Accepted Article
Title: Advances in the understanding of cancer immunotherapy1 [Target Journal: BJUI]
Author: Neal D. Shore, MD, FACS
Author affiliation: Carolina Urologic Research Center/Atlantic Urology Clinics, Myrtle Beach, SC, USA Phone: 843-449-1010 Fax: 843-497-6171 E-mail: [email protected]
Abstract word count: 181 words
Manuscript word count: 3569 words
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bju.12692
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Abstract The principal role of the immune system is to prevent and eradicate pathogens and infections. Key characteristics or features of an effective immune response include specificity, trafficking, antigen spread, and durability (memory).
The immune system is recognized to have a critical role in controlling cancer through a dynamic relationship with tumor cells. Normally at early stages of tumor development, the immune system is capable of eliminating tumor cells or keeping tumor growth abated. However, tumor cells may evolve multiple pathways over time to evade immune control.
Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections, and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumor burden, whereby disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve.
Because immunotherapies may have a different mechanism of action than traditional cytotoxic or targeted biologic agents, immunotherapy modalities have the potential to combine synergistically with traditional therapies.
Keywords: cancer, immunotherapy, immunoediting, cytokine, monoclonal antibody, checkpoint inhibitor, therapeutic cancer vaccine
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Introduction The role of the immune system in cancer pathogenesis has been confirmed by
numerous preclinical studies and clinical trials. Recent advances in therapies that engage the immune system have been shown to improve patient survival and have led to approvals of immunotherapeutic agents to treat different tumor types, including urologic cancers. Therefore, it is timely for practicing clinicians to review the current state of
understanding of the immune system and the role it plays in cancer therapy. This review provides an overview of how the immune system functions, presents evidence for the immune system’s role in cancer, describes several classes of immunotherapeutic modalities, such as cytokines, checkpoint inhibitors, therapeutic vaccines, and monoclonal antibodies, which are being investigated and/or utilized in practice, and summarizes clinical considerations for the current state of immunotherapy for the practicing clinician to optimize the care of patients with cancer.
Overview of the Immune System Function The physiologic and principal role of the immune system is to protect individuals
against foreign pathogens and infections. The immune system is complex and relies upon many interrelated components to target foreign pathogens in order to effectively prevent and eradicate foreign microbes [1]. The initial innate (non-specific) immune 3 This article is protected by copyright. All rights reserved.
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defenses are epithelial barriers, such as the skin, that prevent entry of microbes and contain specialized cells, which thwart microbial proliferation. When microbes breach these epithelial barriers, other non-specific defenses are enlisted. Specific pattern recognition receptors, such as toll-like receptors (TLRs), recognize foreign pathogens and then initiate a rapid, generalized attack using phagocytes, natural killer (NK) cells, and inflammatory mediators to destroy infected cells [2]. If the infectious pathogens overwhelm the innate immune defenses, this can prompt
initiation of an adaptive immune response—a targeted response utilizing specialized defenses that can develop memory and use specialized cells to specifically eliminate these pathogens [1,2]. Vaccination is a classic example of how the adaptive immune
system recognizes foreign microbes to which it has been previously exposed and mounts a specific attack to prevent infection [1,2]. The specialized immune responses comprise two generalized types of immunity,
cellular immunity and humoral immunity, which are mediated by lymphocytes (eg, T cells and B cells) and their products (eg, antibodies). These responses are designed to eliminate pathogens at different locations (intracellular vs extracellular) and in different types of molecules, including proteins, carbohydrates, and lipids [1]. As illustrated in Figure 1, cellular immunity eradicates intracellular microbes through the following sequential phases: antigen recognition, antigen presenting cell (APC) activation, T-cell interaction and activation, proliferation and differentiation into effector cells, which can activate other immune cells and eradicate cells containing the antigen; also, memory T cells, which can respond quickly if the antigen is re-encountered, may too be initiated [1].
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Humoral immunity neutralizes and eradicates extracellular microbes and toxins through antibodies produced by B lymphocytes [1]. The innate immune system plays an important role in activation of the adaptive
immune system. Innate immune system cells release signals, such as cytokines, that are essential to stimulate the responses of T cells and B cells. APCs, such as dendritic cells (DCs), serve as a bridge between the innate and adaptive immune system by processing foreign antigen and presenting it to naive T cells, a step which is necessary for their activation and response. Further, when TLRs on DCs are activated, it can increase expression of factors (eg, major histocompatibility complex [MHC] class II, CD40) on the DC surface required for antigen presentation as well as promote secretion of cytokines that facilitate the adaptive immune response [2]. It is important to note that the immune system can also recognize cancer cells or
tumor antigens as foreign substances and initiate immune response against neoplastic cells [1].
Immune System’s Role in Cancer Clinical evidence for the immune system’s role in cancer pathogenesis includes the
observed relationship between immunosuppression and an increased risk of developing cancers in many study populations as well as the finding that when immune cells infiltrate tumors, overall survival may be improved. For example, it has been demonstrated that patients who undergo organ transplantation and receive immunosuppressant medications to prevent rejection have an increased risk, ranging 5 This article is protected by copyright. All rights reserved.
