Homegrown Guardians: Harnessing the Power of the Immune System to Fight Breast Cancer

Written by: Kassidy Jungles

Edited by: Christina Del Greco and Peijin Han

Cancer is an enemy of your body, starting when your cells turn against you, rapidly divide, and spread. Cancer is clever and conniving. Cancer can rapidly mutate over time, making it difficult for your body to notice and even more difficult to treat. Because of this, it might be hard to imagine your body as the answer to ridding itself of its homegrown enemies. However, this is precisely the future of cancer treatment that scientists are imagining. What if the answer to treating cancer is using homegrown guardians derived from your immune system to beat cancer at its own game?

Meet immunotherapy: a revolutionary anti-cancer tool and the future of cancer care. The term immunotherapy encompasses many therapeutic strategies that have one thing in common: they train your immune system to kill cancer cells. Multiple types of immunotherapies are in various stages of development, including first-generation approaches like immune checkpoint inhibitors and cell transfer therapies, and the more futuristic cancer vaccines. Cancer vaccines specifically may have fewer side effects like hair loss, nausea, and diarrhea, and are currently being developed to prevent people from developing cancers in the first place. While immunotherapy has potential for all types of cancer, it is especially promising for the treatment and prevention of breast cancer, for which studies are currently underway to help bring these therapies to the patients that need them the most.

Current breast cancer therapies have major drawbacks and fail to treat all patients

Breast cancer is a leading cancer diagnosed among females and occurs when malignant cells in the breast uncontrollably divide. In 2023, nearly 300,000 females will be diagnosed and approximately 43,000 will die from breast cancer (1). Treatment outcomes for breast cancer patients have improved significantly in recent years due to advancements in screening for high-risk variants in genes like BReast CAncer (BRCA), allowing at-risk patients to receive treatment earlier or before their cancer develops. Targeted therapies that attack specific components of a patient’s tumor have also significantly improved survival rates. However, breast cancer is complex and varies in how it spreads, what genetic mutations it has, and how well patients respond to therapies. Thus, breast cancer is not just one disease, but many.

Currently, breast cancer is treated using a combination of surgery, radiation, chemotherapy, and, more recently, targeted therapy. The first step in breast cancer treatment is usually surgery to remove either a lump of cancerous tissue (lumpectomy) or the entirety of one or both breasts (mastectomy). Next, any remaining cancer cells that were not removed by surgery are killed of using a combination of the remaining techniques. Radiation involves the highly controlled delivery of small, charged beams of energized particles to the tumor region to cause cancer cell death. While most breast cancer patients receive radiation therapy, it is not the most effective treatment given the high rate of recurrence, or return, of breast cancer. The other mainstay breast cancer therapy is chemotherapy, which refers to drugs that kill cancer cells. While chemotherapy is effective at killing cancerous cells, unfortunately, it also targets healthy cells of the body. This is why cancer patients receiving chemotherapy often have unwanted side effects like hair loss and gastrointestinal distress, because the chemotherapy targets not just cancer cells but all rapidly dividing cells, like those of the hair and the gut.

Furthermore, cancer cells often employ smart techniques to fight back against chemotherapy, which leads to chemotherapy resistance being common. Targeted therapies, such as anti-hormone therapies, are a newer treatment option for breast cancer patients depending on their subtype. To make it easier to classify and treat, breast cancer is divided into subtypes based upon the presence of various hormone receptors. Hormone receptors are like accessories unique to cancer cells that can promote cell signaling and interactions.

Breast cancer is classified based upon the presence or absence of three cellular accessories: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Consequently, breast cancer is defined as ER+, PR+, HER2+, or triple-negative breast cancer (TNBC) — a form of breast cancer lacking all of the above hormone receptors, which cannot be treated with targeted hormone therapies.

Because of these drawbacks of available breast cancer treatments, scientists are looking for alternatives to improve the treatment response rates — particularly for triple-negative breast cancer — and prevention strategies to protect people at high risk. One promising answer exists in breast cancer immunotherapy, an emerging treatment option where physicians can use the power of the immune system to not only provide additional immune support but also prevent the development of breast cancer in the first place.

