A vaccine for cancer? Yes, you heard right! Before diving into this topic, let’s first understand the basics: what is cancer, how it spreads, the therapies available, and why vaccines are being developed against it.
Cancer has been present in human history since ancient times and was described as “tumours” in Egyptian texts. Hippocrates, well known as the “Father of Medicine”, was the first to use the terms “carcinoma” and “carcinos”. In 28–50 BC, Celsus, a Roman physician, coined the term "cancer”(Hajdu, 2010).
Currently, there are about 23.6 million people who have been diagnosed with cancer worldwide, and around 10 million deaths have been reported (Drake, 2022). Cancer can affect anyone irrespective of their age, dietary habits, or lifestyle. But what exactly is cancer? It is a disease in which cells divide abnormally. It can be genetic due to mutations in the genes, but it is not inherited, i.e., it cannot pass on to the offspring.
Our body is made up of trillions of cells, and they follow a cell cycle for their division which in turn has its own particular regulators. If any cells are damaged, new ones replace them; the cell death process involved here is called apoptosis. Now, if both these regulated processes are disrupted, the cells will start growing uncontrollably, forming a mass called a tumour. If the tumour is limited to only a particular area, it is deemed benign or harmless and curable, whereas malignant tumours spread to other regions of the body. When a tumour migrates and spreads to other areas of the body it is called metastasis. During metastasis, cancer cells invade the surrounding normal tissues, go into the bloodstream, stop midway, and start growing near a tissue, where they form a new tumour and later form new blood vessels through a process called angiogenesis.
Cancer has a genetic basis too and involves two types of genes. Proto-oncogenes usually help in the regulation of normal cells. But when these genes get altered due to mutations, they get converted to oncogenes that can contribute to cancer formation. On the other hand, tumour-suppressor genes can prevent the cells from becoming malignant, but aberrations in them too can cause tumours.
According to the World Health Organization, in the year 2020, about 10 million people have succumbed to cancers of the breast, lung, skin, stomach, colon, and rectum (Drake, 2022). Cancers have been classified into more than 100 types based on the organs in which it spreads. Carcinoma, sarcoma, leukaemia, etc., are some familiar terms we might have heard over the years.
A. Normal cells vs. cancer cells (National Cancer Institute, 2021)
B. Hallmarks of cancer (Hanahan and Weinberg, 2011)
C. Tumour suppressor genes (Wijnhoven and Vries, 2020)
D. Angiogenesis (Casanovas and Zuazo-Gaztelu, 2018)
E. Metastasis (Bergers and Fendt, 2021)
Our immune system can recognize and respond against foreign molecules or antigens and thus protect us against infections. There are two types of immunity: innate immunity, which can recognize between self and non-self and is the first-line defence against pathogens, and adaptive immunity, which is activated later during infections and is specific to the pathogen. To generate an immune response, lymphocytes, a type of white blood cell, originate from the bone marrow and are classified as either T cells or B cells. Antigen-presenting cells (APCs) are another important group of immune cells comprising of different cells, for example, the dendritic cells. Both of these types have to undergo a maturation/selection process to function properly during an actual infection.
B cells mainly take part in humoral immunity, which means they produce antibodies. They have an antigen-binding receptor, which is basically an antibody molecule, on their surface. Upon proper stimulation, they can be differentiated into plasma and memory B cells, which have different functions. T cells possess the T cell receptor, which binds to the antigen. T cells, based upon their surface markers and function, can be classified as T helper, T regulatory, and T cytotoxic cells. The helper cells have CD4 membrane glycoproteins on them, whereas the cytotoxic cells have CD8 membrane glycoproteins. These T-cell receptors are capable of recognising antigens only when they are processed and bound to the MHC (Major Histocompatibility Complex) proteins present on the surface of host cells and also on the APCs. Class I MHC is expressed by all nucleated cells, and Class II is expressed only by the APCs. CD4 can identify antigens bound to class II MHC on the APCs, whereas CD8 recognises antigens bound to class I MHC.
Overview of cell-mediated and humoral immune response (Bárcena and Blanco, 2013)
So, even when we have a seemingly effective immune system, why aren’t cancer cells destroyed? Cancer cells have various mechanisms to fool the system, which eventually weakens the immune response. However, the body in many cases does generate helpful tumour-specific antigen responses. If our immune system is incapable of eliminating tumours, can there still be a way to prevent cancer? The answer is yes. Recently, research has shifted its focus to developing anti-cancer vaccines along with anti-cancer therapeutics research. Vaccines are a part of artificial active immunity, meaning they have killed/attenuated parts of organisms and they help to induce immunity, thus preventing the disease. Cancer vaccines work to strengthen the immune system, and so, they can be regarded as a type of immunotherapy. In immunotherapy an individual’s immune system is boosted, enabling it to fight cancer. Cancer vaccines comprise antigens that are expressed only by cancer cells, i.e., tumour antigens that are capable of eliciting an immune response. This is a crucial step in the development of vaccines, and certain tumour antigens are used with adjuvants (a constituent in vaccines that creates a strong immune response) which activate the APCs (Cancer Research UK, 2018). Researchers are focussing on developing vaccines that target tumour-specific antigens and tumour-associated antigens. While tumour-specific antigens are proteins found exclusively on cancer cells (called neoantigens) or on cancer-causing viruses (called oncoviruses), tumour-associated antigens are proteins that are found in all cells at low levels and at abnormal levels in cancer cells.
