Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

Immunotherapy in Castration-Resistant Prostate Cancer:Integrating Sipuleucel-T Into Our Current Treatment ParadigmReview Article [1] | March 15, 2011 | Prostate Cancer [2], Genitourinary Cancers [3], OncologyJournal [4]By Jorge A. Garcia, MD [5] and Robert Dreicer, MD, MS, FACP [6]

Prostate cancer is the second-leading cause of death in men in the United States; more than217,730 new cases were expected to be diagnosed in 2010.[1] Although the majority of patients withadvanced prostate cancer have an initial response to androgen deprivation, essentially all patientseventually progress to a castration-resistant state, manifested by rising levels of prostate-specificantigen (PSA),

ABSTRACT: The availability of several novel antibodies, coupled with viral, DNA, anddendritic-cell vaccines, has renewed interest in immunotherapeutic approaches to thetreatment of advanced prostate cancer. Although promising, none of these approacheshave led to major clinical activity, and in the case of cell-based immunotherapy withGVAX, new concerns about safety arose when this therapy was used in thecastration-resistant setting. A more attractive yet toxic approach has also utilized acheck-point blockade with CTLA-4 antibodies. Although initial clinical efficacy has beenobserved, toxicity appears to be the major limitation of its use in prostate cancer.Sipuleucel-T (Provenge) is an autologous active cellular immunotherapy product thatincludes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusionprotein made of prostatic acid phosphataase (PAP) and granulocyte–macrophagecolony-stimulating factor (GM-CSF). Despite the lack of objective anti-tumor activity seenwith sipuleucel-T, a recently reported phase III trial demonstrated a significantimprovement in the overall survival of men with asymptomatic, minimally symptomaticmetastatic castration-resistant prostate cancer (CRPC). This agent is the firstFDA-approved novel immunotherapeutic compound for the treatment of a solidmalignancy. A better understanding of how clinicians should incorporate this novel agentinto the current management of CRPC is needed.

Introduction

Prostate cancer is the second-leading cause of death in men in the United States; more than 217,730new cases were expected to be diagnosed in 2010.[1] Although the majority of patients withadvanced prostate cancer have an initial response to androgen deprivation, essentially all patientseventually progress to a castration-resistant state, manifested by rising levels of prostate-specificantigen (PSA), progressive disease on imaging studies, and/or worsening of symptoms—all in thesetting of an anorchid testosterone level.[2] Historically, patients were offered a variety of secondaryhormonal manipulations followed by palliative chemotherapy with docetaxel (Taxotere)-basedregimens. Following a long period in which there were limited therapeutic developments, the FDArecently approved cabazitaxel (Jevtana), a second generation taxane for patients with diseaseprogression following docetaxel. In addition, recently presented evidence of improved survival forpatients receiving the selective CYP-17 inhibitor abiraterone following docetaxel-basedchemotherapy will likely result in the approval of another agent in this setting.A better understanding of the role of inflammation and immune activation in prostate cancer,coupled with the long natural history of the disease,[4] its ability to induce auto-antibodies,[5] andthe availability of several tissue-specific proteins that may serve as prostate tumor antigens,[6,7]has facilitated the development of several immune-based therapeutic strategies.[8] In this review,we summarize recent clinical developments in prostate cancer immunotherapy, and we specificallyreview the clinical development of sipuleucel-T (Provenge), a novel immunotherapeutic agentrecently approved by the FDA for the management of asymptomatic or minimally symptomaticmetastatic castration-resistant prostate cancer (CRPC).

