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PROSTVAC® targeted immunotherapy candidate for prostate cancer
Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostatespecific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.
Neal D Shore Carolina Urologic Research Center, 823 82nd Parkway, Myrtle Beach, SC 29572, USA Tel.: +1 843 449 1010 nshore@ gsuro.com
Keywords: biological therapy • cancer vaccine • immunotherapy • prostate cancer • PROSTVAC® • PSA-TRICOM • rilimogene-galvacirepvec
The treatment of advanced prostate cancer has evolved over the last several years and targeted immunotherapies represent a novel therapeutic approach in this evolution. Prostate cancer is a potential target for immunotherapy, as often times prostate cancer proliferates more slowly than other solid malignancies [1] . These growth kinetics allow the necessary time for an immunotherapeutic strategy to generate a targeted immune response, which is expected to translate into clinical benefit. In addition, prostate-specific antigen (PSA) is a unique marker of recurrent or early-stage disease that can be measured and tracked to obtain an estimate of tumor burden. Prostate cancer cells may also generate other unique gene products, or tumor-associated antigens (TAAs), that can be developed as potential immunotherapy targets. TAAs are often weakly immunogenic; thus, immunotherapy has been designed to enhance immune recognition in order to generate an immune response with tumorspecific T-cell-mediated destruction [2] . PSA, prostatic acid phosphatase (PAP) and prostate-
10.2217/IMT.13.176 © 2014 Future Medicine Ltd
specific membrane antigen (PSMA) are key TAAs that have been extensively studied and amply demonstrated to be overexpressed by prostate cancer cells [3–5] . The general process by which T cells mount an immune response to these TAAs is crucial to our understanding of how targeted immunotherapies demonstrate clinical benefit. An antitumor response is generated when the host immune system recognizes immunogenic antigens expressed on the surface of tumor cells. Antigen will bind to major histocompatibility complex (MHC) on APCs and be presented to T cells. This process also involves signalling through costimulatory molecules, such as B7.1, on APCs [6] . Following antigen stimulation, cytotoxic T lymphocytes (CTLs) become activated, proliferate within the local lymph nodes, and are released into the circulation to recognize the same antigens bound to MHC on tumor cells, resulting in lysis of tumor cells. However, tumors often develop tolerance to the immune system through
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Drug Evaluation Shore selection of nonimmunogenic tumor cell variants (a process also called immunoediting) [7] . Several processes have been identified that allow tumor cells to evade the immune system, including downregulation of MHC class I molecules [8] . Immunosuppressive cytokines are also produced in response to malignancies and include IL-4, IL-6, IL-10, TGF-β, VEGF and TNF. Immunosuppression may also occur as a result of an increase in regulatory T cells within the tumor microenvironment, as well as upregulation of checkpoint pathways that inhibit T-cell responses, including CTLA-4 and PD-1. Thus, the goal of immunotherapy is to enhance TAA presentation to the immune system and inhibit immunosuppressive pathways [2] . The ability to induce T-cell responses directed against a TAA and produce antitumor activity has been demonstrated with sipuleucel-T (Provenge; Dendreon Corp., WA, USA), an autologous cellular immunotherapy manufactured from a standard leukapheresis procedure to isolate peripheral blood mononuclear cells, including APCs, from the patients’ serum. The APCs are cultured ex vivo with PA2024, a fusion protein consisting of PAP linked to GM-CSF. The activated cells are infused back into the patient to induce an immune response against prostate cancer cells. Three Phase III trials of sipuleucel-T were conducted in 737 asymptomatic or minimally symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) [9–11] . In the first two trials, the primary end point, time to disease progression (TTP), did not reach statistical significance. Patients were followed for survival over 36 months as a secondary end point. Among patients who received sipuleucel-T, median overall survival (OS) was prolonged by 3.3–4.5 months compared with control [9] . The pivotal Phase III trial in 512 patients employed OS as the primary end point and identified a prolongation of 4.1 months versus control [10] . The safety profile of sipuleucel-T is mainly based on 601 prostate cancer patients who received at least one leukapheresis procedure [12] . Adverse events associated with sipuleucel-T include chills, fatigue, pyrexia, back pain, nausea, arthralgia and headache. Cerebrovascular events occurred more often in the sipuleucel-T group than in the control group (3.5 vs 2.6%). Classic biochemical (PSA) or radiological measures of disease progression have not been reliable markers of sipuleucel-T activity. Other agents recently approved for metastatic CRPC include the cytotoxic agent cabazitaxel (Jevtana®, Sanofi Aventis, Inc., NJ, USA), a microtubule inhibitor for use after docetaxel failure that was shown to provide an absolute improvement in median OS of 2.4 months [13] . Two oral antiandrogen agents, abiraterone