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from two-fold to over 20-fold, of developing a wide variety of cancers [3,4]. Based on data from a UK transplant registry, the 10-year incidence of de novo cancer in transplant recipients is twice that of the general population [5]. In addition, approximately 40% of patients with AIDS develop cancer during their lifetime [6]. On the other hand, T-cell infiltration within tumors was found to be associated with improved overall survival in patients with various cancers [7–9]. The suggestion that inflammatory
response may be correlated with cytokine release and possible T reg suppression (eg, suppression of cells that curb activation of the immune system and prevent selfreactivity) continues to be explored. Additional evidence for the involvement of the immune system affecting cancer
disease progression is that therapies which engage the immune system have been shown to improve patient survival in clinical trials, thus leading to approvals of immunotherapeutic agents to treat cancer in clinical practice. As an example, interferon (IFN) has been studied over the past several decades and is approved for use in a number of clinical applications, including melanoma, renal cell carcinoma, AIDS-related Kaposi’s sarcoma, follicular lymphoma, hairy cell leukemia, chronic myelogenous leukemia among others [10]. More recent examples include approval of sipuleucel-T in 2010 as the first cellular immunotherapy for prostate cancer treatment [11] and ipilimumab in 2011 as the first checkpoint inhibitor to treat melanoma [12]. Taken together, these data support the important role of the immune system in controlling cancer progression. Evading the immune system is one of the mechanisms that allows cancers to grow and spread and is considered to be one of the hallmarks of cancer pathogenesis [13].
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Cancer and the Immune System: A Dynamic Relationship Immunoediting Process The immune system regulates tumor growth through a dynamic process, in which it
can either block tumor growth, development, and survival or may promote tumor progression [14,15]. As shown in Figure 2, there are three stages of the dynamic process of immunoediting, also known as the three E’s: elimination, equilibrium, and escape. In the elimination phase, cancer cells are identified and destroyed long before they become clinically apparent (ie, immune protection) and the host remains free of cancer. If a cancer cell variant is not destroyed, the tumor may enter the equilibrium phase, in which cancer cells persist but outgrowth is prevented by the immune system. This stage is thought to be the longest of the three stages and may last for many years or even the lifetime of the host. During the escape phase, outgrowth of cancer cells is no longer controlled (or even being selected/shaped into a less immunogenic state) by the immune system, leading to clinically apparent and progressive disease (ie, immune evasion). While many of the immune cells and molecules that participate in different stages of this process have been identified, more studies are needed to determine their exact mechanism and sequence of action [15]. It is established that NK cells, cytokines, antigen presenting DCs, and T cells play
important roles in the anti-tumor response. NK cells are a first line of defense against cancer cells with the ability to rapidly identify and eliminate such cells. These cells possess the ability to recognize self and non-self through expression of killer inhibitory 7
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receptors (KIRs). KIRs interact with self-markers (eg, MHC Class I) on healthy cells, and when cells become stressed and lose those markers, this contributes to activation of NK cells [16,17]. Cytokines contribute to the anti-tumor immune response in a variety of ways; they stimulate inflammation and boost the activation of other immune cells. For example, IL-2 can stimulate activation of NK cells, which in turn release INF-alpha and other cytokines that enhance activation of DCs and T cells [16,17]. DCs process and present antigens associated with tumors to T cells; this activates T cells to tumorassociated antigen and initiates a targeted anti-tumor response [2,16]. However, because cancer is an immunoevasive disease, adaptations that occur in the tumor microenvironment can blunt the immune response and contribute to cancer progression [14].
Features 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 or tumors, including specificity, trafficking, antigen spread, and durability (memory) [1]. Specificity ensures that distinct antigens induce specific responses. For example, following annual vaccination against flu virus, the immune system can selectively identify surface antigens of the annual strain and induce a specific attack [1,18]. Trafficking refers to the ability of activated immune cells to migrate to particular antigens throughout the body. T-cell mediated immunity is an example of trafficking. Following exposure to activated APCs, naive T cells become activated and are mobilized to areas containing antigen, which allows for body-wide antigen targeting via the reticuloendothelial system [19,20]. Antigen spread, or antigenic cascade, is another important feature broadening the 8
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immune response to additional antigens on a pathogen or tumor through a process that can activate additional T cells specific to these other antigens [21]. A specific example with related immunotherapy for antigen spread will be further discussed. Finally, memory refers to the ability of the immune system to remember an antigen to which it has previously been exposed, resulting in a repeat and enhanced response. Immunization against smallpox serves as a good example of this characteristic, where 100% of patients maintain a T-cell immune response to smallpox 20-30 years after vaccination, approximately 90% of patients maintain the response after 31-50 years, and more than 50% of patients maintain the response 51-75 years after having received the initial immunization [22]. In summary, these characteristics allow the immune system to effectively target a specific antigen, broaden the immune response to additional antigens, and confer an optimized and long-lasting response [1].
Cancer Immunotherapy Landscape Attempts to treat different types of cancers by stimulating immune responses to
attack cancer cells have been tried for more than a century, but only recently has immunotherapy regained clinical attention with approvals of multiple agents for the treatment of cancer [10,23]. Briefly, Coley developed the first cancer vaccine (based on bacterial toxins) in 1890,
which was shown to have benefit in patients with inoperable cancer, and this initiated interest in the study of cancer immunotherapy. In the 1970s, instillation of bacille Calmette-Guerin (BCG) was found to be an effective form of immunotherapy to treat 9
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bladder cancer and has been considered as one of the milestones of cancer immunotherapy. However, the clinical benefit or promise of cancer immunotherapy did not reach initial expectations. Subsequently, in the late 1990s, there was a resurgence of interest in cancer immunotherapy as a viable treatment option with a number of therapeutic advances in cancer immunotherapy that has resulted in important drug approvals. These approvals include the first monoclonal antibody rituximab in 1997, the first cellular immunotherapy sipuleucel-T in 2010, and the first checkpoint inhibitor ipilimumab in 2011 [10,23]. Immunotherapy, as defined by the National Cancer Institute, refers to any treatment
that boosts or restores the ability of the immune system to fight cancer, infections, and the other diseases [24]. In order to be effective, immunotherapies need to increase the quality or quantity of immune effector cells, expose additional protective tumor antigens (ie, antigen spread), and/or inhibit cancer-induced immunosuppressive mechanisms [15]. While different cancer immunotherapies, such as cytokines, monoclonal antibodies, checkpoint inhibitors, and therapeutic cancer vaccines, have different mechanisms of action, they all are designed to boost or restore the ability of the immune system to thwart cancer progression [25].