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

Cytokines

Granulocyte–macrophage colony-stimulating factor (GM-CSF) is a small secreted polypeptide thatbinds to specific cell surface receptors; it is a potent pleiotropic cytokine capable of enhancinghematopoietic differentiation and activation from several lineage precursors, including phagocyticmacrophages and dendritic cells.[9] This non-specific activation of antigen-presenting cells (APCs)results in increased co-stimulatory molecule expression on host bone marrow–derived APCs. Whenadministered in vivo, GM-CSF promotes the growth and antigen-presenting capabilities of dendriticcells, leading to T-cell cross-priming.[10] The therapeutic effect of recombinant GM-CSF as ananticancer agent has been studied in several models. Injection of a murine tumorigenic T-leukemiacell line expressing mGM-CSF into pre-established tumors of syngeneic mice led to a significantregression of the tumors.[11] Additionally, mice injected with melanoma cells transfected with arecombinant GM-CSF gene either completely rejected the tumor cells or developed tumors with amean volume 50 times smaller than in controls.[12] Furthermore, vaccination withGM-CSF-expressing MPC11 cells has been shown to induce a potent antitumor cytotoxicT-lymphocyte response associated with tumor rejection in the majority of the animals tested.[13]Additional studies of autologous or allogeneic prostate tumor cells transfected to produce GM-CSFhave demonstrated the generation of potentially relevant immune responses.[11,12]Exogenous administration of GM-CSF has been studied in men with advanced prostatecancer.[14-16] Although the dose and schedule of administration has varied among clinical trials, itis clear that GM-CSF administration can lead to declines in PSA levels in patients with hormone-naveand castration-resistant disease. However, these declines are often transient, since diseaseeventually progresses either serologically or radiographically in all patients. The addition ofmaintenance therapy to GM-CSF also appears to increase the rate of PSA reduction, with no evidencethat GM-CSF interferes with PSA measurement or secretion. Although the clinical significance of suchPSA changes remains uncertain, these data suggest a potential biologic effect of GM-CSF on PSA.This observation alone is important, since many vaccination strategies have used GM-CSF as anadjuvant. However, the confounding effect that GM-CSF may have on PSA levels makesinterpretation of studies that utilize GM-CSF somewhat problematic.

CTLA-4–Based Therapy

In recent years, cytotoxic T-lymphocyte (CTL)-associated antigen-4 (CTLA-4)-targeted therapies haveundergone the most extensive evaluation in multiple solid tumors, including prostate cancer. T-cellactivation is dependent on the ability of the T-cell receptor to recognize specific antigen-bound majorhistocompatibility complex (MHC) peptides. Additional antigen-independent costimulatory signals arerequired for the generation of a T-cell response. These include the normal interaction between CD28and CTLA-4, both costimulatory receptors located on the surface of T cells, and costimulatorymolecules B7-1 (CD80) and B7-2 (CD86), present on APCs. While ligand engagement by CD28activates T cells, the binding of CTLA-4 and B7 sends an inhibitory signal that down-regulates T-cellactivation and serves as a natural brake, altering downstream cytokine production and cell-cycleproliferation, both required for growth.[17-19] In vivo inhibition of CTLA-4 and its ligands through theuse of a neutralizing antibody has been shown to induce antitumor activity in several murine tumormodels.[20-22] Therefore, blockade of CTLA-4 may represent an important mechanism forpotentiating T-cell immunity and anti-tumor response.Ipilimumab and tremelimumab are two humanized anti-CTLA-4 antibodies that are the leadcompounds in the investigation of this immune approach in solid tumors. Small et al evaluatedipilimumab both as monotherapy and in combination with GM-CSF in men with CRPC.[23,24] In themonotherapy trial, 14 patients received ipilimumab as a single dose of 3 mg/kg IV. Treatment waswell tolerated, with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritusthat required systemic corticosteroids. Although a trend for an increasing percentage of CD4 andCD8 T cells co-expressing MHC class II was observed, flow cytometry analysis of lymphocytesub-populations failed to demonstrate polyclonal T-cell activation.[23] A subsequent study evaluatedthe combination of CTLA-4 blockade and GM-CSF in 24 patients with CRPC.[24] While GM-CSF wasgiven as a fixed dose of 250 μg/m²/day for 14 days, ipilimumab was dose-escalated from 0.5 mg/kgto 3 mg/kg, given once every 4 weeks in a sequential phase I design. Observed toxicity was similarto that seen in previous CTLA-4 studies, with 4 patients developing grade 3 adverse events, includinga cerebrovascular accident, skin rash, pan-hypopituitarism, temporal arteritis, and diarrhea. Ofinterest, two of these patients were among those who obtained the greatest clinical benefit, as

