The War on Cancer Is Not Over

Cancer is one of the leading causes of death worldwide, accounting for nearly 10 million deaths in 2020 (Sung et al., 2021). Every year, millions of individuals worldwide are diagnosed with cancer, with more than half succumbing to the disease. Population increase and aging are projected to result in 26 million additional cancer diagnoses worldwide by 2030, resulting in 17 million cancer-related deaths per year (Thun et al., 2010). Cancer is a complex and multifactorial disease with numerous genetic and non-genetic factors contributing to malignancy (Clavel, 2007). The uncontrolled proliferation of abnormal cells, capable of invading other tissues or spreading to other organs, via a process known as metastasis, is a major hallmark of cancer. Widespread metastases are the leading cause of death from cancer (Cooper, 2000). While the three pillars of cancer treatment – surgery, radiation therapy, and chemotherapy – have saved and prolonged countless lives, cancer remains a major challenge for modern medicine, an elusive goal that demands innovative thinking as researchers seek breakthroughs. With the advent of personalized medicine, new treatment choices such as targeted therapies and immunotherapy have lately resulted in a paradigm shift in the therapeutic landscape for cancer patients.

The Mainstays of Cancer Treatment

For decades, surgery, anti-cancer drug therapy (chemotherapy) and radiation therapy have been the cornerstones of cancer treatment. While chemotherapy relies on intravenous or oral drug administration to damage and kill rapidly growing cells, radiation treatment uses high doses of radiation to induce DNA damage in rapidly dividing cells, thereby restricting tumor growth (The Three Pillars of Cancer Treatment, n.d.). Both radiation therapy and chemotherapy often carry the risk of damaging healthy body cells, particularly those that proliferate rapidly, including hair and skin cells. This leads to toxicity for the patient, as well as negative side effects and relatively poor therapeutic outcomes (Lacouture & Sibaud, 2018; Pinto et al., 2011). Certain tumors can be treated with radiation alone. Most often these are early-stage malignancies that have not yet spread or developed a large size (National Cancer Institute, 2019). By contrast, chemotherapy is frequently used in patients whose cancer has spread throughout the body and cannot be surgically removed, or when patients have a cancer that cannot be treated locally, such as blood cancer (National Cancer Institute, 2022b). Chemotherapy is also routinely prescribed for palliative care, in patients with advanced, incurable cancer, to enhance disease control and relieve cancer-related symptoms. Most cancer treatment programs, however, include numerous therapy combinations to maximize treatment success.

Figure 1 - In modern medicine, cancer treatment ranges from surgery, chemotherapy and radiation therapy to targeted therapies ("Treating children's cancers", n.d.).

Targeted Cancer Therapy

While surgery, chemotherapy and radiation therapy still remain at the forefront of cancer management, novel therapeutic options have transformed the cancer therapy framework. The first targeted therapies for cancer treatment approved by the United States Food and Drug Administration (FDA) in the 2000s laid the groundwork for personalized medicine, which seeks to tailor medical treatments to each patient (Ali et al., 2019; American Cancer Society, 2014; Gerber, 2008). These targeted therapies consist of monoclonal antibodies, which are laboratory-created proteins designed to bind particular targets on the surface of cancer cells (known as antigens), and small molecule drugs, which easily diffuse and cross the plasma membrane (Gerber, 2008; Røsland & Engelsen, 2015). Imatinib (Gleevec, Novartis Pharmaceuticals Inc.), a small-molecule inhibitor, has emerged as a game-changing therapy for leukemia and other cancers such as gastrointestinal tumors (Deininger et al., 2005). Trastuzumab (Herceptin, Roche), an antibody that binds to the human epidermal growth factor receptor 2 (HER2), has been found to be overexpressed on the surface of several malignancies, including metastatic breast cancer, which is often associated with a poor prognosis and a higher risk of disease progression and reduced survival (LoRusso et al., 2011; Slamon et al., 2001). While some monoclonal antibodies bind to and tag cancer cells, allowing them to be easily recognized and destroyed by the immune system, others directly inhibit cancer cell development or induce tumor cells to self-destruct. Remarkably, in modern medicine, some monoclonal antibodies are also employed in immunotherapy since they help in mobilizing the immune system's response to tumors. Yet, there are also drawbacks, such as cancer cells developing resistance to targeted therapies. As a result, targeted therapy is routinely combined with other cancer treatments such as chemotherapy and radiation.