Immunotherapy has begun to address gaps in current breast cancer care

The immune system is incredibly complex and consists of various cells that ultimately aim to fight of both foreign invaders and also local invaders, such as healthy cells that become cancerous. Fundamentally, immunotherapy is a type of cancer therapy that functions to provide extra support to a patient’s immune system to help eliminate cancerous cells.

The earliest type of immunotherapy to become available for cancer treatment was immune checkpoint inhibitors, first approved by the FDA in 2011 for the treatment of melanoma. The body has natural checkpoints in place to prevent overactivation of the
immune system. Cancer cells can use these checkpoints to their advantage to turn of the immune system, which allows cancer cells to spread through the body unchecked.

Immune checkpoint inhibitors, such as those that target programmed death-ligand/receptor 1 (PD-(L)1), were developed to prevent these checkpoints from being
turned off. Consequently, this results in increased immune system activation, which can promote cancer cell killing. Immune checkpoint therapies have revolutionized cancer care and the scientists that discovered immune checkpoint inhibitors, Dr. James P. Allison and Dr. Tasuku Honjo, were awarded the Nobel Prize in Physiology or Medicine in 2018 for this discovery (2). Currently, the immune checkpoint inhibitor pembrolizumab is approved for both early stage (when the cancer is found locally in the breast) and metastatic (after cancer has spread throughout the body) triple-negative breast cancer.

Adoptive cell transfer therapy, such as chimeric antigen receptor (CAR) T-cell therapy, is another type of immunotherapy that involves collecting immune cells from patients, modifying them to recognize and eliminate a patient’s cancer, and reintroducing these
immune cells into the patients (3). These therapies permit increased immune signaling and promote cancer cell elimination by being modified to express certain signals unique to the cancer. Although these therapies are still in development for breast cancer, they will permit a stronger immune response compared to traditional therapies and train the immune cells specifically against fighting the cancerous cells.

Cancer vaccines are the next generation of breast cancer immunotherapy

One of the most futuristic approaches for treating breast cancer lies in the development of cancer vaccines. In recent years, scientists have made significant advances in vaccine development, such as development in the application of mRNA vaccines for treating COVID-19. These vaccines were the first example of widespread distribution of such new vaccine technology and were proven to be safe and effective in preventing disease progression. Consequently, with these advancements and widespread success of the mRNA vaccines for the treatment of COVID-19, experts predict that cancer vaccines are the future for the treatment and prevention of cancer (4).

Cancer vaccines function by delivering chemicals or biomolecules to patients that recognize components of a patient’s cancer and ultimately promote cancer cell death by turning on the immune system. Specifically, cancer vaccines typically contain two components: a target of the patient’s cancer and molecules that promote immune recognition, known as adjuvants. The first cancer vaccine component — the target — can include tumor proteins, carbohydrates, and genetic material like DNA and mRNA, all designed to mimic certain components of a patient’s tumor (5). Moreover, other cancer vaccines directly target cells of the immune system, like dendritic cells (5, 6). Dendritic cell vaccines can induce an immune response in the patient by delivering these cells as part of the vaccine to target the patient’s cancer (6). In these vaccines, dendritic cells are delivered with components of the tumor in order to trigger an antitumor immune response (6). The second cancer vaccine component — adjuvants — are added to the vaccine to create inflammation and stimulate a general immune response (7). While the adverse symptoms that accompany the inclusion of adjuvants in a vaccine (e.g., fever, body aches) are not always wanted, it is important to cause such inflammation so that the immune system recognizes the signal being delivered by the vaccine as one that is meant to introduce an immune response, instead of simply destroying the foreign particles from the vaccine.

Scientists are starting to conduct extensive studies on breast cancer vaccines due to an increase in breast cancer prevalence and the unmet clinical need for breast cancer therapies, particularly for triple-negative breast cancer. A myriad of preclinical studies – using animals and cells in the lab – and clinical studies – assessing patients with breast cancer – are underway to study the effects of breast cancer vaccines. These vaccines are being developed to work in two different ways. The first strategy, like many other vaccines, is to prevent breast cancer from occurring in high-risk individuals.