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

assessed either radiographically or by PSA level. Immune-based studies have also suggested theenhancing effects of this combination on the activation of circulating CD8+ T cells. Althoughdisappointing clinical results have been observed in other solid tumors in studies using similarantibodies,[25] the recent overall survival (OS) results from a phase III study of ipilimumab with orwithout a gp100 peptide vaccine in patients with metastatic melanoma[26] clearly suggest thatwhen the appropriate antigen is selected, antibody-mediated therapy has significant potential tobecome an an important therapeutic strategy in solid malignancies. Although the ideal antigen forprostate cancer immunotherapy has not been well defined, the clinical experience with ipilimumab inmelanoma provides impetus for continued immune-based research in prostate cancer.

DNA, Viral, and Cell-Based Vaccines

Several vaccine approaches have undergone clinical evaluation in men with prostate cancer.One approach involves DNA-based constructs that ultimately activate a specific antitumor immuneresponse. An advantage of this approach is that PAP is a unique antigen in prostate cancer cells, andunlike other vectors (eg, virus), DNA can be rapidly and precisely synthesized. When contrasted withviral vectors, one of the drawbacks of using DNA as a vector is its low level of immunogenicity.[27]Initial studies in rat models using large and repetitive doses of a GMP-grade plasmid DNA vaccineencoding human PAP (pTVG-HP) demonstrated the ability of this vaccine to elicit effectivePAP-specific CD4 and CD8 T cells.[28] In a subsequent phase I/II study, 22 prostate cancer patientswith biochemical recurrence-only disease were treated in a dose-escalation trial with 100 μg, 500 μg,or 1,500 μg of TVG-HP plasmid DNA, co-administered intradermally with 200 μg of GM-CSF as avaccine adjuvant, six times at 14-day intervals. Although no major changes in PSA levels werereported, treatment was well tolerated, with minimal if any adverse events, and a significantPAP-specific CD4+/CD8+ T-cell proliferation that included interferon gamma (IFN γ)-secreting CTL

activity was observed.[29]FIGURE 1 The diagram illustrates the two

steps involved in sipuleucel-T therapy.

Using viral or bacterial vectors as a vehicle for vaccine delivery is a cost-effective way to allow theinsertion of multiple genes for tumor-associated antigens. Of note, some of these vectors can causedirect local inflammation, which in turn can increase APC recruitment and antigen presentation.Poxviruses have been employed as a vehicle for prostate cancer vaccines in various combinations.Vaccination with recombinant vaccinia virus expressing human PSA (rV-PSA) has been shown to besafe and to induce PSA-specific T-cell responses in animal models and in humans.[30-32]A phase II trial of the Eastern Cooperative Oncology Group (ECOG) evaluated a heterologousprime/boost vaccination schedule with vaccinia and fowlpox viruses expressing human PSA, in menwith BCR-only disease.[33] Patients were randomly assigned to receive four vaccinations withfowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one rV-PSA vaccine, or one rV-PSA vaccinefollowed by three rF-PSA vaccines. The primary endpoint was PSA response at 6 months. There wereminimal adverse events and no autoimmune events, and almost half of the patients (45.3%)remained free from PSA progression at 19.1 months of clinical follow-up. An increase in PSA-specificT-cell precursors was observed in 46% of patients; however, none of the men in the study hadevidence of an anti-PSA antibody response.PROSTVAC, a construct of fowlpox and vaccinia vectors that contains a triad of costimulatorymolecule transgenes (intercellular adhesion molecule 1, B7-1, and leukocyte function associatedantigen 3) has also been studied in prostate cancer. Two phase I studies demonstrated the safetyand immune effects of this compound in patients with CRPC.[34,35] In a subsequent randomizeddouble-blind phase II study, 125 patients with minimally symptomatical metastatic CRPC wererandomly assigned in a 2:1 fashion to receive either PROSTVAC-VF plus GM-CSF or empty vectorsplus saline injections. Although no difference in the primary endpoint of progression-free survival(PFS) was found (3.8 vs 3.7 months; hazard rate [HR], 0.88; P = .60), patients treated with