Figure 2 - Trastuzumab Deruxtecan is a HER2 inhibitor targeted therapy that works against HER2-positive breast tumors by preventing cancer cells from proliferating (Cortés, 2022).

The Immune System as a Driving Force for Cancer Treatment

The immune system is the first line of defense against infection and disease due to its ability to distinguish between body cells (‘self) and foreign substances (‘non-self’). T cells, which are immune cells, contain receptors that recognize and bind to ‘non-self’ proteins at the surface of external substances (also known as antigens), which induces the activation of other components of the immune system to promote elimination (Janeway et al., 2001). As part of its regular function, the immune system scans, recognizes and eliminates invading pathogens and other exogenous threats. It is also capable of detecting and eliminating abnormal cells, such as cancer cells, through recognition of tumor-specific antigens, thus playing a key role in tumorigenesis prevention (Decker et al., 2017). Tumor immune surveillance refers to the later process by which the immune system finds and removes malignant cells before they can cause damage (Goldszmid et al., 2014; Vesely et al., 2011). While immune cells can be detected in and around tumors, showing that the immune system is capable of responding, tumors do thrive in the presence of a functioning immune system (Drake et al., 2006). This is because tumor cells have evolved strategies to avoid destruction by the immune system and become entrenched in the host. Tumor cells not only downregulate antigen presentation, rendering malignant cells less detectable to the immune system, but they also express proteins on their surface that curtail the activity of immune cells, while impairing the functioning of normal cells surrounding the tumor (Khong & Restifo, 2002; Rabinovich et al., 2007).

Despite the activation of immune cells, certain tumor cells may escape destruction over time as a result of tumor evasion mechanisms, leading to tumor progression. The tumor microenvironment (TME) plays a key role in this, since malignant cells do not exist in isolation. This complex environment includes immune cells, blood vessels, extracellular matrix, and signaling molecules (Tamura et al., 2020). Tumor cells exploit their surrounding microenvironment, co-opting nutrients and blocking immune surveillance and host responses. This fosters cancer growth by reducing the immune system's ability to fight cancer cells, eventually leading to the inability to completely remove certain tumors (Polyak et al., 2009). Understanding the dynamic and mutual interactions between cancer cells, host immune cells and the tumor microenvironment is critical to improving patient diagnosis and treatment and has laid the foundation for immunotherapy.

Figure 3 - Three T cells encircle a cancer cell in an attempt to destroy it, however such interactions may not always result in the T cells being victorious (Ritter et al., 2015).

Immunotherapy: A New Hope for Cancer Treatment

The plethora of genetic and epigenetic (not involving changes in the DNA sequence) alterations that are inherent to all cancers provide a diverse array of antigens that the immune system may recognize to discriminate tumor cells from their healthy counterparts. The interaction between antigens and immune receptors is analogous to a lock and key, as each foreign antigen has a unique immune receptor that can bind to it. Cancer cells also contain antigens, but when immune cells lack the corresponding receptors, they are unable to bind and hence fail to destroy malignant cells (Delves, 2022). The concept of deploying the immune system to fight malignant tumor cells dates back to the 19th century (Oiseth & Aziz, 2017), but it took another century before T cells were recognized as critical components of the tumor-specific immune response (Halliday et al., 1995). Immunotherapy has only recently gained traction with a better understanding of the intricacies of the immune system and the cellular and molecular mechanisms that drive carcinogenesis. Immunotherapy is a three-pronged strategy that enhances immune cells to fight cancer, trains the immune system to seek out and specifically kill cancer cells, and enhances the body's immune response (Hunter, 2017; Sanghera & Sanghera, 2019).

A greater understanding of immune surveillance has led to the discovery of immune checkpoints, which can dampen the immune response by conveying an "off" signal to T cells. This is critical to guarantee self-tolerance (thus preventing autoimmunity) and protect organs from damage during an immune response. Immunotherapy drugs known as immune checkpoint inhibitors operate by inhibiting these checkpoints, thus boosting T cells' ability to eliminate tumors permitting a continuous "on" state. (Sharpe, 2017; Yang, 2015). The first immune checkpoint blockade therapy, Ipilimumab (YERVOY, Bristol-Myers Squibb), was approved by the FDA in 2011, ushering in a new age of cancer immunotherapy (Røsland & Engelsen, 2015). Antibodies that inhibit other checkpoints, such as PD-1 or its ligand PD-L1, have since been approved (Waldman et al., 2020). Remarkably, combining PD-1 and CTLA-4 inhibitors has been found to boost anti-tumor activity in melanoma and non-small cell lung cancer (Ott et al., 2017; Pardoll, 2012).