Cytokines Cytokines are proteins that are naturally secreted by immune system cells
(eg, T cells) to mediate inflammatory and immune reactions in the body [1]. Examples of immunotherapies that belong to this category are interleukins (ILs) and IFNs. Specifically, IFN-was the first exogenous cytokine to demonstrate antitumor activity in
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advanced melanoma and IL-2 therapy can induce objective tumor regressions in patients with metastatic renal cell cancer and melanoma [10]. There are multiple mechanisms by which cytokines activate the immune system. IL-2, for example, exerts its effects by binding to its receptor on the surface of T cells and ultimately stimulating their proliferation. This upregulation of T cells allows for a widespread and non-specific response [26]. Evidence shows IL-2 therapy can lead to a complete response in four to six percent of patients with metastatic renal cell carcinoma and the response can potentially be durable. This suggests that for this group of patients, IL-2 therapy is able to successfully manipulate the patient’s own antitumor immune response [27]. Different from other types of immunotherapies, cytokines can produce a wide range of nonspecific effects that may be associated with certain adverse events [28,29].
Monoclonal Antibodies Monoclonal antibodies work in cancer via several different mechanisms of action,
which generally involve binding to a specific target antigen and thereby induce cell death. Some of the mechanisms include blocking signaling pathways needed for tumor cell growth, triggering an immune-mediated cytotoxic response (eg, antigen-dependent cellular cytotoxicity), and blocking angiogenesis [10]. For example, trastuzumab, by specifically targeting extracellular domain of EGFR2 protein (HER2) and mediating antibody-dependent cellular cytotoxicity (ADCC), significantly improved survival with first-line chemotherapy in HER2 overexpressing metastatic breast cancer patients (Figure 3a) [30]. In addition to ADCC by specifically targeting EGFR, cetuximab, used in metastatic colorectal and metastatic squamous cell cancers of the head and neck, was shown to induce another key feature of immune response against cancer, which is 11 This article is protected by copyright. All rights reserved.
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antigen spreading [31]. Study results supported the mechanism that cetuximab can induce tumor antigen spreading and subsequent T-cell activation through cross talk among immune cells including NK cells and DCs (which function as APCs) [32]. Illustrated in Figure 4, cetuximab binds to EGFR on the tumor cell surface and NK cells through a different region of the monoclonal antibody, activates NK cells leading to the lysis of tumor cells, presents additional tumor antigenic materials to the immature DC, and then enhances DC maturation and cross-presentation to T cells resulting in additional tumor antigen-specific T-cell activation and expansion [31]. This process allows the immune system to broaden and adapt to subsequent mutations [21].
Checkpoint Inhibitors The immune system depends on multiple checkpoints or “immunological brakes” to
avoid overproducing immune cells, such as T cells, which could otherwise damage healthy tissue. Tumor cells can take advantage of these checkpoints to escape
detection by the immune system. CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and PD-1 (programmed death 1) are both checkpoints that have been studied as targets for cancer therapy. CTLA-4 has been shown to be upregulated and present on the surface of T cells in certain cancers, dampening T-cell activation in response to tumor cells. PD-1 is another immunologic checkpoint that has been found to be upregulated in certain tumors; it inhibits T-cell function contributing to the tumor’s ability to evade the immune system. Inhibiting a checkpoint (ie, “releasing the brakes”) on the immune system may enhance the anti-tumor T-cell response [33,34]. Immunological checkpoint inhibitors, eg, antibodies against CTLA-4 (ipilimumab) and PD1 (nivolumab), have been explored in clinical trials and have shown efficacy against different types of 12 This article is protected by copyright. All rights reserved.
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cancers [10]. In the pivotal phase 3 study, ipilimumab showed a significant survival benefit in patients with metastatic melanoma and was subsequently approved in 2011as the first checkpoint inhibitor to treat melanoma (Figure 3b) [12,35]. Currently, ipilimumab and nivolumab are being investigated in clinical trials to treat prostate cancer [36].
Therapeutic Cancer Vaccines It is important to recognize the difference between a therapeutic vaccine and a
preventive vaccine such as the measles-mumps-rubella vaccine or flu vaccine. The primary goal of a therapeutic cancer vaccine is not to prevent disease but to target the immune system to help initiate or enhance an active immune response against an existing cancer. Specifically, the mechanism of action for therapeutic cancer vaccines involves activating the immune system with targeted T cells to seek out and destroy target cancer cells [19]. Therapeutic cancer vaccines have been shown to improve overall survival in patients with prostate cancer [37,38]. Sipuleucel-T, an autologous cellular immunotherapy, extended mean overall survival by 4.1 months in patients with metastatic castrate resistant prostate cancer (Figure 3c) and was approved in 2010 as the first cellular immunotherapy for prostate cancer treatment [11,37]. Sipuleucel-T is designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. During ex vivo culture with PAPGM-CSF [PAP-granulocyte-macrophage colony-stimulating factor], APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface. Once infused back to patients, these activated APCs can interact with T cells and initiate downstream immune responses, as described earlier [11,37]. In clinical studies, antibody responses against PAP-GM-CSF and PAP antigen alone as 13 This article is protected by copyright. All rights reserved.