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

PROSTVAC-VF had a superior OS compared with the OS of those in the control arm (25.1 vs 16.6months; HR, 0.56; P = .0061).[36] The toxicity was similar to that seen with other viral vectors testedin prostate cancer. Grade 1 and 2 injection site reactions, fatigue, fever, and nausea were the mostcommon adverse events reported. No detectable antibody response to PSA was observed, and allpatients had an augmented antibody response to the vaccinia and fowlpox vectors. There was noassociation between the antivector antibody production and OS. A pivotal phase III trial ofPROSTVAC-VF is currently planned.The use of allogeneic prostate cancer cells as immunotherapy vectors has been another attractiveimmunotherapeutic approach in advanced prostate cancer. GVAX is a combination of two prostatecarcinoma cell lines (LNCap and PC-3) modified with the GM-CSF gene and thereby engineered toincrease the antigen-presenting capabilities of dendritic cells to T cells.[37-40] Two subsequentphase II studies evaluating the clinical activity and safety of GVAX in men with CRPC[41,42]demonstrated an improvement in the median OS compared with historical data from the Halabinomogram, a validated pre-treatment prognostic model for CRPC.[43] In the first trial, Small et al[41]reported that the median OS for GVAX-treated patients was 26.2 months, compared with the 19.5months (P = .01) predicted by the nomogram. The trial by Higano et al,[42] which employed avaccine construct that was re-engineered to secrete a higher dose of GM-CSF, also demonstrated asuperior OS benefit (35 months) compared with the same historical control. When the immuneeffects of treatment were evaluated, immunoreactivity was found not to be a significant predictor ofsurvival or clinical response. The most common adverse events reported in both studies wereinjection site reactions and flu-like symptoms.On the basis of these results, two large randomized phase III trials were launched. The first (VITAL-1)was a head-to-head comparison of GVAX vs docetaxel/prednisone, and the second (VITAL-2) was acombination of docetaxel and GVAX vs docetaxel/prednisone. Although VITAL-1 completed its targetaccrual of 600 patients with CRPC, VITAL-2 was halted after an early interim analysis demonstratedan imbalance in the number of deaths in the immunotherapy arm (67 vs 47 in thedocetaxel/prednisone arm). On the basis of this finding, an interim analysis for VITAL-1 wasconducted. There was no OS difference between GVAX and docetaxel/prednisone (20.7 and 21.7months, respectively; HR, 1.03; P = 0.78).[44] To date, the relationship between GVAX and docetaxeltreatment and deaths remains unknown. Based on these results, further clinical development ofGVAX for prostate cancer has been terminated.

Dendritic Cell–Based Approaches

Sipuleucel-T is an autologous active cellular immunotherapy product that consists of autologousperipheral blood mononuclear cells (PBMCs) pulsed ex vivo and activated in vitro with a recombinantfusion protein (PA2024). The recombinant fusion protein, PA2024, is composed of a full-length PAPlinked via its COOH terminus to the NH2 terminus of full-length GM-CSF.[45, 46] When administeredin vivo, GM-CSF promotes the growth and antigen-presenting capabilities of dendritic cells, leading toT-cell cross-priming.[10] The preparation of sipuleucel-T involves a standard leukapheresis ofapproximately 1.5 to 2.0 total blood volumes with isolation of PBMCs through density-gradientcentrifugation to allow for the removal of platelets and monocytes. The product is then incubatedwith the recombinant fusion protein PAP2024. After the desired clinical dose has been formulated,the final product is then transported to the respective facility and infused into the patient within 8hours of formulation. Multiple phase I/II sequential trials evaluated the clinical and immune effects ofsipuleucel-T in patients with CRPC. In a trial that included 31 patients with metastatic ornon-metastatic CRPC, treatment with sipuleucel-T was administered in weeks 0, 4, and 8, with afourth infusion in week 24 only to those patients whose disease was stable or better after the initialthree infusions. In all patients receiving sipuleucel-T, a T-cell response developed that was definedby the immune response to the recall antigen influenza and to the naive antigen KLH (keyhold limpethemocyanin). Antibodies to PAP and GM-CSF were also evaluated by specific enzyme-linkedimmunosorbent assay (ELISA) on serum samples obtained at baseline and then every 4 weeks. Noneof the patients had pre-existing antibodies to PAP, whereas after treatment, 16 of 31 patients (52%)had antibodies.[47]Three small prospective phase II studies that included patients with castrate-resistant andandrogen-dependent, biochemically relapsed disease initially demonstrated the safety and modestclinical activity of sipuleucel-T in prostate cancer. The first trial, which included 19 men with CRPC,demonstrated a modest PSA response in 2 of the 19 patients (PSA decline > 50% compared withbaseline) and no objective disease response in those with Response Evaluation Criteria in Solid