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acetate (Zytiga®, Janssen Biotech, Inc., PA, USA), an androgen biosynthesis inhibitor indicated in combination with prednisone therapy, and enzalutamide (Xtandi®, Astellas Pharma, US and Medivation, Inc., Tokyo, Japan and CA, USA), an androgen receptor inhibitor indicated after failure of docetaxel therapy, provided OS benefits of 4.6 and 4.8 months, respectively [14,15] . Radium-223 dichloride (Xofigo®, Bayer Healthcare Pharmaceuticals and Algeta ASA, NJ, USA) was recently approved for use in CRPC patients with painful bone metastases based on an improvement in median OS of 3.6 months [16] . Development of PROSTVAC® The initial development of immunotherapies for prostate cancer patients included poxvirus immunotherapies [17,18] . Poxviruses have several biological advantages when used as vehicles for cancer immunotherapy including the large size of their genomes enabling them to carry various inserted genes encoding for tumor antigens and immune costimulatory molecules. Presentation of tumor antigens within the poxviral context is highly immunogenic [2] . In addition, poxviral replication occurs in the cell cytoplasm and it does not integrate into host DNA, eliminating mutational risks [6] . PROSTVAC immunotherapy (also called PSA-triad of human T-cell costimulatory molecules [TRICOM]; generic name: rilimogene-galvacirepvec) is produced by inserting the transgenes for PSA and three immune costimulatory molecules via recombinant plasmid into the vaccine viral vector [19] . As the virus enters a host cell, the viral core is released and reproduction within the cell creates a proportion of poxviruses containing the recombinant plasmid that can be identified by expression of markers inserted into the plasmid. The plasmid-containing poxviruses are selected and amplified for use as an immunotherapy. PROSTVAC is a combination of two different poxviruses, both engineered to express PSA, modified at amino acid 155 (I to L) to increase immunogenicity [19] . The first PROSTVAC administration uses the vaccinia vector (PROSTVAC-V), which results in an effective priming of the immune system in order to elicit antitumor response. The second and subsequent PROSTVAC boost doses are fowlpox-based (PROSTVAC-F) and nonreplicating, which prevents the development of viral-coated proteins and maintains the targeted immune response to PSA rather than the viral proteins. The prime–boost concept is an approach to optimize immunotherapy by exposing the immune system to the same antigens while using different viral vectors to minimize the amount of viral protein exposed to the immune system [6] . Preclinical and clinical studies
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PROSTVAC® targeted immunotherapy candidate for prostate cancer
have determined and validated that the prime–boost PROSTVAC regimen elicits a robust and prolonged immune response [20,21] . Activation of T cells requires antigen recognition and presentation, as well as costimulation. Thus, LFA‑3,(CD58), ICAM-1 (CD54) and B7.1 (CD80), also known as TRICOM, are encoded with each PROSTVAC dose, both prime and boosts. TRICOM has been shown to significantly enhance T-cell activation in comparison to the use of just one or two costimulatory molecules [20] . TRICOM also enhances the strength of the multiple-antigen binding sites, leading to enhanced T-cell-mediated lysis of tumor cells [19,22] . Expansion of tumor antigen-specific memory T cells and production of multiple cytokines also has been observed with TRICOM [23] . These findings suggest a benefit in sustaining the immune response as the memory T cells remain available to initiate an immune response in the future without the need for ongoing immunotherapy administration. PROSTVAC triggers a targeted immune response to prostate cancer cells that is mediated by APCs and CTLs (Figure 1) [19] . As PROSTVAC is delivered to immune cells, including APCs, the transgenes for PSA and T-cell costimulatory molecules are processed and expressed within the MHC on the surface of APCs. Within locoregional lymph nodes, these activated APCs subsequently lead to activation and proliferation of corresponding CTLs and memory T cells bearing the receptor for the corresponding TAA PSA. Once released from the lymphatic system into the