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well as T cell proliferative response were observed through the follow-up period in patients receiving sipuleucel-T. Clinical significance of the observed immune responses remains to be determined [11]. Therapeutic prostate-specific antigen (PSA)–targeted poxviral vaccines
(PROSTVAC) are currently under investigation for the treatment of prostate cancer [19]. Significantly improved overall survival was observed in a phase 2 study (Figure 3d) [38]. PROSTVAC immunotherapy is a promising approach and is currently being evaluated in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer in a larger pivotal phase 3 trial (PROSPECT) [39]. There are several important characteristics of therapeutic cancer vaccines, which
may make this newer type of immunotherapy an attractive treatment option. First, therapeutic vaccines directly target the immune system, which subsequently expands the immune system’s attack on tumor cells. Second, because the immune response is generated overtime, the observed effect of therapeutic vaccines is not immediate. Furthermore, by engaging the immune system, therapeutic vaccines may create immunologic memory that can extend protection beyond the immediate treatment period. Finally, because the immune response may evolve over time, a broadening of the immune response may be observed such that while the immune system continues to attack the original tumor target, it might also evolve to attack additional tumor-specific antigens (antigen spread) [21].
Clinical Considerations and the State of Immunotherapy 14
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Compatibility of Immunotherapy Approach Certain cancers may be more well-suited for immunotherapy than others; prostate
cancer represents an example of a cancer type that is compatible with this approach [40]. It is often detected early and has a slower progression. In addition, this cancer expresses a number of specific tumor-associated antigens against which immunotherapies may be targeted (eg, PSA, prostate-specific membrane antigen [PSMA], prostate stem cell antigen [PSCA], PAP, and mucin-1 [MUC-1]) [40].
Response Kinetics Immunotherapeutic mechanisms of action are different from traditional cancer
treatments; therefore, the response to immunotherapy may not be ideally measured with traditional clinical metrics. Immunotherapy is associated with a delayed but durable response that differs from the rapid, transient response of traditional chemotherapy (Figure 5a) [41]. The differing immunotherapy response kinetics suggested that biomarkers used to monitor the effects of traditional therapies may not always be appropriate. For example, lack of correlation between overall survival and progressionfree survival has been observed for certain immunotherapies [35,37]. In addition, studies have shown that immunotherapy, in particular therapeutic cancer vaccines, may be more efficacious in patients when administered earlier during the disease course, correlative with lower tumor burden and a more intact immune system capable of responding to an exogenous immunotherapy (Figure 5b) [42]. Therefore, future use and clinical trials should take into consideration that immunotherapies may elicit a better
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immune system response if used while the patient is still immunocompetent with relatively early stage disease.
Potential for Combination Therapy Since immunotherapy offers a different mechanistic approach than traditional
treatments, there is potential for synergy with other traditional treatments, such as chemotherapy, radiation, and hormonal therapy (eg, androgen ablation). The combination of different treatment modalities holds significant potential to improve treatment outcomes. Indeed, synergy between chemotherapeutic agents and CTLA-4 blockade was shown in preclinical tumor models and warranted future investigations to determine which specific chemo-immunotherapy combinations can provide synergistic effects in a clinical setting [43]. In addition, preclinical studies demonstrated that radiation therapy can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of radiation therapy [44]. Finally, it is also reasonable to combine two types of immunotherapy based on complementary mechanisms of action. However, clinical evidence for this approach awaits further clinical trial validation [25].
Discussion and Conclusion The immune system has an important role in cancer pathophysiology. Key features
of an effective immune response include specificity, trafficking, antigen spread, and durability (memory). Over time, cancer cells develop mechanisms to escape control by
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the immune system, leading to disease progression. Immunotherapy is designed to boost or restore the ability of the immune system to combat cancer progression. Immunotherapy oftentimes elicits a delayed response for traditional tumor kinetics
with respect to many approved cancer treatment modalities, but can increase survival in certain cancers. Immunotherapies may elicit a better immune system response if implemented while the patient has a reasonable degree of immunocompetence, usually consistent with lower tumor burden. In addition, immunotherapy can offer the potential for durable clinical effects and synergy with combination or subsequent therapies. In summary, immunotherapy is an established treatment modality for multiple
oncologic diseases, spanning numerous solid tumors and hematologic malignancies. Immunotherapeutic approaches are a mainstay of therapy for several cancer therapies. The future of additional immunotherapeutic approaches is highly promising, as numerous cancer immunotherapies are currently in advanced phases of clinical development.
Conflict of Interest Research/Consultant: Sanofi, Millennium, Bavarian Nordic, Dendreon, Pfizer, Amgen, Astellas, Medivation, Janssen, Algeta, Bayer
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Accepted Article FIGURES
FIGURE 1. Process of cellular immune response.
FIGURE 2. The cancer immunoediting process: elimination, equilibrium, and escape.
FIGURE 3. Overall survival curve for different immunotherapies. (a) Trastuzumab (b) Ipilimumab. (c) Sipuleucel-T. (d) ProstVAC. [Figures reproduced from references 30, 35, 37, and 38.]
FIGURE 4. NK-DC cross talk induced by therapeutic monoclonal antibody promotes tumor antigen cross-presentation and T-cell priming. Antibodies bind to tumor cells; NK cells recognize the antibody and become activated. This results in tumor cell death that exposes additional tumor antigen fragments. DCs process and present these additional tumor antigens to T cells promoting further T-cell activation.
FIGURE 5. The theoretical relationship between type of cancer therapies or initiation of immunotherapy and outcomes. (a) Differential effects of immunotherapy vs chemotherapy. (b) Differential effects of earlier vs later initiation of immunotherapy. [Figures reproduced from references 41 and 42.]
