, putting them at risk of these two cancers. HPV E6 and E7 proteins, could be immediately tested An HPV vaccine was introduced in 2006 that was in combination trials. recommended for females aged 11–26, and since 2011 One variable not addressed by this plan is the cost of this vaccine has also been recommended for males these new improved vaccines. The only FDA-approved aged 11–21. A decade later, and after testing in mul- vaccine, Sipuleucel‑T, costs $90,000 per treatment course. tiple clinical trials64, HPV prevalence among females The current plan is to make vaccines more complex, vec- aged 14–19 had decreased by 64% and had decreased tored and perhaps even personalized. Even as a mono- by 34% in females who were 20–24 years old65. Two therapy, these complex vaccines are likely to be costly, and currently approved vaccines, Gardasil (Merck) and if used in combination therapy, as required for metastatic Cervarix (GlaxoSmithKline), provide effective pro- disease, they will add to the already enormous cost of tection against chronic infection with HPV type 16 or the other agents. One way to reduce the cost of cancer type 18, and, importantly, they also protect against cer- vaccines and improve their effectiveness is to continue to vical intraepithelial neoplasia, adenocarcinoma in situ develop them as monotherapies for individuals without and cervical cancer66. Given already established trends, cancer but who are at risk of cancer to boost spontaneous a substantial decrease in incidence and mortality from immunosurveillance and to prevent cancer development. cervical cancer is projected by 2050 (REF. 67). Vaccine-elicited immune responses against E6 and Preventive cancer vaccines E7 antigens from HPV types 16 and 18 are also remarkable in that they could clear pre-malignant cervical Diseases can rarely be eliminated through early and vulvar lesions68,69. Women with HPV‑16‑positive diagnosis or good treatment, but prevention can grade 3 vulvar lesions were vaccinated with long pep- eliminate disease. Denis Burkitt tides from E6 and E7 oncoproteins admixed with incomplete Freund’s adjuvant. Of the 20 vaccinated Vaccines for prevention of viral cancers. Chronic patients, 12 had a clinical response with relief of symp- infection with HBV leads to chronic liver diseases and toms and 5 had a complete response. At 24 months is a proven cause of HCC. Transmission of infection is after vaccination, 15 of 19 vaccinated patients had a both vertical, from mother to baby at birth, and hori- clinical response and 9 of 19 had a complete response zontal, from person to person throughout life. Children with clearance of HPV‑16. Importantly, the clinical infected with HBV before the age of 5 have a 25–50% response directly correlated with the vaccine-elicited chance of developing chronic liver disease that can lead T cell responses. Another trial using a vaccine com- to HCC, whereas infections later in life carry only a posed of 13 E6‑derived and E7‑derived peptides and 1–5% chance. An HBV immunization programme was the adjuvant Montanide reported similar results70. In started in Taiwan in 1982 initially targeting infants of total, 43 patients received either the vaccine alone or infected mothers, then all infants and finally it was the vaccine together with the TLR7 agonist imiqui- given universally. It is one of the great success stories mod applied to the injection site. At 12 months, 52% of a preventive vaccine for controlling viral infection as of patients had a clinical response, 8 of whom had a means of reducing cancer incidence. The latest study complete viral clearance. looking at the long-term effects of Taiwan’s infant HBV In another trial, a completely different vaccine immunization programme in preventing liver cancer formulation composed of two plasmids encoding showed a significant (P < 0.0001) reduction in HCC HPV‑16 E6 and E7 proteins or HPV‑18 E6 and E7 incidence in vaccinated compared with nonvaccinated proteins was administered by electroporation to birth cohorts61. This study showed for the first time that women with HPV‑16‑positive or HPV‑18‑positive a preventive cancer vaccine given in infancy provides cervical intraepithelial neoplasia (CIN) lesions of protection in adulthood. A similar success story comes grade 2 or 3. Overall, 49.5% of vaccinated women from a programme in Thailand that implemented uni- experienced pathological regression of lesions com- versal HBV immunization between 1988 and 1992 pared with 30.6% of women in the placebo group71. (REF. 62). Finally, the most stringent test of the ability of an Similar immunization strategies, repeated in other HPV vaccine to prevent cancer was the Papilloma countries where HBV is endemic, as well as globally, will Trial Against Cancer in Young Adults (PATRICIA), in time eliminate chronic liver diseases and HCC if man- which was carried out with the HPV‑16 and HPV‑18 datory vaccination remains enforced. A recent model- vaccine Cervarix72. It included women with CIN ling study shows that a target of a 90% reduction in new grade 3 lesions and cervical adenocarcinoma in situ. cases and a 65% reduction in mortality can be reached The vaccine efficacy against both CIN grade 3 and by scaling up the coverage of infant immunization to adenocarcinoma in situ was 100%.