general circulation, the CTLs recognize and destroy PSA-expressing tumor cells throughout the body. Antigen cascade is the development of an immune response to other TAAs found on the tumor cells but not in the vaccine [24] . Studies have found that the immune response generated by targeting PSA with PROSTVAC exposes the immune system to other TAAs released from dying tumor cells, including MUC-1, PSMA and PAP [24,25] . T-cell responses to TAAs that are not present in PROSTVAC argue against using the T-cell response to the TAA (PSA in the case of PROSTVAC) as the only surrogate for immunotherapy efficacy [26] . The possibility also exists for other cellular and molecular entities (such as natural killer T cells) of the immune system to contribute to the efficacy of PROSTVAC [27] . Clinical efficacy: key Phase I & II trials of PROSTVAC-VF A Phase I trial was conducted to evaluate the clinical safety of PROSTVAC in combination with GM‑CSF in patients with metastatic CRPC [28] . Immunologic and clinical responses and kinetics of vaccinia virus
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clearance were also evaluated. In total 15 patients were enrolled and PSA-specific immune responses were observed in four out of six patients who were HLA-A2 positive. Decreases in serum PSA velocity were observed in nine out of 15 patients. No toxicity exceeded grade 2. Results of this trial provided rationale for a Phase II study in patients with less advanced prostate cancer. A double-blind, randomized, multicenter US Phase II trial enrolled 125 subjects with chemotherapy-naive, asymptomatic or minimally symptomatic metastatic CRPC with Gleason scores of 7 or less and no visceral metastases. A total of 122 patients received PROSTVAC (n = 82) or control (n = 40) in a 2:1 ratio [29] . A priming dose of PROSTVAC-V was administered subcutaneously (sc.) on day 1 followed by six booster sc. doses of PROSTVAC-F on days 14, 28, 56, 84, 112 and 140. GM-CSF 100 µg was coadministered with each PROSTVAC administration and for three consecutive days after each administration. Progression-free survival (PFS) was similar among the two treatment groups (3.8 months for PROSTVAC and 3.7 months for control; estimated hazard ratio: 0.88; p = 0.6); however, a significant prolongation in median OS of 8.5 months was observed in the PROSTVAC group (25.1 months) compared with the control group (16.6 months; estimated hazard ratio: 0.56; p = 0.006) (Figure 2) . More patients in the PROSTVAC group were alive at 3 years (30.5%) compared with the control group (17.5%). PSA responses were infrequent and no detectable antibody responses to PSA were observed. All patients developed antibodies to vaccinia vector and all but one patient to fowlpox vector, but there was no correlation between antivector antibodies and OS. To confirm the effect of PROSTVAC on OS, a subset analysis of factors known to be prognostic for OS in metastatic CRPC (e.g., PSA, alkaline phosphatase, lactate dehydrogenase and Halabi-predicted survival [30]) was performed [29] . These analyses consistently favored the PROSTVAC arm over the control arm, confirming the robustness of treatment effect across subgroups. Although some baseline factors appeared to favor the PROSTVAC arm (e.g., age and Halabi-predicted OS), the magnitude of benefit in the PROSTVAC trial could not be attributed to these imbalances. In addition, although post-trial treatment data were not collected, docetaxel was the only chemotherapeutic drug approved at the time the study was conducted. The median improvement in OS with docetaxel was demonstrated to be 2.4 months in metastatic CRPC patients; thus, it is unlikely that differences in post-trial treatment could explain the survival benefit observed in the PROSTVAC trial.
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PROSTVAC PSA
TRICOM† Tumor cell destruction
Subcutaneous injection
Clonal expansion of tumor-specific T cells
APC
Antigen processing
PSA antigen T-cell receptor MHC for PSA
CD80
CD28
Activated cytotoxic T cell T cell
Memory T cell
Immunotherapy © Future Science Group (2014) Figure 1. Mechanism of action of PROSTVAC®. The virus enters APCs, leading to expression of PSA and costimulatory molecules on the surface of APCs. CD80 (on APC) and CD28 (on T cells) are shown as an example of costimulation; LFA-3 (CD58) and ICAM-1 (CD54) also provide costimulation. These stimulated APCs activate T cells to express antigen and proliferate into CTLs and memory T cells. Activated T cells travel through the body and recognize PSA on tumor cells, leading to direct tumor cell lysis or triggering apoptosis. † TRICOM includes LFA-3 (CD58), blue; ICAM-1 (CD54), green; B7.1 (CD80), purple. CTL: Cytotoxic T lymphocyte; MHC: Major histocompatibility complex; PSA: Prostate-specific antigen; TRICOM: Triad of human T-cell costimulatory molecules.