The aim of these vaccines is to deliver antigens to activate the APCs. These APCs will then present them on their surface and stimulate T helper and T cytotoxic cells against the antigen, giving rise to an immune response. (Apostolopoulos, 2019) (Hollingsworth and Jansen, 2019).
How to ensure that the vaccines reach their target in the body? This is possible only if the vaccines are delivered correctly. Various strategies are being developed for the same. Cancer vaccines are of different types- protein or peptide-based vaccines, DNA or RNA-based vaccines, dendritic cell-based vaccines, whole-cell vaccines, and so on. Some DNA or RNA-based vaccines can be directly injected into the body and are made from parts of DNA or RNA of the cancer cells. Nanoparticle-based vaccines are being studied.
Mechanism of cancer vaccines (Crews, Dombroski and King, 2021)
The first Food and Drug Administration (FDA)-approved cancer vaccine was Sipuleucel-T in 2010 against prostate cancer. It specifically targets the prostrate acid phosphate (PAP)- an antigen expressed by prostate cancer cells. The “T” in Sipuleucel-T refers to T cells that identify and destroy the cancer cells expressing the PAP antigen. In males with minimal or no symptoms, in cases where cancer has metastasized, or in those where the hormonal treatment has not worked, this vaccine can be administered (Cheever and Higano, 2011).
Over the past few years, breast cancer cases have increased, and recently, many studies have attempted to develop vaccines against it. A study developed an HER-2 (a tumour-associated antigen)-based cancer vaccine loaded on virus-like particles from plants. This study also showed a strong immune response against HER-2, and the vaccine candidates developed were quite efficient (Hu and Steinmetz, 2021).
Mastectomy, or breast-removal surgery, is used to treat breast cancer. Abdominal flaps are used for the reconstruction of breasts, but there are cases of cancer recurrence even after such a treatment. So, researchers have developed a microparticle-based HER-2 vaccine which when injected into the abdominal flap showed an immune response that did not allow tumour growth (Liu et al., 2022).
Overview of cancer vaccine (Apostolopoulos, 2019).
Presently, different types of vaccines based on the types of cancers are being studied, for example, those against skin cancer, pancreatic cancer, Human Papilloma Virus (FDA-approved), which causes anal or cervical cancer, and Hepatitis B virus, which causes liver cancer. Many researchers are also focusing on combining cancer vaccines with anti-cancer drugs and cancer-based treatments like immunotherapy as a more promising approach to cancer treatment. Since our immune system has memory cells that keep track of all antigenic encounters, it is expected that the vaccines will also work for a longer period and help protect against cancer. Cancer vaccines like HEPLISAV -B have proven to be efficient in preventing hepatitis B infection in almost 13,000 patients (Heplisav B 2022). It is known that this vaccine can prevent all the subtypes of the Hepatitis B virus. Clinical trials were conducted on 9597 individuals in the age group of 18–70 years where the vaccine was administered intramuscularly. However, it did lead to side effects like headache, muscle pain, and fever, but proper treatment can help eliminate them. Studies also showed that people who received the Sipuleucel-T vaccine experienced back pain, nausea, and fatigue (The American Cancer Society, 2015). Clinical trials are being conducted to test the efficacy of mRNA-based personalised cancer vaccines designed for breast, colorectal, and skin cancers (How mRNA Vaccines Might Help Treat Cancer, 2022).
Thus, with extensive research, cancer prevention will be a successful strategy wherein all types of cancer vaccines will be designed as personalized therapeutics. We would definitely need in-depth knowledge of all these vaccine types and the mechanisms of different molecules involved in cancer to develop vaccines tailored against cancer. Also, these vaccines can be used in combination with the existing treatment procedures to enhance the ability of the immune system in eliminating tumours. Imagine how amazing it would be to get a jab that would treat us, or even shield us, from cancer in the future!
Summary of the mechanism of cancer vaccine
References
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[2] Bárcena, J. and Blanco, E. (2013). Design of Novel Vaccines Based on Virus-Like Particles or Chimeric Virions. In: Subcellular Biochemistry. Springer.
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Amazing amd interesting!