Bugs as drugs: Bacteria as a method of cancer vaccination

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Anthony Tao

Smallpox was once a devastating disease, speculated to have incited numerous plagues throughout history including the Plague of Athens in 430 BC and the epidemic that decimated the Aztec population of the once great city of Tenochtitlan in 1520. In the 18^th century, 400,000 deaths a year were attributed to smallpox.¹ The deadly virus continued its pestilent reign until the late 1700s when British scientist Edward Jenner surmised that introduction of a related yet milder virus, cowpox, or vaccinia virus, could render people immune to smallpox. To test this hypothesis, Jenner ‒ in ethically-questionable fashion ‒ infected an eight year-old boy with cowpox and, to everyone’s delight, found that he was protected from smallpox. Thus, the concept of vaccines (born from the word vacca, or “cow” in Latin) was introduced.

The general concept behind vaccines is a simple one: What doesn’t kill you makes you stronger. When a person is infected with a pathogen such as a bacteria or a virus, immune cells known as phagocytes can identify these invaders and consume them, a process known as phagocytosis. However, the immune response does not stop there. Phagocytes can then present pieces of the pathogen’s proteins to another immune cell-type known as T cells. This leads to many effects that help control the pathogen, including activation of pathogen-killing cells and antibodies that can neutralize the pathogen. Most importantly, engagement of T cells results in the generation of “memory cells,” which are long-lasting cells that are poised to attack the virus more efficiently upon a second invasion (Figure 1).

The use of vaccines as a tool to fight cancer is not a new idea, but has faced many setbacks, including several failed late-stage clinical trials.² Unlike normal cells of the body, cancer cells have unstable molecular machinery that results in the production of neoantigens. These are deranged proteins that can be recognized by the immune system, and elicit tumor-attacking, or anti-tumor, immune responses. The idea of cancer vaccines is to introduce these neoantigens to the immune system and elicit a strong anti-tumor immune response.

An effective cancer vaccine is governed by two main characteristics: (1) the quality of the neoantigens and (2) the delivery of these neoantigens in a way that best activates the immune system. Historical attempts to address these concerns have been met with many problems. For instance, certain neoantigens may not be easily recognizable by the immune system as a malicious entity to be targeted, resulting in a poor anti-tumor response. Moreover, different methods by which neoantigens are introduced to a patient, and how they are packaged, vary greatly with regards to anti-tumor efficacy.

To address these concerns, many scientists have proposed an interesting idea: to use bacteria or viruses as delivery devices, or vectors, with which to activate the immune system and coax anti-tumor responses. After all, living pathogens are the most potent way to drive immune activation. For instance, in the 1990s and early 2000s, the cowpox virus generated significant excitement for its ability to effectively activate the immune system and potentially act as delivery system for tumor neoantigens.³ Unfortunately, clinical trials using such vaccines have largely shown little to no benefit in human patients.^4,5

In a recent paper, a group of researchers at Columbia University proposed the use of bacteria as neoantigen delivery vectors ‒ specifically, Escherichia coli (E coli), a strain which most people will associate with food poisoning.⁶ Of course, the strain used by the researchers is indolent, meaning non-disease causing. Bacteria are especially useful vectors for neoantigen delivery and immune stimulation due to their ability to proliferate quickly, their capacity for protein production, and their amenability for genetic manipulation.

To create an E coli-based vaccine, the researchers first made improvements to the E coli strain. First, they introduced a genetic code that allows for higher levels of neoantigen production by the bacteria. Higher doses of neoantigen correlates with better immune recognition and thereby, anti-tumor activity. Second, the scientists deleted natural genes that help E coli evade the immune system, thus making them much more recognizable to immune cells, notably phagocytes. As expected, they found that this new E coli strain was more effectively engulfed by phagocytes, which would allow better activation of the immune system. Lastly, the researchers, introduced a gene into the bacteria that enhances the ability of neoantigens to be presented by phagocytes to T cells. In this manner, a more efficient T cell response is elicited, which has strong anti-tumor activity and can generate protective, long-term immunity.

The scientists next wondered about the effectiveness of this new E coli strain in protecting hosts against cancer, specifically colorectal cancer. First, they engineered the E coli to produce several different neoantigens, each associated with colorectal cancer. These were then injected directly into active colorectal tumors in mice. Excitingly, the scientists found that these mice exhibited stronger anti-tumor responses and ultimately enhanced cancer survival. Furthermore, these mice also had lower metastatic burden, meaning the colorectal cancer was less likely to spread to distant locations. Importantly, the scientists also show similar findings with a different cancer type, specifically melanoma, confirming the broad applicability of such a vaccine.

These results had clearly shown that E coli is a powerful vector to engage anti-tumor immunity for existing cancers. However, the scientists also wanted to know whether the vaccine can protect hosts from developing cancer in the first place. To test this, they injected healthy mice with the vaccine and after several weeks, grafted the mice with colorectal cancer. Encouragingly, the scientists found that vaccination reduced the growth of these tumors, indicating that the E coli vaccine was able to generate immune memory against cancer.

Overall, using bacteria as a delivery method tumor neoantigens holds great potential toward improving the efficacy of cancer-fighting vaccines. Historically, vaccines have represented a paradigmatic shift in the war against infections. In 1978, three centuries after Jenner’s cowpox experiment, a medical photographer and her mother were the last two documented people to have contracted smallpox. Beyond smallpox, the advent of vaccines drastically lowered the rates of other devastating childhood and congenital infections such as rubella, measles, mumps, diphtheria, and tetanus. Thus, it is no wonder that a cancer-fighting vaccine has such enormous appeal. 

Figure 1. Immune response to pathogens. Upon ingestion of the pathogen by phagocytes, proteins (or antigens) within the pathogen are degraded and presented to T cells. This results in T cell activation, which (1) induces long-lasting immune protection in the form of immune memory, (2) coordinates efficient antibody responses, and (3) exerts direct killing responses by spilling molecules toxic to cells.

Header image: Reproduced under a Creative Commons license held by Wellcome Collections

Edited by Shan Grewal

References

1. Hollingham, R. The chilling experiment which created the first vaccine.
2. Smith, A. D. Cancer Vaccine Field Remains Lively Despite Setbacks: 10+ Agents in Advanced Testing.  16 (2015).
3. Guo, Z. S. et al. Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics. J Immunother Cancer 7, 6, doi:10.1186/s40425-018-0495-7 (2019).
4. Kaufman, H. L. et al. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med 5, 60, doi:10.1186/1479-5876-5-60 (2007).
5. Amato, R. J. et al. Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial. J Immunother 32, 765-772, doi:10.1097/CJI.0b013e3181ace876 (2009).
6. Redenti, A. et al. Probiotic neoantigen delivery vectors for precision cancer immunotherapy. Nature, doi:10.1038/s41586-024-08033-4 (2024).