A single-arm Phase II trial was conducted by the National Cancer Institute (NCI) in 32 patients with metastatic CRPC to investigate the effects of PROSTVAC with or without GM-CSF on immunologic and prognostic factors of median OS [26] . Patients with visceral metastases and any Gleason score were eligible for enrolment. The primary end point was immune response as measured by the ELISPOT assay for IFN-γ production, with TTP, objective response and OS as secondary end points. A total of 29 patients were evaluable for immune response, and of these, 13 patients (44.8%) demonstrated enhanced PSA-specific T-cell immune responses greater than or equal to twofold after PROSTVAC administration. Decreased
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PSA occurred in 12 out of 32 patients (37.5%) and five patients had decreases in PSA of 30% or more. The median OS was 26.6 months. The predicated survival by the Halabi nomogram for the study population was 17.4 months, providing a difference of 9.2 months. No differences in OS were observed for patients who received GM-CSF and those who did not. Patients with PSA-specific T-cell responses of greater than sixfold showed a trend toward prolonged survival (p = 0.055). Subgroup analysis of subjects by predicted survival indicated that those who had a predicted survival of greater than 18 months responded with an actual OS of 37 months or more (median was not reached at time of publication)
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PROSTVAC® targeted immunotherapy candidate for prostate cancer
Survival (% of patients)
100 n
80 25.1 months
60 40
37
16.6
PROSTVAC 82
65
25.1
Hazard ratio 0.56 (95% CI: 0.37–0.85)
16.6 months
20
Median Deaths survival (months) (n)
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Control
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p = 0.0061
0 0
12
24
36
48
60
Months Figure 2. Overall survival in Phase II trial of PROSTVAC® versus control in patients with metastatic castrationresistant prostate cancer using Kaplan–Meier estimates. The estimated median overall survival was 25.1 months for the PROSTVAC treatment group and 16.6 months for the control group. Reproduced with permission from [29] © 2010 American Society of Clinical Oncology. All rights reserved.
compared with those who had a predicted survival of less than 18 month; their actual median OS was 14.6 months. These results suggest that patients with a lower disease burden might derive particular benefit from immunotherapy, matching comparable observations recently reported for another immunotherapy (sipuleucel-T) in metastatic CRPC [31] . The safety, immunologic and tumor response effects of intraprostatic administration of
PROSTVAC were evaluated in a single-arm Phase II trial [32] . A total of 21 patients with locally recurrent hormone-naive prostate cancer after radiation were enrolled into five cohorts and received initial priming administration with subcutaneous PROSTVAC and booster administrations of intraprostatic PROSTVAC. Cohorts 3–5 also received intraprostatic GM-CSF. Cohort five received concurrent subcutaneous and intraprostatic boosters. Priming was given
Treatment
Asymptomatic/minimally symptomatic mCRPC patients
R A N D O M I Z A T I O N
Long-term follow-up Trial assessments every 6 months up to 5 years
PROSTVAC + GM-CSF†
PROSTVAC
S U R V I V A L
Control
1 3 Prime
5
9
13
17
21
Boosts Treatment weeks
Figure 3. PROSPECT study design. † Low-dose adjuvant (100 µg) subcutaneous administration, days 1–4 of each treatment [34] . mCRPC: Metastatic castration-resistant prostate cancer.