Figure 4 - Immunotherapy is now a standard cancer treatment, which directly targets tumor cells while boosting the generation of long-lasting anti-tumor immune responses (Philips, 2022).

CAR T-Cell Therapy: Arming the T Cells

The ability to isolate and expand immune cells, particularly T cells, in vitro paved the way for the use of adoptive cell transfer (ACT; the transfer of cells to a patient) in cancer immunotherapy (Rosenberg & Restifo, 2015). The development of chimeric antigen receptor (CAR) T-cell therapy represents a watershed moment in cancer treatment. The early development of CAR T-cell treatments was primarily focused on the most frequent pediatric malignancy, acute lymphoblastic leukemia (ALL). More than 80% of children diagnosed with ALL can be cured with rigorous chemotherapy, yet effective therapies for children whose malignancies recur after chemotherapy have been limited (National Cancer Institute, 2022a). Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals Inc.), the first CAR T-cell therapy licensed by the FDA in 2017, has shown notable success in children and adolescents with recurrent and relapsing disease, with complete response rates, that is the eradication of all cancer-related symptoms, of 70-90% (Cummins & Gill, 2018). As the name suggests, T cells are at the heart of CAR T-cell therapy, which consists of modifying the genes within T cells to help them target and eliminate cancer cells (Sadelain et al., 2013). Currently available CAR T-cell therapies are tailored to each patient, making them effective against difficult-to-treat malignancies while delivering long-term therapeutic outcomes (Melenhorst et al., 2022). These are made by collecting T cells from the patient via a method known as leukapheresis: the patient's blood is collected and white blood cells are separated (including T cells), with the remaining blood being returned to the body. In the laboratory, isolated T cells are re-engineered to express particular proteins on their surface known as chimeric antigen receptors, or CARs. Because different cancers express different markers, or proteins on their surface, each CAR is customized for a particular tumor and patient.

Once revamped, T cells are expanded in the laboratory and re-infused into the patient, where they continue to multiply and, under the guidance of their engineered receptor, recognize and kill cancer cells harboring the target antigen on their surfaces. Although CAR T-cell therapies are not as routinely used as immune checkpoint inhibitors, they can be exceedingly effective in aggressive cancers, with long-term clinical responses (June et al., 2018). However, as cellular products, CAR T-cells are associated with unique toxicities which can lead to life-threatening side effects (Schubert et al., 2021). Cytokine release syndrome (CRS), a systemic inflammatory response, is the most prevalent toxicity reported, with symptoms such as high fever, rigors, sweating, anorexia, headache, altered mental status, capillary leak and multiorgan dysfunction (Bonifant et al., 2016; Varadarajan et al., 2020). Recognition, management and differentiation of CAR T-cell toxicities are essential for safe and broad employment of this therapy, and patients must be monitored continuously for many weeks after receiving the CAR T-cells.

Figure 5 - CAR T-cell Therapy Process ('Chimeric Antigen Receptor', n.d.).

Conclusions

Cancer research has come a long way in the last few decades, evolving from a systemic treatment with chemotherapy/radiation to a more targeted approach employing novel therapies such as monoclonal antibodies, small molecule inhibitors, immunotherapy, and cellular therapy such as CAR T-cells. Before President Richard Nixon announced the “War on Cancer” in the early 1970s, the scientific community knew little about cancer cells and what governs their division. Evidence gathered by experts around the world showed that cancer is often caused by genetic defects in cells. The fact that every tumor is unique is now generally accepted. Each patient's cancer is caused and fueled by a unique set of mutations, each of which in its own unique way hides or evades the immune system. The discovery of these potentially carcinogenic genes, such as HER2 (which is frequently mutated in breast cancer), has contributed to the development of novel targeted therapies with less adverse effects on healthy cells. While these are notable success stories, limited therapeutic indications, occasional treatment failure and relapses, toxicity, high production costs, and high patient expenses are just a few of the challenges associated with these therapies. While the battle against cancer is far from over, the fruits of mankind's efforts are now visible, with survival rates at an all-time high due to new therapies. People suffering from incurable cancer forms live now longer. However, while modern technology has improved the treatment of local tumors, the prospects for treating metastatic cancer still remain limited. When it comes to cancer treatment, the road has been long, slow and gradual. Although there is still a long way to go, contemporary science's ever-increasing advancements are boosting the battle against cancer step by step, and a clear route in the fight against this incredibly complex disease is taking shape.

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