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

Tumors (RECIST)-defined measurable disease. In terms of immune parameters, T-cell responses toPAP2024 were elicited in all evaluated patients; the responses lasted for the entire duration of theclinical trial.[48] Similarly, two small single-institution studies demonstrated that treatment withsipuleucel-T alone[49] or in combination with bevacizumab (Avastin), a monoclonal humanizedantibody against all active isoforms of vascular endothelial growth factor (VEGF),[50] leads to anincrease in PSA doubling time in patients with androgen-dependent, biochemically relapsed prostatecancer. While the study of sipuleucel-T monotherapy demonstrated a median increase in PSAdoubling time of 62% (4.9 months before treatment vs 7.9 months after treatment; P = .09;signed-rank test), the median increase in PSA doubling time when bevacizumab was added tosipuleucel- T appeared to be greater than 150% (6.9 months vs 12.7 months; P = .01). Although noimmune parameters were reported in the monotherapy trial, all patients in the combination studywith bevacizumab demonstrated induction of an immune response against sipuleucel-T.The phase III development program for sipuleucel-T included 2 parallel randomized, double-blind,placebo-controlled studies, D9901 and D9902A.[51,52] D9901 was a multi-institution double-blind,placebo-controlled, randomized phase III trial designed to test the effect of sipuleucel-T on time toprogression (TTP) and OS in 127 men with asymptomatic metastatic CRPC. Patients in this trial wererandomized in a 2:1 ratio to receive 3 infusions of sipuleucel-T (n=82) or placebo (n=45) every 2weeks. On disease progression, placebo patients received a similar product made with frozenleukapheresis cells. D9902A was an identical study to D9901 but was prematurely stopped after theinitial TTP results from D9901 were reported. Thus, the study was underpowered; it ultimatelyenrolled only 98 patients.The primary endpoint of both studies was TTP. Imaging studies were completed every 8 weeks untilweek 32, then every 12 weeks thereafter, and progression was confirmed by independent review.PSA was not used to determine disease progression or to trigger radiographic evaluations. Themedian TTP for patients receiving sipuleucel-T in study D9901 was 11.7 weeks, compared with 10.0weeks for placebo (P = .052; HR, 1.45). Similarly, the TTPs in study D9902A were 10.9 and 9.9weeks, respectively (P =.719; HR, 1.09). Of the 147 patients from both trials who receivedsipuleucel-T, only 5 had a PSA reduction of > 50%; the overall PSA response rate was 4.8%. Noobjective responses were observed in those patients with measurable disease who receivedsipuleucel-T.While neither study was powered to determine the impact of sipuleucel-T on OS, a pre-planned3-year OS assessment was carried out. The median OS in the D9901 study was 25.9 months forsipuleucel-T–treated patients and 21.4 months for those who received placebo (P = .01; HR, 1.70).Although no survival benefit was observed in the D9902A trial (19 months vs 15.7 months; P =.331),[52] when both trials were integrated together, the median OS was 23.2 months forsipuleucel-T and 18.9 months for placebo (P = .011). Similarly, the percentage of patients alive at 36months was 33% for those who received sipuleucel-T and 15% for those who received placebo. TheOS benefit found in these studies was maintained after adjusting for multiple predefined CRPCprognostic factors,[53,54] including the subsequent use of docetaxel-based chemotherapy (P =.022).[52] Also provocative was the strong correlation between CD54 up-regulation and survival (P =.009), observed in both studies. CD54, also known as intracellular adhesion molecule 1, is expressedon dendritic cells and plays an important role in the synapse between dendritic cells and T cells.To confirm the survival impact of sipuleucel-T, 512 men with metastatic CRPC were randomized (in a2:1 ratio) in a phase III, double-blind, placebo-controlled, multicenter trial called the Immunotherapyfor Prostate Adenocarcinoma Treatment (IMPACT) study.[53] Eligibility for this trial was similar tothat in previous CRPC studies.[51,52] All patients were stratified according to Gleason grade, numberof bone metastases, and bisphosphonate use. Progressive disease (PD) was independentlymonitored using PSA and imaging studies at weeks 6, 14, 26, and 34, and every 12 weeks thereafter.During the trial, placebo patients in whom PD developed could enroll in an open-label salvageprotocol and receive APC8015F, a product manufactured according to the same specifications assipuleucel-T from cells cryopreserved at the time the placebo was prepared.Survival was the primary endpoint of the study, and it was analyzed on the basis of a stratified Coxregression model, with adjustment for the natural logarithm of the baseline levels of PSA and lactatedehydrogenase and stratified according to randomization factors.[54,55] The median OS was 25.8months for sipuleucel-T–treated patients and 21.7 months for patients who received placebo, with anadjusted HR for death of 0.78 (95% confidence interval [CI], 0.61 to 0.98), which represents arelative reduction in the risk of death of 22% (P = .03). Similar results were obtained with the use ofthe unadjusted, stratified model and the log-rank test (HR, 0.77; 95% CI, 0.61 to 0.97; P = .02). Thereduction in the risk of death from prostate cancer in the sipuleucel-T group (HR, 0.77; 95% CI, 0.61

