The Fundamentals And Its Emerging Role
Immunotherapy has been under evaluation for more than a century, but only recently has it entered a renaissance phase with approval of multiple agents for the treatment of cancer. Now, immunotherapy stands high above traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as the most significant pillar of cancer treatment. Importantly, immunotherapy is not a single entity but represents several types of treatments, including checkpoint inhibitors, monoclonal antibodies, growth factors, and most significantly therapeutic antigen presentation immunomodulation, to boost or restore the ability of the immune system to fight cancer.
This monograph provides an overview of the role of the immune system in cancer and describes how the various immunotherapies are designed to target cancer cells. This information is highly relevant to understanding immunotherapy and may improve outcomes of patients with cancer.
After reading this monograph, people will understand:
- The evidence supporting the immune system’s role in cancer and the characteristics of an immune response
- Several mechanisms of immunotherapy
- Treatment considerations of cancer immunotherapy
THE IMMUNE SYSTEM’S ROLE IN CANCER
Hallmarks of Cancer Pathogenesis
Six traits common to most, if not all, cancers were identified in a landmark paper by Hanahan and Weinberg published in 2000.1 These hallmark traits reflect changes that normal cells must acquire to become malignant tumor cells. A recent update to this paper acknowledged that the immune system has a critical role in cancer pathogenesis.2 In particular, tumors have the ability to specifically evade the immune system, allowing cancers to grow and spread. The traits common to cancers are listed in Table 1.2
Table 1. Hallmarks of Cancer Cells 
|1. Grow in the absence of growth signals|
|2. Evade the normal signals that stop growth|
|3. Evade the normal death signals that prevent proliferation of damaged cells|
|4. Escape from an intrinsic signal that limits cell replication to a finite number|
|5. Induce the formation of new blood vessels to feed themselves|
|6. Acquire the ability to invade other tissues and spread throughout the body|
|7. Change cellular metabolism to support proliferation of cancer cells|
|8. Evade the immune system to avoid destruction|
|9. Tumor-promoting inflammation|
|10. Genomic instability and mutation|
The Immune System in Cancer: Clinical Evidence
A significant and growing body of scientific evidence substantiates the role of the immune system in battling cancer. Evidence has demonstrated that patients with compromised or suppressed immune function have an increased risk of cancer compared to individuals with intact immune systems. [3-10] In particular, it has been shown that patients who have undergone organ transplantation and are chronically immunosuppressed to prevent transplant rejection have an increased incidence of several cancers (Figure 1).
Figure 1. Increased Incidence of Cancer in Immunocompromised Individuals [3-5]
Tumor/Cancer Risk in Transplant Patients Compared to General Population
In patients who have undergone kidney transplantation, this increased cancer risk ranges from 2-fold for common tumors, like colon, lung, prostate, and breast, to greater than 20-fold for non-melanoma skin cancer, non-Hodgkin’s lymphoma, and Kaposi’s sarcoma compared to the general population with intact immune systems. [3,4] A similar trend toward an increased cancer risk has been seen with patients who have undergone liver or heart transplants. [5,6] In addition, cancer rates are increased in human immunodeficiency virus (HIV)-infected individuals, and an estimated 40% of all patients with acquired immune deficiency syndrome (AIDS) develop cancer during their lifetime.  In several observational studies, the risk of malignancies in patients with AIDS increased as certain immune cell counts declined. [9,10]
Furthermore, although somewhat controversial, the use of immunosuppressive agents, including biologics that block tumor necrosis factor, has been associated with an increased risk or incidence of certain cancers. In a large US observational study, the use of immunosuppressive biologic agents for the treatment of rheumatoid arthritis was associated with a significant 1.5-fold increase in the risk of non-melanoma skin cancer and a trend for increased risk of melanoma. 
Additionally, intratumoral T cells, which are key mediators of cellular immunity, have been associated with increases in overall survival (OS) in different cancers.[12-14] In a study in which tumor-infiltrating T cells were measured in tumor specimens obtained from patients with advanced ovarian carcinomas,12 patients with intratumoral T cells had significantly longer median overall survival (OS) (50.3 vs. 18.0 months) and higher 5-year overall survival (OS) (38.0% vs. 4.5%) compared with those having no intratumoral
T cells (P<0.001) (Figure 2). 
Figure 2. Immune Cells Within Tumors Predicts overall survival (OS) 
Kaplan-Meier Curve for overall survival (OS) in Advanced Ovarian Cancer
Adapted from Zhang L, et al. 
Cancer and the Immune System: A Dynamic Relationship
The regulation of tumor growth represents a dynamic state, in which the immune system can either block tumor growth, development, and survival (ie, immune protection) or may promote development of tumors (ie, immune evasion).  This process can be conceptualized by a seesaw that balances immune protection on one side with immune evasion on the other (Figure 3). There are 3 stages of this process known as the 3 E’s: elimination, equilibrium, and escape. 