CANCER IMMUNOTHERAPYREVIEWS

The remarkable results for HPV vaccines and viral pre-malignant lesions is either surgical removal or fre- antigens that had not shown previous clinical efficacy quent screening. However, many resected lesions recur in invasive disease73–75 suggested that vaccines based on after surgery, or those that are untreated can progress to nonviral antigens that failed in the therapeutic setting cancer. A vaccine administered at this early stage could were also likely to succeed in the prevention setting. boost immunosurveillance to eliminate pre-malignant lesions, prevent their recurrence after surgery or prevent Vaccines for prevention of nonviral cancers. The idea their progression to cancer. This setting has many advan- of developing vaccines for the prevention of nonviral tages, including a shorter time of interaction of abnormal cancers is not new76–81. Work by chemoprevention cells with the immune system, thus presumably avoiding researchers and pharmaceutical companies over the immune exhaustion, and a less immunosuppressive local past 30 years to develop drug compounds for cancer microenvironment that allows vaccine-elicited T cells to prevention and large phase III trials led to FDA approv- function at the site of the lesion. als of chemopreventive agents such as tamoxifen, and The importance of boosting pre-existing immuno- a question that was frequently raised was why these surveillance of pre-malignant lesions with a vaccine, trials could not be a blueprint for preventive vaccine even if the lesion is surgically removed, is illustrated trials. Ironically, despite a steady and marked accu- by one of many studies showing that apparently nor- mulation of publications on tumour antigens between mal tissue adjacent to a lesion is different from normal the 1950s and the 1990s, there was a general belief that tissues from healthy controls98. For example, in the there were no suitable antigens for preventive vaccines colonic mucosa adjacent to unifocal colon polyps, there for nonviral cancers. It was assumed that immune were marked alterations in gene expression that pre- responses against nonviral antigens, specifically TAAs dicted polyp recurrences98. A strong immune memory derived from self-molecules, would cross-react with response elicited by vaccination would be expected to the respective self-molecules on healthy tissues and prevent these polyp recurrences. Many pre-malignant cause damaging autoimmunity. Unfortunately, the lesions have now been shown to be under immune minority of TAAs that warranted such caution, such as surveillance, and multiple target antigens have been some melanoma antigens that caused vitiligo, received identified. In patients with monoclonal gammopathy of the majority of the attention82. In the meantime, many undetermined significance (MGUS), which is a precursor TAAs expressed on liquid and solid tumours (includ- to multiple myeloma, the presence of pre-existing T cell ing melanoma) were being safely incorporated into immunity and antibody responses against the stem cell therapeutic vaccines that caused no autoimmunity antigen transcription factor SOX2 independently corre- either in preclinical models, where safety could be ade- lates with a reduced risk of progression to multiple mye- quately tested, or in clinical trials, where therapeutic loma99. This suggests a benefit from boosting anti‑SOX2 effects were not accompanied by any substantial toxic immunity in all patients with MGUS by using a pre- effects. Furthermore, the cancer-reactive antibodies ventive vaccine. Patients diagnosed with intraductal and T cells found in patients with cancer that led to papillary mucinous neoplasms (IPMNs), which are the discovery of many TAAs were increasingly being precursors to pancreatic cancer, have circulating IgG reported as memory responses in healthy individu- antibodies against MUC1, which is overexpressed in als83–88, and their presence at diagnosis was associated a hypoglycosylated abnormal form in IPMNs as well with better prognosis89,90. These immune responses as in pancreatic cancer. In addition, the dysplastic could be induced either by tumours eliminated before regions of the IPMN cysts are heavily infiltrated by becoming clinical disease or more likely by abnormal CD4+ and CD8+ T cells100, suggesting that both pre- expression of self-molecules during nonmalignant existing humoral and cellular immunity can be boosted events such as viral and bacterial infections or acute or by a MUC1‑based vaccine. Similarly, oral leuko- chronic inflammation (FIG. 3). In a case–control study plakias, which are pre-malignant precursors of oral