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Title: Advances in the understanding of cancer immunotherapy1 [Target Journal: BJUI]
Author: Neal D. Shore, MD, FACS
Author affiliation: Carolina Urologic Research Center/Atlantic Urology Clinics, Myrtle Beach, SC, USA Phone: 843-449-1010 Fax: 843-497-6171 E-mail: [email protected]
Abstract word count: 181 words
Manuscript word count: 3569 words
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bju.12692
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Abstract The principal role of the immune system is to prevent and eradicate pathogens and infections. Key characteristics or features of an effective immune response include specificity, trafficking, antigen spread, and durability (memory).
The immune system is recognized to have a critical role in controlling cancer through a dynamic relationship with tumor cells. Normally at early stages of tumor development, the immune system is capable of eliminating tumor cells or keeping tumor growth abated. However, tumor cells may evolve multiple pathways over time to evade immune control.
Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections, and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumor burden, whereby disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve.
Because immunotherapies may have a different mechanism of action than traditional cytotoxic or targeted biologic agents, immunotherapy modalities have the potential to combine synergistically with traditional therapies.
Keywords: cancer, immunotherapy, immunoediting, cytokine, monoclonal antibody, checkpoint inhibitor, therapeutic cancer vaccine
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Introduction The role of the immune system in cancer pathogenesis has been confirmed by
numerous preclinical studies and clinical trials. Recent advances in therapies that engage the immune system have been shown to improve patient survival and have led to approvals of immunotherapeutic agents to treat different tumor types, including urologic cancers. Therefore, it is timely for practicing clinicians to review the current state of
understanding of the immune system and the role it plays in cancer therapy. This review provides an overview of how the immune system functions, presents evidence for the immune system’s role in cancer, describes several classes of immunotherapeutic modalities, such as cytokines, checkpoint inhibitors, therapeutic vaccines, and monoclonal antibodies, which are being investigated and/or utilized in practice, and summarizes clinical considerations for the current state of immunotherapy for the practicing clinician to optimize the care of patients with cancer.
Overview of the Immune System Function The physiologic and principal role of the immune system is to protect individuals
against foreign pathogens and infections. The immune system is complex and relies upon many interrelated components to target foreign pathogens in order to effectively prevent and eradicate foreign microbes [1]. The initial innate (non-specific) immune 3 This article is protected by copyright. All rights reserved.
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defenses are epithelial barriers, such as the skin, that prevent entry of microbes and contain specialized cells, which thwart microbial proliferation. When microbes breach these epithelial barriers, other non-specific defenses are enlisted. Specific pattern recognition receptors, such as toll-like receptors (TLRs), recognize foreign pathogens and then initiate a rapid, generalized attack using phagocytes, natural killer (NK) cells, and inflammatory mediators to destroy infected cells [2]. If the infectious pathogens overwhelm the innate immune defenses, this can prompt
initiation of an adaptive immune response—a targeted response utilizing specialized defenses that can develop memory and use specialized cells to specifically eliminate these pathogens [1,2]. Vaccination is a classic example of how the adaptive immune
system recognizes foreign microbes to which it has been previously exposed and mounts a specific attack to prevent infection [1,2]. The specialized immune responses comprise two generalized types of immunity,
cellular immunity and humoral immunity, which are mediated by lymphocytes (eg, T cells and B cells) and their products (eg, antibodies). These responses are designed to eliminate pathogens at different locations (intracellular vs extracellular) and in different types of molecules, including proteins, carbohydrates, and lipids [1]. As illustrated in Figure 1, cellular immunity eradicates intracellular microbes through the following sequential phases: antigen recognition, antigen presenting cell (APC) activation, T-cell interaction and activation, proliferation and differentiation into effector cells, which can activate other immune cells and eradicate cells containing the antigen; also, memory T cells, which can respond quickly if the antigen is re-encountered, may too be initiated [1].
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Humoral immunity neutralizes and eradicates extracellular microbes and toxins through antibodies produced by B lymphocytes [1]. The innate immune system plays an important role in activation of the adaptive
immune system. Innate immune system cells release signals, such as cytokines, that are essential to stimulate the responses of T cells and B cells. APCs, such as dendritic cells (DCs), serve as a bridge between the innate and adaptive immune system by processing foreign antigen and presenting it to naive T cells, a step which is necessary for their activation and response. Further, when TLRs on DCs are activated, it can increase expression of factors (eg, major histocompatibility complex [MHC] class II, CD40) on the DC surface required for antigen presentation as well as promote secretion of cytokines that facilitate the adaptive immune response [2]. It is important to note that the immune system can also recognize cancer cells or
tumor antigens as foreign substances and initiate immune response against neoplastic cells [1].
Immune System’s Role in Cancer Clinical evidence for the immune system’s role in cancer pathogenesis includes the
observed relationship between immunosuppression and an increased risk of developing cancers in many study populations as well as the finding that when immune cells infiltrate tumors, overall survival may be improved. For example, it has been demonstrated that patients who undergo organ transplantation and receive immunosuppressant medications to prevent rejection have an increased risk, ranging 5 This article is protected by copyright. All rights reserved.
