By Olivia Marx

Most people know someone affected by cancer and are familiar with the toll the disease takes on a person’s life – from tangible impacts on their body to intangible ones on their close relationships. Since the early 1990s, clinical and research advancements have supported a 31% decline in the overall cancer death rate. However, the speed of this progress is slowing as things like early detection and smoking awareness have become widely implemented¹. To continue this progress, researchers must think of new strategies to combat cancer.

Current cancer treatment guidelines vary by cancer type but often involve chemotherapy, radiation, and surgical removal of the affected area. Chemotherapy and radiation generally induce DNA damage, which kills dividing cells like cancer cells, but also damages non-cancerous cells. For example, hair follicles and the dividing cells of the gastrointestinal tract can be caught in the crossfire, causing the hair to fall out and patient discomfort while allowing dormant cancer cells to remain. Surgery, when possible, may remove the majority of the tumor, but there is no way to completely prevent metastasis, or cancer cells that have left the primary tumor site to colonize elsewhere in the body. Furthermore, surgery is not an option for some patients who may be older or have other medical complications.

In addition to those conventional treatments, personalized cancer treatments against an individual’s tumor have improved the prognosis for some cancers. Personalized treatments aim to find a unique difference between a person’s cancer cells and their regular healthy cells. Breast cancer is a shining example of how adjusting cancer treatment to an individual’s tumor makeup can benefit patients. You may have heard of “triple negative”, or “HER2 positive” breast cancers. These terms refer to markers that breast cancer cells may or may not express. In fact, there are three common markers that may pop up in breast cancer, including the hormone receptors for estrogen (ER), progesterone (PR), and the growth receptor HER2. One or more of these receptors may become over-expressed in cancer cells, and oncologists use drugs that can selectively kill cells which highly express any of these markers. Triple-negative breast cancer is negative for these three markers, and thus, personalized treatments targeting the markers will not be effective in triple-negative breast cancer patients. Therefore, despite its success, more research is needed to identify other treatable cancer markers to expand the number of cancer types this treatment works for.

So – what other options are there? A growing vein of research seeks to explore a bold approach: combating cancer by strategically weaponizing a patient’s own immune system to fight against the disease.

The immune system is composed of specialized cells that recognize and eliminate unhealthy cells or pathogens. Adaptive immune cells, such as T-cells, produce antibodies that can be taught to recognize and target pathogens or unhealthy cells. Vaccines leverage the body’s natural defense system by training the adaptive immune response to recognize a pathogen. Tumors develop complex ways to evade the immune system, so recent studies focus on finding new ways “teach” a person’s immune cells to attack cancer.

The idea of cancer-fighting immunotherapy began in the late 1800s with the injection of bacteria into a cancer lesion that stimulated tumor regression². Now, bacillus Calmette-Guerin (BCG) Treatment is an FDA-approved treatment for bladder cancer that involves injecting live bacteria into the bladder to stimulate an immune response. More elegant approaches have since been developed, and the real boom in cancer immunology began with the Nobel-prize winning discovery of “immune checkpoints” – signals that tumor cells may send out telling an immune cell “I’m normal, don’t kill me”. This discovery ultimately led to the 2017 FDA approval of chimeric antigen receptor (CAR) T cell therapy, which entails engineering a patient’s T-cells to better recognize and attack their cancer cells. While CAR-T therapy has been widely effective against blood cancers (such as leukemia and lymphoma), its implementation against solid tumors has been more difficult. This is especially true when facing “immune- cold” tumors, or tumors better at disguising themselves, making it tougher for immune cells to differentiate “foe” (tumor) from “friend” (the rest of the body). CAR-T therapy is also costly and not covered by all insurances, and even when it can be administered, around half of patients still relapse and require other cancer treatment.

These advances in cancer immunotherapy have paved the way for a new and personalized way to treat cancer: with vaccines. Not cancer-preventing vaccines, like the HPV vaccine – cancer-treating vaccines. Cancer vaccines may either inject the patient with a modified version of cancer cells, or with a peptide or nucleic acid sequence that may be unique to their tumor cells. For older patients, or those with late-stage cancer who opt against chemotherapy or surgery to maintain quality of life, a cancer vaccine could provide treatment without making the patient feel sicker. This strategy of injecting a patient with modified cells to stimulate the immune response has had some success. Provenge, which is used to treat prostate cancer, is the only FDA-approved cancer vaccine (apart from BCG, discussed previously). To administer Provenge, a patient’s white blood cells are incubated with prostate cancer antigens and injected back into the patient². While successful in treating prostate cancer, this strategy has not shown as much promise in other cancer types.

In contrast to injecting modified cancer cells, injecting a patient with a peptide or nucleic acid sequence is quite routine, like an annual flu shot. In fact, the success of RNA vaccines has provided a new avenue for cancer treatment. These vaccines would utilize a similar concept to the COVID-19 RNA vaccine: introducing RNA into the body which results in production of antigens that immune cells can then recognize and attack. Cancer vaccines using this technology make use of the fact some tumor cells produce unique proteins (reflecting mutations present in the tumor), called tumor-specific antigens, to target the treatment. Antigens are specific protein sequences recognized by the immune system and used to activate and target T-cells (Figure 1). Sometimes tumors go unnoticed, despite the presence of tumor-specific antigens. By presenting the body with bite-sized blueprints of cancer-specific proteins, cancer vaccines would train immune cells to recognize cancer cells that bear these markers and eliminate them.

The use of neo-antigen cancer vaccines is promising, as it specifically targets the tumor, limiting side effects, and would be cheaper and less invasive than removing a person’s immune cells and re-engineering them outside of the patient. Vaccines are still quite new to the cancer field, however, early-phase clinical trials with RNA-based cancer vaccines show promising results, exhibiting little toxicity and leading to patients showing a reduction in cancer markers³. One promising phase 2 clinical trial is for the cancer vaccine SurVaxM. In this trial, patients were injected with a peptide mimic of the protein survivin, and the study found that this nearly doubled survival time of glioblastoma patients. SurVaxM has been fast-tracked for FDA approval⁴.

Cancer vaccines are quite new, and there are still major challenges, including optimizing the personalized approach to an individual’s own tumor and immune system and predicting what neo-antigens will most likely be recognized by immune cells. Despite these remaining hurdles, cancer vaccines are an extremely promising treatment for use alone or in combination with other treatments. One thing is certain: the future of cancer treatment will be personal, and it’s up to us to take a shot at cancer.

TL;DR

• Current cancer treatments are uncomfortable and imperfect.
• Personalized medicine and immune oncology are promising ways to treat cancer.
• Cancer vaccines train immune cells to target tumor-specific peptides that may be presented on the MHC complex.
• Early clinical trials of cancer vaccines suggest improved prognosis with minimal side effects.

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References

1          Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer Statistics, 2021. CA Cancer J Clin 71, 7-33 (2021). https://doi.org:10.3322/caac.21654

2          Igarashi, Y. & Sasada, T. Cancer Vaccines: Toward the Next Breakthrough in Cancer Immunotherapy. J Immunol Res 2020, 5825401 (2020). https://doi.org:10.1155/2020/5825401

3          Morse, M. A. et al. Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Therapy 30, 803-811 (2023). https://doi.org:10.1038/s41417-023-00587-1

4          Ahluwalia, M. S. et al. Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma. J Clin Oncol 41, 1453-1465 (2023). https://doi.org:10.1200/jco.22.00996