Can Cancer Vaccines Provide a Shield Against Tumors?
From chickens to humans, a look at the evolving and exciting field of cancer vaccines
Cancer the emperor of all maladies was recognized as a disorder several thousand years ago. Since then different models of cancerogenesis were developed over time. Nevertheless, an infectious etiology was not considered until the beginning of the 20th century.
Preventive vaccines for cancer
With the discovery of the Rous sarcoma virus by Peyton Rous in 1911 at the Rockefeller University in New York City, the foundation was laid for the field of tumor virology. His discovery of a transmissible virus that induces tumors in chickens took over 40 years to be recognized as groundbreaking by the scientific community. Finally, he was awarded the Nobel Prize in Physiology or Medicine for the significance of his discovery in 1966. With his work he paved the way for major discoveries in the 1960s and 1970s, when for the first time human tumor viruses like Epstein-Barr virus, hepatitis B virus, and the papillomaviruses were identified. These findings played a pivotal role in the development of the first cancer vaccines against cancer types with an infectious etiology.
Another pioneer in the field, Harald zur Hausen identified the human papilloma virus HPV16 and HPV18 as the major cause for cervical cancer. Two decades later the first clinical trials of HPV vaccines conferred immunized women with type-specific protection against HPV infection. As a result it prevented them from associated cervical, vulvar, and vaginal diseases. Based on current estimates, these vaccines could prevent more than 300,000 cervical cancer cases per year on a global scale.
The prophylactic vaccines (vaccines given to prevent disease) discussed above have the potential to make a real impact on the number of people developing oncogenic virus-associated tumors. The other type of vaccine scientists are developing are therapeutic tumor vaccines; the aim of these vaccines is to mobilise the immune response against the tumor in individuals who have been diagnosed with cancer. To drive an immune response to attack a tumor, scientists need to identify proteins which are ideally present on the tumor but not at high levels on healthy tissue. These proteins are often called tumor-associated antigens (TAAs) (1). These may include derivatives of aberrant proteins termed neo-antigens – which arise specifically in tumor cells due to the high mutational burden in rapidly proliferative tumor cells; our immune system will never have seen these ‘new’ proteins and therefore detect them as foreign if presented along with a ‘danger’ signal. The challenge with many of these neo ‘new’ antigens is that they are often unique to a single individual and therefore we need vaccine strategies that take this into account. The other challenge is that for antigens that are not unique to the tumor but expressed by other cells in our body our immune system is ‘tolerant’ of these antigens. It has been educated to detect that this is self and not to attack cells expressing these proteins. Vaccines must therefore strike a balance between activating these ‘self-tolerant’ often low affinity (weakly binding) T cells and make them potent killers that can capably attack tumor cells without evoking damaging autoimmune responses.
125 years of research in tumor vaccines
There are many clinical trials looking at the potential of various therapeutic vaccine strategies to treat different types of cancer. A search of www.clinicaltrials.gov on ‘tumor’ and ‘vaccine’ shows that there are currently 153 active clinical trials in the USA alone for tumor vaccines. However tumor vaccines are by no means a novel concept, one of the first reports of a tumor vaccine was back in 1891, when Coley injected sarcoma tumors with a heat inactivated bacterial mixture (Coley’s toxins) and observed in some patients a decrease in tumor metastasis (2). Although Coley’s toxins are not used today, BCG (Bacillus Calmette-Guérin vaccine) bacilli, a live attenuated strain of Mycobacterium bovis, are licensed for use in the treatment of bladder cancer and are thought to work by stimulating the immune response in a similar way (3).
The types of therapeutic vaccines being investigated to treat tumors continues to grow wider and includes cellular vaccines, peptide vaccines, viral vectored vaccines, DNA vaccines and RNA vaccines (4). Interestingly, while mRNA vaccines are now something the majority of us have heard of because of the licensing of the Moderna and Pfizer/BioNtech COVID-19 messenger RNA vaccines, these types of vaccines also have a strong history of being investigated as tumor vaccines. RNA tumor vaccines have been used in clinical trials in two different ways:
- To transiently express fragments of tumor antigens in professional antigen presenting cells, called dendritic cells, isolated from patients; these autologous dendritic cells could then be transfused back into the patient where they activated tumor specific T cell responses
- Injected directly into the patient (5).
While there are many possible strategies being investigated for tumor vaccines the only tumor vaccines currently licensed by the FDA are BCG for the treatment of some bladder cancers and sipuleucel-T for the treatment of some prostate cancers (6). As our understanding of the immune system continues to grow, along with advances in the ‘omics’ to identify potential tumor antigens, this in combination with advances in personalized medicine and vaccine delivery systems should unlock the ability of therapeutic tumor vaccines to make a real impact on the treatment of some cancers.
1. Haen, S. P., Löffler, M. W., Rammensee, H.-G. & Brossart, P. Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire. Nat. Rev. Clin. Oncol. 17, 595–610 (2020).
2. McCarthy, E. F. The Toxins of William B. Coley and the Treatment of Bone and Soft-Tissue Sarcomas. Iowa Orthop. J. 26, 154–158 (2006).
3. Morales, A. BCG: A throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy. Can. J. Urol. 24, 8788–8793 (2017).
4. Hollingsworth, R. E. & Jansen, K. Turning the corner on therapeutic cancer vaccines. Npj Vaccines 4, 1–10 (2019).
5. Miao, L., Zhang, Y. & Huang, L. mRNA vaccine for cancer immunotherapy. Mol. Cancer 20, 41 (2021).
6. Kantoff, P. W. et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N. Engl. J. Med. 363, 411–422 (2010).