Tamoxifen in ovarian cancer, immune responses against the TAA squamous cell carcinomas, are heavily infiltrated with A drug used for the prevention MUC1, which is abnormally expressed by epithelial Langerhans cells and T cells, indicating active immuno- of oestrogen receptor cells in conditions such as breast mastitis, pelvic sur- surveillance of these lesions101. (ER)-positive breast cancer. gery and mumps or in individuals who are currently Using the pre-malignant setting to improve the Tamoxifen is a pro-drug that is smoking was revealed as a potential protective mech- effectiveness of cancer vaccines is a good compromise metabolized in the liver into 91,92 active metabolites that have a anism . Epidemiological evidence has accumulated between preventing cancer in completely healthy indi- high affinity for the ER and can to show that such events are associated with a marked viduals, for whom vaccines may be most effective but compete with endogenous reduction in lifetime risk of many different cancers93. carry a certain degree of risk, and treating patients with oestrogen. advanced cancer, for whom vaccine effectiveness is

Monoclonal gammopathy of Pre-malignant lesions as initial targets. An important profoundly diminished. A new focus on understand- undetermined significance advance in the field of cancer immunoprevention has ing the pre-malignant microenvironment has revealed (MGUS). A medical condition been the development of increasingly sophisticated that highly advanced lesions may already exert multiple characterized by the presence clinical imaging tools and other modalities that can types of immunosuppression100,102–106 that could affect of abnormal immunoglobulins diagnose early cancer and even pre-cancer changes. responses to preventive vaccines. This should motivate and expanded clones of plasma cells that can progress Pre-malignant lesions are beginning to have an impor- further studies in vaccine safety so that vaccines may to multiple myeloma, thus tant role in all modes of cancer prevention, includ- eventually be given to young and healthy individuals requiring periodic surveillance. ing immunoprevention94–97. Current management of who are at risk of nonviral cancers.

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Cancer Early Advanced pre-malignant pre-malignant lesion lesion No pre-existing immunity

Progression and escape

Equilibrium

Pre-existing Cancer immunity Advanced pre-malignant Early lesion pre-malignant lesion

Progression and escape

Pre-existing Equilibrium immunity and preventive + vaccine Early pre-malignant lesion Elimination

Figure 3 | Boosting antitumour immunosurveillance with a vaccine determines disease outcome. Cancers develop from an early pre-malignant lesion, to an advanced pre-malignant lesion and to a malignant cancer. Immunosurveillance of cancer can have three different outcomes: elimination, which is a full victory for the immuneNature system; Reviews equilibrium, | Immunology which is a tie between the immune system and cancer; or escape, which is a full victory for the cancer. At the time of diagnosis, in some patients, there is no evidence that the immune system has detected pre-malignant or malignant changes (no pre-existing immunity), which allows unopposed progression (escape). Other patients have some antitumour antibodies and T cells (pre-existing immunity) and, depending on their strength, the result can be either equilibrium or escape. If this pre-existing immunity is boosted and strengthened with a preventive vaccine, the expected result would be either equilibrium or elimination, with potentially lifelong protection from immune memory elicited by the vaccine.