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from two-fold to over 20-fold, of developing a wide variety of cancers [3,4]. Based on data from a UK transplant registry, the 10-year incidence of de novo cancer in transplant recipients is twice that of the general population [5]. In addition, approximately 40% of patients with AIDS develop cancer during their lifetime [6]. On the other hand, T-cell infiltration within tumors was found to be associated with improved overall survival in patients with various cancers [7–9]. The suggestion that inflammatory
response may be correlated with cytokine release and possible T reg suppression (eg, suppression of cells that curb activation of the immune system and prevent selfreactivity) continues to be explored. Additional evidence for the involvement of the immune system affecting cancer
disease progression is that therapies which engage the immune system have been shown to improve patient survival in clinical trials, thus leading to approvals of immunotherapeutic agents to treat cancer in clinical practice. As an example, interferon (IFN) has been studied over the past several decades and is approved for use in a number of clinical applications, including melanoma, renal cell carcinoma, AIDS-related Kaposi’s sarcoma, follicular lymphoma, hairy cell leukemia, chronic myelogenous leukemia among others [10]. More recent examples include approval of sipuleucel-T in 2010 as the first cellular immunotherapy for prostate cancer treatment [11] and ipilimumab in 2011 as the first checkpoint inhibitor to treat melanoma [12]. Taken together, these data support the important role of the immune system in controlling cancer progression. Evading the immune system is one of the mechanisms that allows cancers to grow and spread and is considered to be one of the hallmarks of cancer pathogenesis [13].
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Cancer and the Immune System: A Dynamic Relationship Immunoediting Process The immune system regulates tumor growth through a dynamic process, in which it
can either block tumor growth, development, and survival or may promote tumor progression [14,15]. As shown in Figure 2, there are three stages of the dynamic process of immunoediting, also known as the three E’s: elimination, equilibrium, and escape. In the elimination phase, cancer cells are identified and destroyed long before they become clinically apparent (ie, immune protection) and the host remains free of cancer. If a cancer cell variant is not destroyed, the tumor may enter the equilibrium phase, in which cancer cells persist but outgrowth is prevented by the immune system. This stage is thought to be the longest of the three stages and may last for many years or even the lifetime of the host. During the escape phase, outgrowth of cancer cells is no longer controlled (or even being selected/shaped into a less immunogenic state) by the immune system, leading to clinically apparent and progressive disease (ie, immune evasion). While many of the immune cells and molecules that participate in different stages of this process have been identified, more studies are needed to determine their exact mechanism and sequence of action [15]. It is established that NK cells, cytokines, antigen presenting DCs, and T cells play
important roles in the anti-tumor response. NK cells are a first line of defense against cancer cells with the ability to rapidly identify and eliminate such cells. These cells possess the ability to recognize self and non-self through expression of killer inhibitory 7
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receptors (KIRs). KIRs interact with self-markers (eg, MHC Class I) on healthy cells, and when cells become stressed and lose those markers, this contributes to activation of NK cells [16,17]. Cytokines contribute to the anti-tumor immune response in a variety of ways; they stimulate inflammation and boost the activation of other immune cells. For example, IL-2 can stimulate activation of NK cells, which in turn release INF-alpha and other cytokines that enhance activation of DCs and T cells [16,17]. DCs process and present antigens associated with tumors to T cells; this activates T cells to tumorassociated antigen and initiates a targeted anti-tumor response [2,16]. However, because cancer is an immunoevasive disease, adaptations that occur in the tumor microenvironment can blunt the immune response and contribute to cancer progression [14].
Features 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 or tumors, including specificity, trafficking, antigen spread, and durability (memory) [1]. Specificity ensures that distinct antigens induce specific responses. For example, following annual vaccination against flu virus, the immune system can selectively identify surface antigens of the annual strain and induce a specific attack [1,18]. Trafficking refers to the ability of activated immune cells to migrate to particular antigens throughout the body. T-cell mediated immunity is an example of trafficking. Following exposure to activated APCs, naive T cells become activated and are mobilized to areas containing antigen, which allows for body-wide antigen targeting via the reticuloendothelial system [19,20]. Antigen spread, or antigenic cascade, is another important feature broadening the 8
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immune response to additional antigens on a pathogen or tumor through a process that can activate additional T cells specific to these other antigens [21]. A specific example with related immunotherapy for antigen spread will be further discussed. Finally, memory refers to the ability of the immune system to remember an antigen to which it has previously been exposed, resulting in a repeat and enhanced response. Immunization against smallpox serves as a good example of this characteristic, where 100% of patients maintain a T-cell immune response to smallpox 20-30 years after vaccination, approximately 90% of patients maintain the response after 31-50 years, and more than 50% of patients maintain the response 51-75 years after having received the initial immunization [22]. In summary, these characteristics allow the immune system to effectively target a specific antigen, broaden the immune response to additional antigens, and confer an optimized and long-lasting response [1].
Cancer Immunotherapy Landscape Attempts to treat different types of cancers by stimulating immune responses to
attack cancer cells have been tried for more than a century, but only recently has immunotherapy regained clinical attention with approvals of multiple agents for the treatment of cancer [10,23]. Briefly, Coley developed the first cancer vaccine (based on bacterial toxins) in 1890,
which was shown to have benefit in patients with inoperable cancer, and this initiated interest in the study of cancer immunotherapy. In the 1970s, instillation of bacille Calmette-Guerin (BCG) was found to be an effective form of immunotherapy to treat 9
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bladder cancer and has been considered as one of the milestones of cancer immunotherapy. However, the clinical benefit or promise of cancer immunotherapy did not reach initial expectations. Subsequently, in the late 1990s, there was a resurgence of interest in cancer immunotherapy as a viable treatment option with a number of therapeutic advances in cancer immunotherapy that has resulted in important drug approvals. These approvals include the first monoclonal antibody rituximab in 1997, the first cellular immunotherapy sipuleucel-T in 2010, and the first checkpoint inhibitor ipilimumab in 2011 [10,23]. Immunotherapy, as defined by the National Cancer Institute, refers to any treatment
that boosts or restores the ability of the immune system to fight cancer, infections, and the other diseases [24]. In order to be effective, immunotherapies need to increase the quality or quantity of immune effector cells, expose additional protective tumor antigens (ie, antigen spread), and/or inhibit cancer-induced immunosuppressive mechanisms [15]. While different cancer immunotherapies, such as cytokines, monoclonal antibodies, checkpoint inhibitors, and therapeutic cancer vaccines, have different mechanisms of action, they all are designed to boost or restore the ability of the immune system to thwart cancer progression [25].
