Currently, science of cancer prevention is in its infancy, especially for non-infectious origin cancer (1, 2, 3). Since the question focuses on vaccines, answer’s limited to cancer immuno– and not chemo–prevention, which is an entirely different field of study.
Prophylaxis means prevention. A prophylactic cancer vaccine means inducing a sustained cancer-specific immune response in an individual who doesn’t yet harbor it or at least hasn’t yet been diagnosed with that specific cancer. Not as easy for cancers as it is for infectious diseases. Consider classical vaccines, i.e., vaccines against infectious diseases. Polio virus typically causes a debilitating paralytic disease. Its vaccine contains polio virus antigens formulated to drive a specific immune response against it. Vaccinate healthy, i.e., non-polio-infected, people, with this vaccine and they make an anti-polio immune response effective in preventing it from establishing a foot-hold. How to do the same with cancer? Do we know enough about the unique and yet universal features of each cancer to devise vaccines that stoke effective and long-lasting anti-cancer immune responses in as-yet non-cancerous individuals?
- Unique in that only cancer cells but not normal cells express them.
- Universal in that each individual with that cancer would express such antigens.
- Would such immune responses effectively prevent such cancers from ever establishing a foot-hold?
- Long-lasting because there’s no predicting when after vaccination an individual might develop the cancer they were vaccinated against, could be months to years, a situation in striking contrast to communicable (infectious) diseases where such assessments are at least possible based on community incidence of such infections.
Having thus defined the essence of a prophylactic cancer vaccine, at least three obvious problems present themselves.
- One, which cancer antigens would work as vaccines? Cancer antigens overlap much more with those of the body’s own tissues compared to those from microbes. This increases risks that cancer vaccines could trigger autoimmunity so composition of a prophylactic cancer vaccine has a much higher safety burden compared to classic anti-infectious disease vaccines. Cancer-associated antigens overlap far more compared to cancer-specific ones meaning far higher autoimmune potential with the former. Problem is far more of the former and far fewer of the latter have been identified thus far.
- Two, who should get prophylactic cancer vaccines? Even if defined cancer-specific antigens for a particular cancer are identified, could such vaccines be given to everyone, similar to classical infectious disease vaccines?
- Since cancers aren’t typically communicable like infectious diseases, there isn’t a public health case for vaccinating everyone. Only carriers of rare cancer syndromes such as familial adenomatous polyposis coli (FAP) are almost certain to develop cancer if left untreated (4).
- OTOH, BRCA1/2 mutations induce defects in DNA repair with increased risks for tumors in breast, ovary, pancreas and prostate.
- However, since cancer risk isn’t 100% concordant even in monozygotic twins, obviously environmental factors play a major role in cancer manifestation.
- Thus, for the vast majority of cancers, preventative cancer vaccine need exists for individuals at increased risk for specific cancers. How to identify such individuals? In general, precancer and cancer diagnosis need defined screening, diagnostic and prognostic biomarkers that can reliably screen and identify individuals at highest risk for specific cancers (2),
- screening biomarkers to identify those at highest risk (For precancers and early stage cancers)
- diagnostic biomarkers to identify lesions for invasive biopsy (For precancers, early stage cancers, and cancers).
- prognostic biomarkers to identify aggressive tumors that need to be treated (For cancers).
- Precancers and early stage cancers may shed unique DNA, RNA or biomolecules into circulation but their reliable detection is still far from reality. Circulating cancer biomarkers are most useful from convenience point of view. A rare example is ovarian cancer where unique cancer-specific mRNA isoforms were recently identified (5).
- Major obstacle is design and implementation of prospective studies to validate such biomarkers in the clinic.
- Two recent successes in such cancer biomarker discovery and validation for pre-cancer diagnosis are
- A highly sensitive stool DNA screening test validated for colorectal cancer (6).
- Two prospective multi-center trials (7) validated bronchial airway gene-expression alterations in cytologically normal bronchus epithelium of smokers with lung cancer (8) for early lung cancer detection.
- Thus, unlike communicable diseases, not so easy to define who should/shouldn’t get prophylactic cancer vaccines. It will become feasible only with more such defined, confirmed genetic markers for specific cancers, i.e., a Pre-Cancer Genome Atlas (9). Such markers are the minimum building blocks necessary to be able to assemble prophylactic cancer vaccines. However, since a call to action for creating such an atlas has only occurred in 2016, clearly we’re at the very beginning of this process.
- Three, can preventative anti-cancer immune responses be both immediately effective and capable of long-lasting memory to eliminate tumor recurrence far in the future?
Based on these three most important considerations an ideal prophylactic cancer vaccine needs to
- Discriminate between tumor and normal cells as unerringly as possible.
- Drive a strong and effective immune response capable of eliminating not just primary but also residual or micrometastatic tumor cells.