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

to 0.98; P = .04) was similar to the reduction in the risk of death from any cause. There was nodifference in the median time to objective PD (3.7 months in the sipuleucel-T group vs 3.6 months inthe placebo group; HR, 0.95; 95% CI, 0.77 to 1.17; P = .63). Similar results were observed for thetime to clinical PD (HR, 0.92; 95% CI, 0.75 to 1.12; P = .40). Only one patient who receivedsipuleucel-T achieved a partial remission; 2.6% had a PSA decline of < 50%. The estimated effect ofsipuleucel-T treatment in those patients who received subsequent docetaxel-based chemotherapywas consistent with the results of the primary efficacy analysis (HR for death, 0.78; 95% CI, 0.62 to0.98; P = .03).With regard to immune changes during the study, titers of antibodies against the immunizingantigen PA2024 at any time after baseline were observed in 100 of 151 patients (66.2%) in thesipuleucel-T group and in 2 of 70 patients (2.9%) in the placebo group. Similarly, titers of antibodiesagainst PAP were observed in 43 of 151 patients (28.5%) in the sipuleucel-T group and in 1 of 70patients (1.4%) in the placebo group. At week 6 of treatment, T-cell proliferation responses(stimulation index, >5) to PA2024 were observed in 73% of patients in the sipuleucel-T groupcompared with 12% in the placebo group. No changes in the immune correlative studies conductedin this trial correlated with outcome.Overall, therapy with sipuleucel-T is well tolerated. Almost all patients in the IMPACT trial received allthree planned infusions, and no patient withdrew from the study secondary to toxicity. The mostcommon toxicities were grade 1 and grade 2 and included chills, fever (pyrexia), headache,influenza-like illness, myalgia, hypertension, hyperhidrosis, and groin pain. Most of these adverseevents occurred within 1 day after infusion and resolved within 1 to 2 days. Among patients in thesipuleucel-T group, grade 3 events that were reported for at least 1 patient within 1 day afterinfusion were chills (in 4 patients), fatigue (in 3 patients), and back pain, hypertension, hypokalemia,and muscular weakness (in 2 patients each); one grade 4 event was reported (intravenouscatheter–associated bacteremia).

