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Immunotherapy for prostate cancer: concepts and practice Jacques Banchereau Jackson Laboratory for Genomic Medicine, Farmington, CT, USA Bertrand Tombal Service d’Urologie, Cliniques universitaires Saint-Luc, Brussels, Belgium Karim Fizazi Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France Disclosures Dr Banchereau has acted as a consultant for Dendreon; Prof Tombal has been an advisor for Dendreon; Dr Fizazi has participated in advisory boards and as a speaker for Dendreon and Bristol Meyers Squibb.

Introduction Recent developments are elucidating the central role of the immune system in controlling the proliferation of cancer cells. This has resulted in the development of a plethora of immune‑mediated anticancer therapies, some of which are now established components within the oncology armamentarium. In 2010, the US Food and Drug Administration (FDA) approved sipuleucel-T, the first immunotherapy for the treatment of advanced prostate cancer (also currently under review by the European Medicines Agency [EMA]). A number of other immunotherapeutics for prostate cancer are under development. This article summarizes current knowledge of antitumor immune responses, data on current and emerging immunotherapies in prostate cancer, and considerations for their use.

The role of the immune system in cancer protection It is now recognized that the immune system is key in controlling cancer, and can play both host‑protective and tumor-promoting roles [1,2]. Immune responses can suppress tumor growth by destroying or inhibiting cancer cells, and the presence of immune cells within tumors can be

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Figure 1. Kaplan-Meier curve for overall survival (OS) in advanced ovarian cancer according to the presence or absence of T cells within tumors (adapted from [3]).

associated with better outcomes (Figure 1) [3,4]. In fact, evasion of immune destruction has become recognized as a hallmark of cancer pathogenesis [5]. This concept is supported by the increased incidence of malignant tumors in immunocompromised individuals. In transplant patients, this increased risk versus the general population ranges from a 2-fold higher incidence of lung and colon cancer to a 20-fold or more increased incidence of non-melanoma skin cancer, non-Hodgkin’s lymphoma and Kaposi’s sarcoma [6]. Similarly, in patients with acquired immunodeficiency syndrome (AIDS), the risk of Kaposi’s sarcoma and non-Hodgkin’s lymphoma increases with increasing levels of immunosuppression [7]. However, immune cells may also promote tumor progression [4], either by applying ‘selective pressure’ that encourages the growth of more pathogenic tumor cells or by establishing conditions within the tumor micro-environment that facilitate cell proliferation [1,2]. The generation of an immune response is a dynamic process that requires several sequential steps, starting with the engagement of antigen-presenting cells (APCs). APCs process and present tumor antigens and, once activated themselves, can activate tumor antigen-specific T cells to proliferate and target tumor tissue [8]. The fundamental characteristics of an antitumor immune response are: specificity (targets tumor tissue, spares healthy tissue), adaptability (adapts to emergence of new tumor variants), focus (locates effect at tumor site), effectiveness (demonstrates antitumor cytotoxicity), and potential durability (immune memory maintains antitumor activity beyond initial challenge). Engagement of the immune system with immunotherapies offers the potential for the ideal anticancer therapy, combining many desirable therapeutic attributes into a single modality.

Current and emerging immunotherapies in prostate cancer Immunotherapy is defined as treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases [9]. Cancer immunotherapy is an established treatment strategy and examples of available immunotherapies include monoclonal antibodies against various targets  (e.g. cluster of differentiation  [CD] 20 [ibritumomab tiuxetan, ofatumumab, rituximab,