- Drive development of long-lasting immunological memory to help prevent tumor occurrence, even years post-vaccination.
- Have tolerable side effects and minimal or no toxicity, across genders and a broad age range.
Prophylactic cancer vaccines are thus easier to envisage and develop for infectious origin cancers, cancers caused by viruses for example, since their design principles and public health argument for their usage are the same as those for classic anti-microbial vaccines.
Immunoprevention for Infectious Origin Cancers: Solid Track Record
Hepatitis B (HBV): The WHO estimates ~2 billion HBV infected worldwide with ~350 million chronic infections. Along with Hepatitis C virus (HCV), HBV accounts for ~85% of liver cancer (10). Most compelling data supporting the value of prophylactic cancer vaccines comes from Taiwan which began a nationwide HBV vaccination program in 1984 (11).
- It led to a >90% reduction in mortality rates from 1977-1980 to 2001-2004, confirming such prophylaxis prevents hepatocellular carcinoma (HCC).
- It reduced HCC incidence by >80%.
Human papillomavirus (HPV): Cervarix and Gardasil, HPV vaccines against certain strains of HPV are currently among the most relevant examples of prophylactic cancer vaccines.
- Epidemiology shows that >99% of cervical cancers result from HPV infection and >70% of such cancers are associated with just two HPV strains, HPV types 16 and 18 (12).
- Medical and epidemiological argument for the HPV vaccine is based on estimates of annual country-specific cervical cancer rates. For example, between 2006 and 2010, an average of 33,160 annual HPV-associated cancer diagnosis in the US (20,589 or 62% women and 12,571 or 38% men) (13) and ~4000 deaths per year.
- Even with such clear and compelling public health need for HPV vaccines, unsubstantiated claims of adverse reactions (14) combined with moral policing concerns that getting such vaccines would increase promiscuity among young girls, i.e., sexual disinhibition, has left HPV vaccination rates far lower than that necessary to reduce HPV transmission and cervical cancer rates among women.
- Meantime since their approvals starting in 2006, >120 million doses of these vaccines have been distributed worldwide (15), and studies continue to pile up data showing both that these vaccines are safe (16, 17, 18, 19, 20) and that contrary to the moral police, greater knowledge associated with proactive HPV vaccination correlated positively with safer sexual behaviors (21, 22).
- As-yet unanswered questions with these HPV vaccines are the duration of protection they induce, whether boosters are necessary, and if so, how long after the primary jab and what doses.
Immunoprevention for Non-Infectious Origin Cancers: Very Early Stage
Colorectal cancer: A recent preventative non-infectious cancer vaccine trial for colorectal cancer was one of the first such (23).
- MUC1 is significantly over-expressed in colonic polyps with increased cellular abnormalities (24, 25).
- Consisting of a 100 amino acid peptide derived from the tumor-associated MUC1 antigen, this vaccine was adjuvanted with the TLR-3 agonist poly-LCIC (Oncovir) (23).
- People with recent history of advanced colorectal adenomas are at high risk of colorectal cancer. When injected in such patients, this vaccine drove strong MUC1-specific immunity, both cellular and antibody-based, in 43% of patients.
- A booster injection one year later drove increased circulating anti-MUC1 IgG antibody responses, meaning this vaccine was capable of inducing strong anti-MUC1 immunological memory.
- Patients without increased anti-MUC1 IgG antibody instead had high levels of circulating myeloid-derived suppressor cells (MDSCs), which are supposed to suppress effective anti-tumor immune responses. This means vaccines for non-infectious cancers need to be formulated with specific enhancers and/or modulators capable of decreasing cancer-associated immunosuppression.
- Vaccine was well-tolerated without any evidence of toxicity or autoimmunity.
- This 100 amino acid peptide vaccine was immunogenic in most HLA-DR and HLA-DQ haplotypes, negating the need to HLA type prior to vaccination or to only vaccinate individuals with specific HLA haplotypes.
- Ongoing trial is assessing efficacy of this vaccine in preventing adenoma recurrence (NCT02134925; Vaccine Therapy in Treating Patients With Newly Diagnosed Advanced Colon Polyps).
Breast cancer: Currently in Phase I, STEMVAC’s a preventative cancer vaccine clinical trial of a five-antigen (CD105, Yb-1, SOX-2, CDH3, MDM2) vaccine targeting breast cancer stem cells (NCT02157051; Vaccine Therapy in Treating Patients With HER2-Negative Stage III-IV Breast Cancer).