Discussion

The management of CRPC has evolved slowly over the past decade. The evolution ofdocetaxel-based chemotherapy as a standard of care has been notable but until recently was anisolated therapeutic development. The recent FDA approval of sipuleucel-T and cabazitaxel,[56] andthe anticipated approval of abiraterone,[57] will over a very short period of time add three newagents to the treatment armamentarium, all of which independently have improved OS in prostatecancer.REFERENCE GUIDETherapeutic Agents

Mentioned in This Article

Abiraterone

Bevacizumab (Avastin)

Cabazitaxel (Jevtana)

Docetaxel (Taxotere

Gefitinib (Iressa)

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

Gp100 peptide vaccine

GVAX

Ipilimumab

Prednisone

PROSTVAC-VF

Sipuleucel-T (Provenge)

Tremelimumab Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Unlike cabazitaxel and abiraterone, which in addition to a survival advantage have clear evidence ofobjective anti-tumor activity (as documented by both response rates and impact on PFS),sipuleucel-T’s demonstrated ability to improve OS occurs without evidence of a measurableanti-tumor effect (TTP, objective response rate, and serologic response [PSA reduction]). Someclinicians find it somewhat perplexing that despite the lack of tumor burden reduction whenmeasurable disease was present, treatment with sipuleucel-T was nonetheless able to impact thenatural history of this disease in a positive manner. Although sensitivity analyses in the IMPACT trialdemonstrated that subsequent treatment (mostly docetaxel-based chemotherapy) did not accountfor the survival difference observed, the study design was not powered to detect such a difference.An especially intriguing—but still unanswered—question is what the true mechanism of action ofsipuleucel-T is. Therapy with sipuleucel-T has been demonstrated to produce antigen-specific T-cellresponses, and patients with elevated antibody titers after treatment appear to have improvedsurvival compared with those without titer elevations. However, these findings require furthervalidation. A better understanding of the immune effects of sipuleucel-T is needed to help improvethe selection of patients who are likely to derive the greatest benefit from treatment with this agent.With the rapid introduction of a number of new agents and the clinical limitations of sipuleucel-T, thequestion of how to optimally integrate sipuleucel-T into the management paradigm will requireadditional study and clinical experience. Some early observations can be made in an effort to helpguide clinicians in making management choices. Given the absence of direct anti-tumor activity,sipuleucel-T should not be presented to patients as—or utilized as—a “bridge” therapy betweentreatments (ie, administration of sipuleucel-T will not delay the need for chemotherapy in a patientwith a clinical picture of rapidly progressive radiographic disease or with early disease-relatedsymptoms (progressive pain, fatigue, weight loss, etc) With the anticipated approval of abiraterone,the use of corticosteroids in combination with this lyase inhibitor will no doubt raise issues regardingthe potential impact of long-term corticosteroid use on the “effectiveness” of sipuleucel-T; therecurrently is no evidence to guide decision making regarding this vaccine and subsequent use ofcorticosteroids.Notwithstanding the challenges involved in the development of immunotherapy for prostate cancer,the regulatory approval of sipuleucel-T has opened the door to multiple opportunities for immune

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Immunotherapy in Castration-Resistant Prostate Cancer: Integrating Sipuleucel-T Into Our Current Treatment ParadigmPublished on Cancer Network (http://www.cancernetwork.com)

drug development. Future studies will require thoughtful clinical trial designs, including appropriatepatient selection and translational and clinical endpoints.Financial Disclosure: The authors have no significant financial interest or other relationship withthe manufacturers of any products or providers of any service mentioned in this article. References: References

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Links:[1] http://www.cancernetwork.com/review-article[2] http://www.cancernetwork.com/prostate-cancer[3] http://www.cancernetwork.com/genitourinary-cancers[4] http://www.cancernetwork.com/oncology-journal[5] http://www.cancernetwork.com/authors/jorge-garcia-md[6] http://www.cancernetwork.com/authors/robert-dreicer-md-ms-facp

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