Like the development of human papillomavirus (HPV) vaccines that prevent the development of HPV-induced cancers, researchers are currently studying novel ways to prevent the development of breast cancer. Currently, a first-of-its-kind phase 1 clinical trial out of Case Western Reserve University is studying the effects of a preventative breast cancer vaccine for healthy individuals who are at high risk for developing breast
cancer (8). This vaccine specifically targets a molecular signature expressed in triple-negative breast cancer, and, like discussed previously, contains an adjuvant to activate the immune system (9).

While preventative breast cancer vaccines are still in early stages of clinical development, more research has been devoted to studying breast cancer vaccines for treating patients once they get breast cancer – the second cancer vaccine strategy. Unlike preventative breast cancer vaccines, these vaccines are designed to treat breast cancer, similar to the rabies vaccine, which can be delivered to rabies-infected individuals after exposure. Currently, researchers are trying to find ways to make cancer vaccines more effective at activating the immune system, since the vaccines being examined have not always been able to elicit long-term effects (5). Consequently, scientists are working to determine the optimal dosage and timing of delivery and develop boosters to make these vaccines more effective (5). If successful, these preclinical discoveries may translate into helping treat breast cancer patients in the clinical setting and may have less adverse side effects than the normal treatment regimen.

Much research remains to be done before rolling out breast cancer vaccines

While breast cancer vaccines will revolutionize how we treat and prevent cancer, there is still significant work needed to bring such therapies to patients. Numerous studies have assessed the effects of breast cancer vaccines in clinical trials; unfortunately, there has been little success in moving such therapies into treating patients due to limited improvement in patient survival (5, 10).

One promising way for improving patient outcomes may be combining cancer vaccines with other available therapies like immune checkpoint inhibitors and hormone receptor-targeted therapies (4, 5, 17). In a preclinical study, immune checkpoint inhibitors combined with a cancer vaccine were found to prolong survival in mouse models of breast cancer (15). Additionally, in a clinical trial combining cancer vaccines with anti-HER2 targeted therapies in patients with triple-negative breast cancer (16), researchers observed improved survival and decreased cancer recurrence, even though these patients did not express the HER2 receptor (15)! It is believed that this combination was the most effective in this subgroup due to triple-negative breast cancer having the most immune cells present that can consequently be targeted via immunotherapy, but more research is needed to understand these complex interactions.

Furthermore, more work is warranted to address healthcare disparities and what patients have access to immunotherapy treatment options. There are significant disparities in the field of breast cancer; for example, triple-negative breast cancer disproportionately impacts women of color (11). However, of the existing clinical trials for breast cancer immunotherapies, the patients that enroll are often white and do not reflect the patients of color that are often most affected (12). Additionally, while immunotherapies like adoptive cell therapies are promising, they are incredibly costly and only available to select patient populations that can afford the high costs (13). While cancer vaccines hold the promise of being more widespread and more cost-effective than adoptive cell transfer therapies, additional research is needed to not only study these vaccines in diverse patient populations, but also determine how to best promote accessibility of such therapies to the patients that desperately need them. Finally, there is the issue of educating the public on the safety of and scientific support for vaccinations. Existing vaccines undergo rigorous studies to prove safety and efficacy before being given to patients in the clinical setting. However, more discussions are needed to inform the public on the benefits of vaccines, help eliminate the stigma of vaccinations, and educate patients to prevent vaccine hesitancy (14). These discussions will be vitally important considering the ongoing public discussion and misunderstanding originating in the anti-vaccine movement and stimulated by the COVID-19 pandemic.

Cancer vaccines are incredibly promising for fighting off breast cancer. In the future, patients may no longer have to suffer from toxic side effects of chemotherapy or recurrence after radiation. Instead, they could receive a vaccine to rid the body of its homegrown enemies using its homegrown guardians. Furthermore, in the future, healthy patients who are at increased risk for developing breast cancer will be able to rest easy knowing they can receive a simple vaccine to prevent cancer development. While there is still much work to be done to bring these futuristic therapies to patients, cancer vaccines are incredibly promising treatment options that could help alleviate healthcare disparities and bring relief to cancer patients and at-risk individuals across the world.

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