Cytokines Cytokines are proteins that are naturally secreted by immune system cells
(eg, T cells) to mediate inflammatory and immune reactions in the body [1]. Examples of immunotherapies that belong to this category are interleukins (ILs) and IFNs. Specifically, IFN-was the first exogenous cytokine to demonstrate antitumor activity in
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advanced melanoma and IL-2 therapy can induce objective tumor regressions in patients with metastatic renal cell cancer and melanoma [10]. There are multiple mechanisms by which cytokines activate the immune system. IL-2, for example, exerts its effects by binding to its receptor on the surface of T cells and ultimately stimulating their proliferation. This upregulation of T cells allows for a widespread and non-specific response [26]. Evidence shows IL-2 therapy can lead to a complete response in four to six percent of patients with metastatic renal cell carcinoma and the response can potentially be durable. This suggests that for this group of patients, IL-2 therapy is able to successfully manipulate the patient’s own antitumor immune response [27]. Different from other types of immunotherapies, cytokines can produce a wide range of nonspecific effects that may be associated with certain adverse events [28,29].
Monoclonal Antibodies Monoclonal antibodies work in cancer via several different mechanisms of action,
which generally involve binding to a specific target antigen and thereby induce cell death. Some of the mechanisms include blocking signaling pathways needed for tumor cell growth, triggering an immune-mediated cytotoxic response (eg, antigen-dependent cellular cytotoxicity), and blocking angiogenesis [10]. For example, trastuzumab, by specifically targeting extracellular domain of EGFR2 protein (HER2) and mediating antibody-dependent cellular cytotoxicity (ADCC), significantly improved survival with first-line chemotherapy in HER2 overexpressing metastatic breast cancer patients (Figure 3a) [30]. In addition to ADCC by specifically targeting EGFR, cetuximab, used in metastatic colorectal and metastatic squamous cell cancers of the head and neck, was shown to induce another key feature of immune response against cancer, which is 11 This article is protected by copyright. All rights reserved.
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antigen spreading [31]. Study results supported the mechanism that cetuximab can induce tumor antigen spreading and subsequent T-cell activation through cross talk among immune cells including NK cells and DCs (which function as APCs) [32]. Illustrated in Figure 4, cetuximab binds to EGFR on the tumor cell surface and NK cells through a different region of the monoclonal antibody, activates NK cells leading to the lysis of tumor cells, presents additional tumor antigenic materials to the immature DC, and then enhances DC maturation and cross-presentation to T cells resulting in additional tumor antigen-specific T-cell activation and expansion [31]. This process allows the immune system to broaden and adapt to subsequent mutations [21].
Checkpoint Inhibitors The immune system depends on multiple checkpoints or “immunological brakes” to
avoid overproducing immune cells, such as T cells, which could otherwise damage healthy tissue. Tumor cells can take advantage of these checkpoints to escape
detection by the immune system. CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and PD-1 (programmed death 1) are both checkpoints that have been studied as targets for cancer therapy. CTLA-4 has been shown to be upregulated and present on the surface of T cells in certain cancers, dampening T-cell activation in response to tumor cells. PD-1 is another immunologic checkpoint that has been found to be upregulated in certain tumors; it inhibits T-cell function contributing to the tumor’s ability to evade the immune system. Inhibiting a checkpoint (ie, “releasing the brakes”) on the immune system may enhance the anti-tumor T-cell response [33,34]. Immunological checkpoint inhibitors, eg, antibodies against CTLA-4 (ipilimumab) and PD1 (nivolumab), have been explored in clinical trials and have shown efficacy against different types of 12 This article is protected by copyright. All rights reserved.
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cancers [10]. In the pivotal phase 3 study, ipilimumab showed a significant survival benefit in patients with metastatic melanoma and was subsequently approved in 2011as the first checkpoint inhibitor to treat melanoma (Figure 3b) [12,35]. Currently, ipilimumab and nivolumab are being investigated in clinical trials to treat prostate cancer [36].
Therapeutic Cancer Vaccines It is important to recognize the difference between a therapeutic vaccine and a
preventive vaccine such as the measles-mumps-rubella vaccine or flu vaccine. The primary goal of a therapeutic cancer vaccine is not to prevent disease but to target the immune system to help initiate or enhance an active immune response against an existing cancer. Specifically, the mechanism of action for therapeutic cancer vaccines involves activating the immune system with targeted T cells to seek out and destroy target cancer cells [19]. Therapeutic cancer vaccines have been shown to improve overall survival in patients with prostate cancer [37,38]. Sipuleucel-T, an autologous cellular immunotherapy, extended mean overall survival by 4.1 months in patients with metastatic castrate resistant prostate cancer (Figure 3c) and was approved in 2010 as the first cellular immunotherapy for prostate cancer treatment [11,37]. Sipuleucel-T is designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. During ex vivo culture with PAPGM-CSF [PAP-granulocyte-macrophage colony-stimulating factor], APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface. Once infused back to patients, these activated APCs can interact with T cells and initiate downstream immune responses, as described earlier [11,37]. In clinical studies, antibody responses against PAP-GM-CSF and PAP antigen alone as 13 This article is protected by copyright. All rights reserved.