1. Meyskens, Frank L., et al. “Cancer prevention: obstacles, challenges and the road ahead.” Journal of the National Cancer Institute 108.2 (2016): djv309. http://cache1.medsci.cn/webedito…
2. Kensler, Thomas W., et al. “Transforming cancer prevention through precision medicine and immune-oncology.” Cancer Prevention Research 9.1 (2016): 2-10. Transforming Cancer Prevention through Precision Medicine and Immune-oncology
3. Maresso, Karen Colbert, et al. “Molecular cancer prevention: Current status and future directions.” CA: a cancer journal for clinicians 65.5 (2015): 345-383. http://onlinelibrary.wiley.com/d…
4. Goss, Kathleen Heppner, and Joanna Groden. “Biology of the adenomatous polyposis coli tumor suppressor.” Journal of Clinical Oncology 18.9 (2000): 1967-1979.
5. Barrett, Christian L., et al. “Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy.” Proceedings of the National Academy of Sciences 112.23 (2015): E3050-E3057. http://www.pnas.org/content/112/…
6. Imperiale, Thomas F., et al. “Multitarget stool DNA testing for colorectal-cancer screening.” New England Journal of Medicine 370.14 (2014): 1287-1297. https://www.wesleyobgyn.com/pdf/…
7. Silvestri, Gerard A., et al. “A bronchial genomic classifier for the diagnostic evaluation of lung cancer.” New England Journal of Medicine 373.3 (2015): 243-251. http://www.nejm.org/doi/pdf/10.1…
8. Gustafson, Adam M., et al. “Airway PI3K pathway activation is an early and reversible event in lung cancer development.” Science translational medicine 2.26 (2010): 26ra25-26ra25. http://www.bumc.bu.edu/pulmonary…
9. Campbell, Joshua D., et al. “The Case for a Pre-Cancer Genome Atlas (PCGA).” Cancer Prevention Research 9.2 (2016): 119-124 The Case for a Pre-Cancer Genome Atlas (PCGA)
10. Aly, Hamdy AA. “Cancer therapy and vaccination.” Journal of immunological methods 382.1 (2012): 1-23).
11. Chiang, Chun-Ju, et al. “Thirty-year outcomes of the national hepatitis B immunization program in Taiwan.” JAMA 310.9 (2013): 974-976. http://website2.infomity.net/829…
12. Smith, Jennifer S., et al. “Human papillomavirus type distribution in invasive cervical cancer and high‐grade cervical lesions: A meta‐analysis update.” International journal of cancer 121.3 (2007): 621-632. http://onlinelibrary.wiley.com/d…
13. Markowitz, Lauri E., et al. “Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP).” MMWR Recomm Rep 63.RR-05 (2014): 1-30. http://origin.glb.cdc.gov/mmwr/p…
14. HPV Vaccine: The Science Behind The Controversy. NPR, September 19, 2011. HPV Vaccine: The Science Behind The Controversy
15. Arnheim-Dahlström, Lisen, et al. “Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study.” (2013): f5906. http://www.bmj.com/content/bmj/3…
16. Slade, Barbara A., et al. “Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine.” Jama 302.7 (2009): 750-757. http://archderm.jamanetwork.com/…
17. Haupt, Richard M., and Heather L. Sings. “The efficacy and safety of the quadrivalent human papillomavirus 6/11/16/18 vaccine gardasil.” Journal of Adolescent Health 49.5 (2011): 467-475.
18. Gee, Julianne, et al. “Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink.” Vaccine 29.46 (2011): 8279-8284. https://www.researchgate.net/pro…
19. Donegan, Katherine, et al. “Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK.” Vaccine 31.43 (2013): 4961-4967. http://www.pfizerpro.com.co/site…
20. Vichnin, Michelle, et al. “An overview of quadrivalent human papillomavirus vaccine safety: 2006 to 2015.” The Pediatric infectious disease journal 34.9 (2015): 983-991. https://www.researchgate.net/pro…
21. Bednarczyk, Robert A., et al. “Sexual activity–related outcomes after human papillomavirus vaccination of 11-to 12-year-olds.” Pediatrics 130.5 (2012): 798-805. http://pediatrics.aappublication…
22. Madhivanan, Purnima, et al. “Human Papillomavirus Vaccination and Sexual Disinhibition in Females: A Systematic Review.” American Journal of Preventive Medicine (2016).
23. Kimura, Takashi, et al. “MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study.” Cancer Prevention Research 6.1 (2013): 18-26. A Cancer Immunoprevention Feasibility Study
24. Ajioka, Y., H. Watanabe, and J. R. Jass. “MUC1 and MUC2 mucins in flat and polypoid colorectal adenomas.” Journal of clinical pathology 50.5 (1997): 417-421. MUC1 and MUC2 mucins in flat and polypoid colorectal adenomas.
25. Ho, Samuel B., et al. “Altered mucin core peptide immunoreactivity in the colon polyp-carcinoma sequence.” Oncology research 8.2 (1995): 53-61.