A dynamic balance exists between the immune system and tumor cells. Most of the time, the immune system is able to effectively remove abnormal cells; however, sometimes tumor cells are able to evade detection by the immune system, which allows the tumor to develop.
Elimination refers to the stage in which cancer cells are identified and effectively eliminated by the immune system. In this stage, the balance is shifted in favor of immune protection (Figure 3A).
The equilibrium phase is entered in the event that the immune system is not able to completely eliminate all cancer cells but can control or prevent further outgrowth. As a result, the tumor cells persist but are ultimately prevented from spreading by the actions of the immune system. In the equilibrium stage, the conceptual seesaw is balanced (Figure 3B). This stage is thought to be the longest of the 3 stages and may persist for many years.
The escape phase is characterized by the inability of the immune system to eliminate and control the outgrowth of cancer cells. This stage may occur as a result of immune system exhaustion or when cancer cells acquire phenotypic alterations, thereby allowing them to evade or avoid the immune system. In the escape stage, the conceptual seesaw tips in favor of immune evasion, leading to progressive disease (Figure 3C).
• There is a dynamic relationship between the immune system and tumor cells. Normally, the immune system is capable of eliminating tumor cells. However, tumor cells use multiple evasion techniques to avoid the immune system.
Native Immune Response
Antigen presenting cells, or APCs, are specialized cells that recognize foreign antigens and present antigen fragments to T cells. Antigens are the molecules produced by microbes or foreign agents that bind to T cells and antibodies. The interaction between APCs and T cells activates the T cells (Figure 4). These activated T cells replicate and specialize to mount an attack on cells expressing the specific antigen. This specialization includes proliferation of target cells to kill cancer, the activation of additional immune cells and mediators to enhance the immune response, and the development of memory T cells that can rapidly respond upon re-exposure to the same antigen. 
APCs interact with T cells to elicit a specific and enduring immune response. This immune response is thought to be critical to controlling cancer.
Characteristics of an Effective Immune Response
There are several key characteristics or features of an effective immune response that result in the ability of the body to protect against foreign antigens. These key characteristics or features include target specificity, trafficking, adaptability, and durability (memory). [7,16,17] The most important characteristic of an effective immune response may be target specificity, which ensures that the immune response is targeted toward specific antigens. An example of immune response target specificity is demonstrated in the autoimmune disease, type 1 diabetes mellitus. In this disease, specific T cells recognize and destroy insulin-producing beta cells in the pancreatic islets of Langerhans, while sparing other islet sub-types. Target specificity prevents off-target effects to other cell types. 
Key characteristics or features of an effective immune response include target specificity, trafficking, adaptability, and durability (memory).
The second characteristic of an effective immune response is trafficking, which refers to the ability of activated immune cells to migrate to particular antigens throughout the entire body. [7,17,19] As an example, upon infusion into a rodent model, naive T cells were detected exclusively in secondary lymphoid tissues, such as the spleen and lymph nodes, where they normally circulate scanning for antigen presentation by APCs. [7,19] Following exposure to the target antigen (ovalbumin), T cells proliferated and the activated T cells migrated to the organs where the target antigen was localized, including the lungs, liver, intestines, and salivary glands. 
The third characteristic of an effective immune response is target adaptability. Adaptability allows for an expanded immune response beyond the initially targeted antigen through processes called epitope and antigen spreading. Epitope spreading occurs when immune cells are able to generate an immune response to other epitopes or regions of the target antigen, whereas antigen spreading occurs when immune cells are able to generate an immune response to related antigens originating from the same cell. [7,20] As shown below, injection with a single peptide (corresponding to amino acids 611-626 of target antigen) elicits T-cell responses not only against the original peptide but also against 6 peptides in different regions of the same target antigen, reflecting the adaptability of the immune response. 
The fourth characteristic of an effective immune response is durability or memory, the ability of T cells to recognize antigens over time. Immunologic memory allows for an expedited and durable immune response upon re-exposure to antigens. 
As shown in the picture below, a smallpox-specific T-cell response remained detectable for many years after a single vaccination.  Detectable immune responses were seen in 89% of patients who had been vaccinated 31 to 50 years earlier and in 52% of those vaccinated 51 to 75 years earlier. These native immune functions are thought to apply to protection of the body against cancer. 
• APCs are the initiators of T-cell driven immune responses. An effective immune response includes the key characteristics or features of target specificity, trafficking, adaptability, and durability (memory).