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Drug Evaluation Shore on day 1. Boosters were given on days 29, 57 and 85. During the study, stable or improved PSA was observed for 19 out of 21 patients (90.4%) and stable or improved PSA-DT occurred in nine out of 21 patients (42.9%). After administration, three out of nine (33%) evaluable HLA-A2 positive patients had immunological response to PSA by ELISPOT assay. Patients also developed a T-cell response to another prostate antigen, NGEP peptide, probably due to cross-priming of destroyed tumor cells. Overall, four out of nine patients (44%) evaluated had peripheral immune responses to either PSA or NGEP. Tumor immunologic infiltrates were tested in 13 biopsies before and after administration of PROSTVAC: CD3 + cells increased from 12.3 to 21.3 per highpower field (hpf; p = 0.0079), CD4 + cells increased from 1.7 to 12.3 per hfp (p = 0.0005) and CD8 + cells increased from 6.5 to 14.0 per hpf (p = 0.0007). One grade 3 toxicity (fever) occurred and the most common grade 2 adverse events were fever and injection site reactions. The authors concluded that intraprostatic PROSTVAC administration is safe, feasible and can generate a significant immune response [32] . Ongoing Phase III clinical trial Based on the median OS benefit of 8.5 months observed in the randomized Phase II trial [26,29] , a pivotal Phase III trial (PROSPECT) has been designed with OS as the primary end point. PROSPECT is a global, multicenter, randomized, double-blind, placebo-controlled Phase III trial of PROSTVAC in 1200 patients with asymptomatic or minimally symptomatic metastatic CRPC (ClinicalTrials.gov identifier: NCT01322490) [33] . Men are eligible if they have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, life expectancy of more than 1 year, and have not received prior chemotherapy. Patients requiring narcotics for cancer-related pain or metastases to organs other than lymph nodes or bone are excluded because these conditions would signify more advanced disease where the remaining survival might be too short to enable immunotherapy to exert its full therapeutic potential. Eligible patients are randomized in a 1:1:1 ratio to one of two active treatment arms or placebo (Figure 3) . The primary end point is OS with and without GM-CSF (100 µg/ day for 4 days following PROSTVAC administration) compared with placebo. Secondary outcomes include the proportion of patients who remain event free (i.e., radiological or pain progression, initiation of chemotherapy or death) at 6 months, immune response to TAAs and characterization of T-cell populations. Enrolment is ongoing and additional information is available at www.continueyourfight.com.
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Safety & tolerability In the randomized, double-blind Phase II trial, PROSTVAC was well tolerated; the most common adverse events reported were injection site reactions, fatigue, fever and nausea [29] . The majority of these adverse reactions were mild to moderate, with only one grade 3 injection site reaction of cellulitis. The safety of poxviral vaccines containing PSA, either alone or with costimulatory molecules, has been recently summarized by Kim et al. for 297 patients enrolled in nine clinical trials at the US NCI [35] . A total of 1793 poxviral injections were administered, with grade 2 adverse events in 32% and grade 3 adverse events in 1%; one patient experienced serious grade 4 myocardial infarction and thrombotic thrombocytopenic purpura. Overall, 77% of these events were local injection site reactions and none were serious. No vaccinia-related serious adverse events or cases of unintentional transmission to caregivers or household contacts have been reported to date. There has been no indication of immune-related side effects (e.g., autoimmune disorders). PROSTVAC offers advantages over current treatments as a more practical option that can be used ‘off the shelf’. Sipuleucel-T requires patients to undergo apheresis and wait 3 days for the processing of the product at a dedicated facility followed by intravenous administration in a hospital or specialized setting [12] . The PROSTVAC manufacturing process is less complex, and the subcutaneous route of administration allows for use in various clinical practice settings, including urology, radiation oncology and medical oncology. Treatment considerations for PROSTVAC immunotherapy GM-CSF
Immune system adjuvants have been used to enhance the immune response to therapeutic cancer vaccines. In animal models, GM-CSF facilitated recruitment of APCs leading to T-cell activation, and increased the production of multiple cytokines including IL-1, TNF and IL-6 that promote T-cell differentiation [34] . Despite the scientific rationale, the role of GM‑CSF as an immune adjuvant in clinical trials is less clear [19] . In the NCI Phase II trial of 32 patients with metastatic CRPC, the addition of GM-CSF to PROSTVAC did not appear to increase immune responses or OS [26] . The ongoing PROSPECT Phase III trial will clarify the need for GM-CSF as an immune adjunct to PROSTVAC [33] . IL-2 also has been used as an immune adjuvant. The cytokine is a T-cell growth factor that has antitumor effects against advanced melanoma and renal cell carcinoma [6] . However, its use is limited by significant toxicity and dose reductions are often required.