Candidate antigens. To start testing preventive cancer are also expressed to the same degree in its precursor vaccines, it is important to identify nonviral candidate lesions108. One of the best-known breast cancer TAAs, antigens that are abnormally expressed by pre-malignant HER2, is overexpressed in ductal carcinoma in situ lesions and cancers and to investigate their immuno- (DCIS), is a precursor to invasive breast cancer and is a genicity107. In addition to SOX2 and MUC1, other TAAs target of T cell surveillance. It was recently shown that that have been identified on tumours are expressed by T helper 1 cell responses directed against HER2 are lost pre-malignant lesions. The TAA cyclin B1, which is over- during tumorigenesis109. These responses are greatly expressed in the cytoplasm of many different tumours diminished even in stage 1 breast cancer compared including lung cancer, is also abnormally expressed in with those seen in DCIS109. These observations set the pre-neoplastic lung lesions in individuals who smoke stage for applying HER2 vaccines, which have had lim- heavily and who are at high risk of developing lung can- ited effectiveness in invasive breast cancer, to this early, cer. These lesions are subject to immune surveillance, as pre-malignant stage as preventive vaccines. cyclin B1‑specific IgG is present in people who smoke In addition to investigating the expression of the heavily87. Cancer–testis antigens, such as MAGEA anti- known TAAs, other approaches are revealing new candi- gens, NY‑ESO‑1, G antigen (GAGE), sarcoma antigen 1 date antigens. A recent study identified 150 genes in exist- (SAGE1), cancer–testis antigen 47A (CT47A), nuclear ing microarray data sets that were upregulated more than RNA export factor 2 (NXF2), MAGEC1 and MAGEC2, twofold in colorectal cancer as well as in pre-malignant that are commonly expressed by oesophageal cancer colonic adenomas compared with normal colon tissue.