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well as T cell proliferative response were observed through the follow-up period in patients receiving sipuleucel-T. Clinical significance of the observed immune responses remains to be determined [11]. Therapeutic prostate-specific antigen (PSA)–targeted poxviral vaccines
(PROSTVAC) are currently under investigation for the treatment of prostate cancer [19]. Significantly improved overall survival was observed in a phase 2 study (Figure 3d) [38]. PROSTVAC immunotherapy is a promising approach and is currently being evaluated in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer in a larger pivotal phase 3 trial (PROSPECT) [39]. There are several important characteristics of therapeutic cancer vaccines, which
may make this newer type of immunotherapy an attractive treatment option. First, therapeutic vaccines directly target the immune system, which subsequently expands the immune system’s attack on tumor cells. Second, because the immune response is generated overtime, the observed effect of therapeutic vaccines is not immediate. Furthermore, by engaging the immune system, therapeutic vaccines may create immunologic memory that can extend protection beyond the immediate treatment period. Finally, because the immune response may evolve over time, a broadening of the immune response may be observed such that while the immune system continues to attack the original tumor target, it might also evolve to attack additional tumor-specific antigens (antigen spread) [21].
Clinical Considerations and the State of Immunotherapy 14
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Compatibility of Immunotherapy Approach Certain cancers may be more well-suited for immunotherapy than others; prostate
cancer represents an example of a cancer type that is compatible with this approach [40]. It is often detected early and has a slower progression. In addition, this cancer expresses a number of specific tumor-associated antigens against which immunotherapies may be targeted (eg, PSA, prostate-specific membrane antigen [PSMA], prostate stem cell antigen [PSCA], PAP, and mucin-1 [MUC-1]) [40].
Response Kinetics Immunotherapeutic mechanisms of action are different from traditional cancer
treatments; therefore, the response to immunotherapy may not be ideally measured with traditional clinical metrics. Immunotherapy is associated with a delayed but durable response that differs from the rapid, transient response of traditional chemotherapy (Figure 5a) [41]. The differing immunotherapy response kinetics suggested that biomarkers used to monitor the effects of traditional therapies may not always be appropriate. For example, lack of correlation between overall survival and progressionfree survival has been observed for certain immunotherapies [35,37]. In addition, studies have shown that immunotherapy, in particular therapeutic cancer vaccines, may be more efficacious in patients when administered earlier during the disease course, correlative with lower tumor burden and a more intact immune system capable of responding to an exogenous immunotherapy (Figure 5b) [42]. Therefore, future use and clinical trials should take into consideration that immunotherapies may elicit a better
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immune system response if used while the patient is still immunocompetent with relatively early stage disease.
Potential for Combination Therapy Since immunotherapy offers a different mechanistic approach than traditional
treatments, there is potential for synergy with other traditional treatments, such as chemotherapy, radiation, and hormonal therapy (eg, androgen ablation). The combination of different treatment modalities holds significant potential to improve treatment outcomes. Indeed, synergy between chemotherapeutic agents and CTLA-4 blockade was shown in preclinical tumor models and warranted future investigations to determine which specific chemo-immunotherapy combinations can provide synergistic effects in a clinical setting [43]. In addition, preclinical studies demonstrated that radiation therapy can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of radiation therapy [44]. Finally, it is also reasonable to combine two types of immunotherapy based on complementary mechanisms of action. However, clinical evidence for this approach awaits further clinical trial validation [25].
Discussion and Conclusion The immune system has an important role in cancer pathophysiology. Key features
of an effective immune response include specificity, trafficking, antigen spread, and durability (memory). Over time, cancer cells develop mechanisms to escape control by
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the immune system, leading to disease progression. Immunotherapy is designed to boost or restore the ability of the immune system to combat cancer progression. Immunotherapy oftentimes elicits a delayed response for traditional tumor kinetics
with respect to many approved cancer treatment modalities, but can increase survival in certain cancers. Immunotherapies may elicit a better immune system response if implemented while the patient has a reasonable degree of immunocompetence, usually consistent with lower tumor burden. In addition, immunotherapy can offer the potential for durable clinical effects and synergy with combination or subsequent therapies. In summary, immunotherapy is an established treatment modality for multiple
oncologic diseases, spanning numerous solid tumors and hematologic malignancies. Immunotherapeutic approaches are a mainstay of therapy for several cancer therapies. The future of additional immunotherapeutic approaches is highly promising, as numerous cancer immunotherapies are currently in advanced phases of clinical development.
Conflict of Interest Research/Consultant: Sanofi, Millennium, Bavarian Nordic, Dendreon, Pfizer, Amgen, Astellas, Medivation, Janssen, Algeta, Bayer
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FIGURE 1. Process of cellular immune response.
FIGURE 2. The cancer immunoediting process: elimination, equilibrium, and escape.
FIGURE 3. Overall survival curve for different immunotherapies. (a) Trastuzumab (b) Ipilimumab. (c) Sipuleucel-T. (d) ProstVAC. [Figures reproduced from references 30, 35, 37, and 38.]
FIGURE 4. NK-DC cross talk induced by therapeutic monoclonal antibody promotes tumor antigen cross-presentation and T-cell priming. Antibodies bind to tumor cells; NK cells recognize the antibody and become activated. This results in tumor cell death that exposes additional tumor antigen fragments. DCs process and present these additional tumor antigens to T cells promoting further T-cell activation.
FIGURE 5. The theoretical relationship between type of cancer therapies or initiation of immunotherapy and outcomes. (a) Differential effects of immunotherapy vs chemotherapy. (b) Differential effects of earlier vs later initiation of immunotherapy. [Figures reproduced from references 41 and 42.]
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