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tositumomab], CD52 [alemtuzumab], and cytotoxic T-lymphocyte antigen 4 [CTLA-4; ipilimumab]), cytokines (e.g.  interleukin [IL]-2, interferon  [IFN]-α), and active cellular immunotherapies (e.g. sipuleucel-T) [10,11]. Immunotherapies present several features that typically distinguish them from more traditional therapies, including a distinct mechanism of action, delayed kinetics, and the potential for increased long-term efficacy and durability. For example, unlike standard treatments, therapeutic cancer vaccines prime T cells to seek out and destroy target cancer cells [12]. Although immunotherapies can increase OS [10,13,14] the clinical effect shows delayed kinetics, therefore traditional measures may show subtle or absent objective responses. A significant effect on progression-free survival (PFS) may be absent, and Response Evaluation Criteria in Solid Tumors (RECIST) response criteria [15] may not be appropriate. As such, groups including the Association for Cancer Immunotherapy (CIMT) and the Cancer Immunotherapy Consortium (CIC) are involved in efforts to better report immunological outcomes through the Minimal Information About T cell Assays (MIATA) project. Since the clinical effect takes time to develop, early use should be considered when the patient is healthier and the disease burden is lower. The patient’s immune system may also be more intact and functional in earlierstage disease [16]. Finally, the beneficial effects of immunotherapies are potentially durable and may interact favorably with subsequent therapies once appropriate sequential and/or combination strategies have been developed. There are several current and emerging immunotherapies in prostate cancer, including PSA-tricom (PROSTVAC®, Bavarian Nordic), sipuleucel-T (PROVENGE®, Dendreon Corporation), and ipilimumab (YERVOY®, Bristol-Myers Squibb) (Table 1).

Table 1. Current and emerging immunotherapies in prostate cancer [13,14,17]. Agent

Description

Mechanism of action

PSA-tricom [13] (emerging in PCa)

Viral-based vaccine

Immunization with a vaccinia co-expressing PSA and immunostimulatory molecules. Boosted with a fowlpox expressing the same

Ipilimumab [17]* (emerging in PCa)

Monoclonal antibody that binds and blocks CTLA-4

Non-specifically inhibits immune suppression, augmenting ongoing immune responses

Sipuleucel-T [14]† (approved [USA] PCa)

Active cellular immunotherapy

Recombinant PAP-GM-CSF activates the patients immune cells ex vivo. Cells are then re-infused and stimulate PAP-specific immune response in vivo

*Approved in the EU & USA for the treatment of advanced melanoma in adults †

Approved in the USA for treatment of asymptomatic or minimally symptomatic patients with mCRPC

EU: European Union; GM-CSF: granulocyte-macrophage colony-stimulating factor; PAP: prostatic acid phosphatase; PCa: prostate cancer; PSA: prostate-specific antigen; USA: United States of America

PSA-tricom, an active viral vaccine-based approach (Table 1), has demonstrated promise in metastatic castrate-resistant prostate cancer (mCRPC). In a phase II study, patients with asymptomatic or minimally symptomatic mCRPC were randomized to receive PSA-tricom plus GM-CSF (N = 84) or placebo (N = 41) and were followed until disease progression [13]. There was an 8.5 month survival benefit with PSA-tricom versus placebo and a significant reduction in the risk of death (hazard ratio [HR]: 0.56; P = 0.0061), which was not accompanied by a PFS benefit (primary endpoint; Figure 2a). Phase III trials are ongoing in mCRPC.

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Figure 2. Efficacy of a) PSA-tricom in patients with mCRPC [13], b) sipuleucel-T in patients with mCRPC [14,18], c) and d) ipilimumab in melanoma [17]. CI: confidence interval; gp100: melanocyte peptide-derived vaccine against gp100; ipi: ipilimumab; mo: months; NS: not significant

Ipilimumab potentiates the antitumor immune response by non-specific inhibition of immune regulation via blockade of CTLA-4, which itself reduces immune responses. Ipilimumab is approved (EU and USA) for the treatment of malignant melanoma. In a phase III study of ipilimumab in patients with unresectable stage III or IV melanoma, participants were randomized to receive ipilimumab plus a melanocyte peptide-derived vaccine against gp100 (N = 403), ipilimumab alone (N = 137), or vaccine alone (N = 136) [17]. A significant OS benefit (primary endpoint) was seen with ipilimumab versus vaccine (3.6 month survival benefit; HR: 0.66; P < 0.001; Figure 2c). This was not accompanied by a benefit in median time to PFS, but did show a significant reduction in the risk of progression (19%; HR: 0.81; P < 0.05; Figure 2d). Ipilimumab is currently undergoing phase III trials in prostate cancer. Sipuleucel-T is an active cellular immunotherapy approved (by the FDA) for the treatment of asymptomatic or minimally symptomatic mCRPC. During treatment, the body’s own cells are primed to generate antitumor immune responses (Figure 3). First, the patient’s peripheral blood mononuclear cells (PBMCs) are isolated using leukapheresis, purified, and cultured with PA2024, a fusion protein of PAP and the APC-stimulator GM-CSF. The PA2024-cultured cells are then re-infused back into the patient. Sipuleucel-T is designed to generate antitumor immune responses through in-vivo engagement with T cells following re-infusion. Overall, 3 cycles of leukapheresis and re-infusion are performed at 2-week intervals. In a pivotal phase III study of sipuleucel-T, patients with mCRPC (N = 512) were randomized to receive sipuleucel-T or control and were followed until disease progression [14,18]. A 4.1 month survival benefit (primary endpoint) and a significant reduction in