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Silencing of the most upregulated genes — CDH3 (which since been defined. A similar effort to prioritize anti- encodes cadherin 3), CLDN1 (which encodes claudin 1), gens for preventive vaccines is warranted and could be KRT23 (which encodes keratin 23) and MMP7 (which especially useful in these early steps in the development encodes matrix metalloproteinase 7) — in colon cancer of preventive vaccines. cell lines resulted in cell death. Most importantly, sera In addition to the challenge of selecting the right anti- from patients with early stage colorectal cancer con- gens, there will be challenges in selecting or developing tained IgG antibodies specific for three of these proteins the right adjuvants and the right delivery systems. These (cadherin 3, keratin 23 and matrix metalloproteinase 7), issues have been under intense investigation and are the identifying these proteins as biologically relevant targets subjects of other reviews116–121. for preventive cancer vaccines110. The antigens men- tioned above are shared, nonmutated TAAs (TABLE 1) and Towards clinical application are excellent candidate antigens for preventive vaccines These are very early days for the clinical testing of preven- because they are proven targets of spontaneous immune tive cancer vaccines. Justifiably, the initial trials involve surveillance. They are expressed by a large number of antigens that have been previously characterized in human cancers and would therefore be very broadly appli- great detail for their immunogenicity and safety in both cable. Furthermore, TAAs such as HER2 and MUC1 are preclinical and clinical studies as components of thera essential for cancer progression and therefore cannot be peutic cancer vaccines. Also justifiably, the chosen set- lost by the tumour as a means to escape immune control. ting is the advanced pre-malignant state that immediately Recent evidence suggests that mutated antigens are precedes stage 1 cancer, such as DCIS. In a clinical trial more immunogenic than nonmutated TAAs and will testing the effect of a HER2‑based vaccine in DCIS122, 13 elicit higher affinity antibodies and higher numbers patients were vaccinated before surgery with four weekly of T cells. Although this still needs to be conclusively injections of their own in vitro-matured and activated shown, new personalized therapeutic vaccines are being DCs loaded with HLA class I-binding and HLA class designed based on sequencing of each patient’s tumour II‑binding HER2‑derived peptides. To increase immuno- to identify potential biologically and immunologically genicity, the vaccine was injected into the regional lymph important mutated antigens111. Personalized preventive nodes. All patients developed peptide-specific CD4+ and vaccines would then be possible in the setting of pre- CD8+ effector T cells as well as complement-binding, malignant lesions that could be biopsied and sequenced, tumour-lytic antibodies. At the time of surgery, 7 of 11 an approach that is currently highly impractical and patients showed decreased DCIS size; the residual DCIS resource-demanding. A more practical approach that showed infiltration of T cells and B cells and a marked could yield an off-the-shelf vaccine against mutated decrease in HER2 positivity. These encouraging results antigens would be to use predictable mutations, such as were replicated or bettered in a second trial in 27 patients those in the RAS family of oncogenes or the cancer sup- with DCIS123. At surgery, 5 of 27 vaccinated patients had pressor gene TP53. Mutated oncogenes initially held a lot no evidence of DCIS and in the 22 patients with the of promise as highly cancer-specific, immunogenic and disease, 50% had lost HER2 expression. The vaccine broadly applicable cancer vaccine antigens, but thera seemed to be more effective in patients who were neg- peutic vaccines based on mutated oncogenes did not ative for oestrogen receptor (ER), as it eradicated DCIS perform any better than vaccines based on nonmutated in 40% of these patients compared with 5.9% of patients shared antigens112,113. This result might be different in who were positive for ER. There was also considerable a preventive setting. Mutations in oncogenes and can- immunoediting of the DCIS phenotype. If these obvi- cer suppressor genes occur very early in the process of ously effective immune responses are confirmed to be tumorigenesis, and many pre-malignant lesions, such as long-lived, women with mutations in BRCA1 or BRCA2 those leading to pancreatic, breast, lung or colon cancers, should be the next candidate population for preventive already harbour KRAS or TP53 mutations that could be HER2‑based vaccines and other new vaccines. targeted with off-the-shelf preventive mutated-antigen The other well-known TAA that has gone into clin- vaccines. A set of antigens that falls somewhere between ical testing as a preventive cancer vaccine is MUC1. the shared mutated and the unique mutated antigens Therapeutic MUC1‑based vaccines have been tested is found in cancers associated with Lynch syndrome in numerous trials around the world124 and were the (also known as hereditary nonpolyposis colorectal can- first vaccines based on a self-molecule to be tested22. A cer), which are caused by germline mutations in DNA 100‑amino-acid-long MUC1 peptide admixed with the mismatch repair genes. These tumours induce potent TLR3 agonist polyinosinic–polycytidylic acid stabilized immunosurveillance directed in part against frameshift with polylysine and carboxymethylcellulose (poly- mutations, some of which give rise to predictable immu- ICLC) was administered to individuals with a history of

Immunoediting nogenic frameshift peptides. Carriers of Lynch syndrome pre-malignant villous adenomas, which are immediate 103 A process by which the mutations would be good candidates for preventive precursors of colon cancer . The goal was to test vaccine immune system of a host may vaccination against frameshift-peptide antigens114. safety and immunogenicity in healthy people without alter the gene expression of an In 2009, a successful effort was made to prioritize the cancer but who were at risk of adenoma recurrence and emerging tumour such that the further development of hundreds of tumour antigens as colon cancer. The vaccine was given at weeks 0, 2 and most immunogenic epitopes 115 are removed or edited, thereby candidates for therapeutic cancer vaccines . Many of 10, and a booster was given after 1 year. Of the 39 vac- facilitating tumour escape from these antigens are also candidates for preventive vaccinated individuals, 17 (43.6%) developed high levels of immune recognition. cines, and new antigens and antigen categories have MUC1‑specific IgG and long-lasting memory responses