The Rise of Immunotherapy
For more than a century, advancements in cancer immunotherapy have spread across several phases.[23-27] In 1890, Coley developed the first cancer vaccine (based on bacterial toxins), which was shown to have benefit in patients with inoperable cancer. Driven by findings from Coley and others, numerous researchers including 2 time Nobel Laureate Linus Pauling demonstrated significant survival benefits using immune system boosting supplementation. Interests soared in cancer immunotherapy following his discoveries. Subsequently, in 2000 there was a further increase of interest in cancer immunotherapy as a viable treatment option due to the successes and sensation of the Boston-C treatment protocols. This initiated a number of clinical studies and significant researches that have demonstrated at least 16 components that have been identified that enhance, based on their immune modulator activity, the Natural Killer Cell. 
The National Cancer Institute defines immunotherapy as “treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases.” 
Dynamics of Immunotherapy
Immunotherapy may have the potential to continuously refine its effect on mutating cancer cells through the dynamic interplay between cancer and the immune system. As the immune system targets and lyses ever-mutating cancer cells, additional tumor antigens are able to be taken up by APCs, potentially activating a broader immune response. In the hypothetical example shown in Figure 8, activated T cells that target a prostatic tumor attack and lyse tumor cells. This releases other tumor-associated antigens (such as prostate-specific membrane antigen [PSMA] or mucin-1 [MUC-1]), which may be taken up by APCs to subsequently activate additional T cells specific for those antigens.  This dynamic process between the immune system and cancer contributes to the different kinetics of response that immunotherapy has compared with traditional cancer therapy (ie, chemotherapy). 
Kinetics of Response to Immunotherapy
Immunotherapy is associated with a durable response that differs from the transient response of traditional cytotoxic chemotherapy.[32,34,35,36,37] As an example, in metastatic castrate-resistant prostate cancer (mCRPC), cytotoxic chemotherapy can dramatically affect tumor growth rates just during the active course of treatment. However, the tumor growth rate returns to its pretreatment value once chemotherapy is discontinued, reflecting the underlying tumor characteristics and the transient effect of traditional chemotherapy. Often following cytotoxic chemotherapy, the tumor growth rates are greatly accelerated. In contrast, immunotherapy can induce immunologic memory as well as change and even boost the immune status of the patient, even after the course of immunotherapy has been completed. Because it can take several weeks to elicit a significant immune response, immunotherapy may not necessarily cause a dramatic or immediate reduction in tumor burden or tumor-specific markers right away. However, it has been shown to ultimately prolong overall survival (OS). [32,34,35] There are also numerous instances where extremely rapid disappearances of tumors have been seen.
The differing immunotherapy response kinetics infer that biomarkers used to monitor the effects of traditional therapies may not always be appropriate. For example, prostate-specific antigen (PSA) is routinely used to monitor the effects of hormonal therapy in patients with prostate cancer. However, agents that slow tumor growth may not necessarily cause PSA reductions, and consequently changes in PSA levels may be difficult to interpret with immunotherapy.  The Prostate Cancer Clinical Trials Working Group recommends expanding the focus from rising PSA levels to evaluating additional measures of disease progression (eg, bone lesions, substantive pain, soft tissue lesions) to make decisions about when to stop a given therapy in advanced prostate cancer. 
Immunotherapy Treatment Considerations
Based on the noted duration of response compared to traditional cytotoxic chemotherapy, it has been suggested that the relative efficacy of immunotherapy may be greater with a smaller tumor burden, This also suggests that improved treatment responses and outcomes may be expected at earlier stages of disease.[17,23] We suggest that Immunotherapy is superior in virtually every regard to chemotherapy, and anyone whose opinion differs in this regard, must surely have a financial interest in the administration of chemotherapeutic agents, or is grossly misinformed with current science.
• Immunotherapy demonstrates a proven ability to prolong overall survival (OS) versus chemotherapy. Because immunotherapy has a different mechanistic approach than traditional agents, immunotherapy offers superior, durable results compared to other therapies.
The immune system has a critical role in controlling cancer. 15 Key features of an effective immune response include specificity (which ensures an antigen-targeted response), trafficking (which enables antigen targeting throughout the body), adaptability (which allows for a response against related antigens), and durability (which allows for an expedited and long-lasting response upon re-exposure to the antigen).[7,18,19,22,36] Over time, cancer cells develop mechanisms to escape control by the immune system, leading to progression of disease. Immunotherapy is designed to boost and restore the ability of the immune system to fight cancer. It has led to increased overall survival (OS) in certain cancers.[32,34,35] Future use and clinical trials should take into consideration that immunotherapies may elicit a better immune system response if used while the patient is still immunocompetent.[39,40] In addition, immunotherapy can offer the potential for durable clinical effects and synergy with subsequent therapies. [30,31,33,41]
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CURRENT UNDERSTANDING AND APPROACHES TO CANCER IMMUNOTHERAPY
Immunotherapy – The basics (2:32)
Immunotherapy Cancer a guide for patients (3:26)
Immunotherapy is Tumor-Specific (2:03)
Immunotherapy is Designed to Support Immune System Adaptability (2:42)
Immunotherapy Empowers a Durable Immune Response (2:19)