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Figure 3. Proposed mechanism of action of sipuleucel-T. The precise mechanism of action is unknown.

risk of death (HR: 0.775; P = 0.032) were observed with sipuleucel-T versus control, but a PFS benefit was not seen (Figure 2b). Following FDA approval, sipuleucel-T is currently under review by the EMA. Overall, immunotherapy is an established cancer treatment modality that has been approved for use in several malignant conditions, including prostate cancer. In clinical trials, several different immunotherapies have demonstrated a significant effect on OS without a significant effect on PFS. This highlights the fact that immunotherapies generally demonstrate a time-lag in clinical response that may mask currently applied secondary measures of clinical outcome. Phase III trials are ongoing to study potential future immunotherapies across several different malignancies [19].

Treatment considerations for the use of immunotherapies in prostate cancer treatment Data correlating an immune mechanism of action with clinical outcomes The majority of data on immunological outcomes following immunotherapy for prostate cancer are with sipuleucel-T, which is the most advanced in terms of clinical development (approved by the FDA in 2010 and currently under review by the EMA). Data for sipuleucel-T suggest a link between immune responses and clinical outcomes. With sipuleucel-T, the patient’s own APCs are cultured in vitro with PAP-GM-CSF and form the active component of the sipuleucel-T product (Figure 3, upper part). Key product attributes include the total nucleated cell (TNC) count, the number of cells expressing the APC-specific marker CD54, and the degree of CD54 upregulation by APCs (a measure of APC activation during manufacture). Sipuleucel-T activates APCs, with greater activation noted at the week 2 and 4  infusions compared with week 0 (i.e. an immunological prime-boost effect). Importantly, correlation between OS and the key sipuleucel-T product parameters was noted in a

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Figure 4. Post-hoc correlation between OS and a) sipuleucel-T product parameters or b) immune responses against PAP or PA2024 (recombinant PAP-GM-CSF) [20]. These post-hoc analyses are intended for informative purposes only and have not been verified or approved by any regulatory agency as correlates of clinical outcome.

post-hoc analysis (Figure 4a). Furthermore, in-vivo immune responses, such as T cell and antibody responses, are generated following sipuleucel-T treatment (Figure 3, lower part) and correlate with OS (Figure 4b). A trend for enhanced survival in patients with greater T cell responses has also been reported with PSA-tricom [21]. The durability of T cell responses generated with sipuleucel-T were investigated in non-metastatic, androgen-dependent patients, and these were found to be long lasting [22]. Antigen-specific immune responses could be detected in patients after a median of 2 years (range 2â&#x20AC;&#x201C;5 years) following initial treatment with sipuleucel-T. These durable antitumor responses were subsequently boosted by administration of a further single sipuleucel-T infusion. Evidence also suggests that immune responses detected within the blood may translate to local immune activity in the tumor, since T cell infiltration has been noted at the tumor interface following sipuleucel-T neoadjuvant therapy. In this analysis, a 3-fold or more increase in mean T cells was observed at the tumor interface compared with the pretreatment biopsy, internal tumor tissue, or benign prostatic tissue [23].