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a c e Because MUC1 is expressed by many tumours and their pre-malignant lesions (FIG. 4), other preventive vaccine trials are currently being considered, including a trial in people who smoke and are therefore at risk of lung cancer that was due to start in November 2017 (REF. 126). As this section illustrates, these are early days for preclinical and clinical studies of preventive can- b d f cer vaccines in several different settings, from fairly advanced lesions (for example, DCIS) to less advanced pre-malignant lesions (for example, colonic polyps and MGUS) or in individuals with genetic (such as Lynch syndrome), environmental or lifestyle (such as smoking) risks for cancer. Thorough evaluation in appropri- ate animal models of the immune responses induced in Figure 4 | Mucin 1 as an example of candidate shared antigens for broadly applicable various preventive settings will be required. A preven- preventive vaccines. Mucin 1 (MUC1) is abnormally expressedNature by multipleReviews pre-malignant| Immunology tive vaccine given early in life to an individual who is a lesions and related cancers: Barrett oesophagus and oesophageal cancer (parts a,b); carrier for a cancer mutation might elicit lifelong pro- intraductal papillary mucinous neoplasms and pancreatic cancer (parts c,d); and Crohn tection, whereas a vaccine given to an older individual disease and colitis-associated colon cancer (parts e,f). Tissues were stained with a mouse who smokes or to a patient with advanced colonic pol- monoclonal antibody that recognizes the tumour-associated form of MUC1. yps might require yearly boosters to maintain protective immunity. This research will be helped by already on with no evidence of any toxic effects involving normal going efforts to understand early biomarkers of vaccine tissues. The absence of an immune response in 56.4% of effectiveness127. individuals correlated with increased numbers of circulating MDSCs, indicating that this advanced pre-malig- Concluding remarks nant stage is already establishing an immunosuppressive Cancer is the second leading cause of death worldwide, microenvironment that could promote progression to and cancer treatments continue to be a major burden on cancer. The complete safety of the elicited immunity in health-care costs. It is clear that the great heterogeneity the vaccine responders suggests that vaccinating individ- of cancer cells and the highly organized tumour micro uals diagnosed with earlier-stage polyps would be a better environment that can resist many forms of therapy, choice. Nevertheless, the safety and immunogenicity of including immunotherapy, will compromise even the this vaccine in the responders supported the design of most scientifically sophisticated current attempts at a an ongoing multicentre, placebo-controlled and blinded cure. A profoundly different approach to the cancer prob- efficacy trial125. The MUC1‑based vaccine was admin- lem is needed, and, ironically, it might be an old approach istered to 110 individuals who had advanced adenomas that has resolved major health plagues throughout his- removed within 6 months to 1 year before vaccination. tory — disease prevention through vaccination. For the Of the total, 55 participants were given the MUC1 vac- past three decades, cancer vaccines have been designed cine at weeks 0, 2 and 10 with a booster given at week 55. for the treatment of late-stage disease rather than for The other 55 participants were injected with a placebo. prevention. Now, with better insight into the importance So far, there have been no adverse events beyond reac- of cancer immunosurveillance during cancer develop- tions at the injection site. The trial is still blinded and has ment and the benefits of maintaining strong immunity just entered the observation phase. Villous adenomas are to slow tumour progression, researchers are starting to expected to recur within 1–3 years after surgical resection turn their attention to vaccines for cancer prevention. It in 48% of the participants. This timing allows for clinical is hoped that vaccines given to individuals with a known trials with a somewhat small number of individuals and genetic risk of cancer or to those showing early stages a moderately short time to completion. In the case of the of tumour development, such as pre-malignant lesions, MUC1 vaccine efficacy trials, the study should reveal could strengthen and/or prolong immune surveillance the protective effect of the vaccine within 3–5 years. and ensure a cancer-free life.

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