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Why are objective responses difficult to demonstrate with immunotherapies? Although treatment with sipuleucel-T, PSA-tricom or ipilimumab may achieve an OS benefit for prostate cancer patients, there may not be a significant impact on median PFS or objective disease progression. There are several potential reasons for this. Firstly, objective disease progression can be a difficult endpoint to measure reliably (predominance of bony disease). Secondly, the correlation between OS and time to progression or PFS in mCRPC has not always been consistent, even with traditional therapies [24]. There may also be a time-lag in the response to immunotherapy (Figure 5), such that short-term changes in PSA values might not reflect the impact on OS. This model is supported by data in sipuleucel-T-treated, non-metastatic, androgen-dependent patients, where the earlier disease stage allowed a longer period of observation prior to subsequent therapeutic intervention. In this patient group, sipuleucel-T treatment achieved a 47% increase in PSA doubling time versus control (P = 0.038) [22].

Figure 5. A theoretical mathematical model of differential effects of immunotherapy versus chemotherapy (adapted from [25]).

Given the delayed kinetics of response to immunotherapies, traditional measures of objective response, such as the RECIST criteria [15], may occur too rapidly for a treatment difference to be demonstrated. Therefore, other measures of response are needed and new definitions of progression may be required (e.g. immune-related response criteria) [26]. In addition, response criteria may need to be measured at later time points after treatment than with traditional therapies. For example, overall data on treatment with sipuleucel-T showed no statistically significant impact on time to objective disease progression versus control. Subsequent analysis of time to disease-related pain, although not statistically significant, demonstrated a pronounced trend in favor of sipuleucel-T versus control. Further analyses on yet more proximal endpoints, such as time to first use of an opioid analgesic and OS, were statistically significant [13,27]. Data informing appropriate patient selection for immunotherapy Given the time-lag in deriving the greatest benefit from immunotherapy, patients with earlier-stage disease may be optimal candidates for treatment. Sipuleucel-T therapy has demonstrated a clear association between increased OS and lower versus higher baseline PSA [28]. This is supported by data

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demonstrating greater APC activation, as measured by CD54 upregulation, in sipuleucel‑T‑treated patients with early versus late-stage disease [29]. These data are further corroborated by similar analyses from melanoma patients treated with ipilimumab in which the OS benefit was more pronounced in patients with less advanced melanoma (based on M stage at baseline) versus those with more advanced disease [17].

Conclusions The immune system plays a critical role in cancer control and protection, which may be augmented by immunotherapy. Immunotherapy is an established cancer treatment modality that is approved for the treatment of several malignant conditions, including prostate cancer. Immunotherapy can combine several anticancer features into a single treatment and may augment existing therapies through combination or appropriate sequencing. Immunotherapies generally demonstrate a time‑lag in clinical response, and therefore appropriate patients are likely those with high performance status, earlier-stage disease and greater immune responsiveness. In addition, this time-lag may mask currently applied secondary measures of clinical outcome, which may be absent or delayed. This requires understanding from the healthcare provider, appropriate patient selection, and management of the patient’s expectations.

Acknowledgments This article is based on a symposium presented at the Global Congress on Prostate Cancer 2013, which was supported by Dendreon. Medical writing assistance was provided by Gardiner-Caldwell Communications and was funded by Dendreon.

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Copyright figures Figure 1: From N Engl J Med, Zhang L, Conejo-Garcia JR, Katsaros D, et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer, 348, 203–13. Copyright © 2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Figure 2: a) Kantoff PW, Schuetz TJ, Blumenstein BA, et al., J Clin Oncol 28(7), 2010:1099–1105. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved. b) From N Engl J Med, Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, 363, 411–422. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. c) and d) From N Engl J Med, Hodi FS, O’Day SJ, McDermott DF, et al., Improved survival with ipilimumab in patients with metastatic melanoma, 363, 711–723. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Figure 4: Adapted from Sheikh NA, Petrylak D, Kantoff PW, et al. Cancer Immunol Immunother 2013;62:137–47, published under Creative Commons license 2.0 CC-BY. Figure 5: Republished with permission of The Oncologist, from Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression, Madan RA et al., 15(9), 2010; permission conveyed through Copyright Clearance Center, Inc.

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Immunotherapy for prostate cancer: concepts and practice