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PROSTVAC® targeted immunotherapy candidate for prostate cancer
Growth rate concept
Clinical studies of active immunotherapy have identified a consistent pattern regarding the timing and type of clinical response. Antitumor activity from immunotherapy occurs over a longer time period and lacks the immediate cytotoxicity and subsequent reduction in tumor size and serum tumor markers (PSA) frequently observed with traditional hormonal therapies, chemotherapy or radiation therapy [10,29] . As a result, the slower tumor growth rate translates into improved OS with no significant effssect on TTP or PSA responses [2,36,37] . With specific regard to PROSTVAC, prolonged tumor growth rates were observed within 3 months based on improved PSA kinetics, including PSA levels and PSA doubling time (DT) [36,37] . Similar findings have been reported for other immunotherapies, including sipuleucel-T and ipilimumab, an immune checkpoint inhibitor [10,38] . In the ipilimumab trial, patients with an apparently enlarging liver lesion on scans ultimately experienced significant tumor responses, suggesting that tumor infiltration with active immune cells can impair the ability to assess progression and may actually disguise an immune response as progressive disease [38,39] . Thus, OS remains the most reliable and objective end point for trials of immunotherapy [2] . A pooled analysis of five NCI-sponsored trials in patients with prostate cancer supports the kinetics of responses to immunotherapies and suggests the potential use of growth rates constants, which correlate with survival, as an intermediate efficacy end point for immunotherapies [40] . These findings also highlight important considerations for patient selection. The most appropriate candidates for immunotherapy of metastatic CRPC are likely those with newly diagnosed asymptomatic disease that does not require urgent treatment with chemotherapy to halt tumor growth. Patients with low disease burden and an uncompromised immune system (i.e., those patients who have not received substantial prior immunosuppressive therapy) may benefit most from activating immunotherapies [39] . Patients with more aggressive disease and a larger tumor burden (i.e., those with Halabi predicted survival of 3× p < 0.0005 6/8 had antigen cascade to other prostate TAAs
NR
rPSA well tolerated with grade 2 or less toxicity
TTP: flutamide alone = 85 days TBD (56–372) Flutamine + rPSA = 223 days (70–638)
TTP: nilutamide = 7.6 months vs rPSA 4/8 rPSA increased ≥2× = 9.9 months 8/21 nilutamide patients added rPSA and gained 5.2 months for 15.9 months overall 12/21 rPSA patients added nilutamide and gained 13.9 months for 25.9 months overall from rPSA start Median OS for all patients = 4.4 years with trend favoring rPSA then nilutamide (5.1 vs 3.4; p = 0.13)
Hematologic toxicities similar to Sm-153 alone
rPSA: grade 1 or 2 injection site reactions Grade 3 toxicities to IL-2 led to dose reduction
Immune response § Safety
PFS at 4 months: Sm-153 = 2/18 NR (11.1%) Sm-153 + P = 5/21 (23.8%) Median PFS days: 51 vs 112 (p = 0.045)
Biochemical failure: RT alone = 2/9 (22%) vs RT + rPSA = 2/17 (12%)
Clinical response‡
§
‡
rV-PSA + rB7.1 followed by rF-PSA; results with PROSTVAC that include the TRICOM of multiple costimulatory molecules are generally more robust [20]. Increase in PSA or evidence of disease progression. Immune response defined as an increase in PSA-specific T cells measured by ELISPOT. ADT: Androgen deprivation therapy; CRPC: Castration-resistant prostate cancer; IPI: Ipilimumab; NCT: National Clinical Trials; NR: Not reported; OS: Overall survival; P: PROSTVAC®; PFS: Progression-free survival; PSA: Prostate-specific antigen; rPSA: PROSTVAC precursors; RT: Radiation therapy; TAA: Tumor-associated antigen; TBD: To be determined; TTP: Time to progression.
†
Nilutamide ± n = 42 nonmetastatic CRPC rPSA with rising PSA Phase II Arlen et al. (2005) Madan et al. (2008) NCT00020254
Flutamide ± rPSA Phase II Bilusic et al. (2011) NCT00450463
Flutamide 400 mg TID alone (n = 13) Flutamide + monthly rPSA (n = 13)
Sm-153 1 mCi/kg on day 8 and every 12 weeks (n = 22) Sm-153 + PROSTVAC (n = 22) days 1,15, 29, then every 4 weeks +GM-CSF 100 μg/day × 4 days
Samarium-153 n = 44 metastatic CRPC after (Sm-153) ± PROSTVAC (P) docetaxel treatment Phase II Heery et al. (2013) NCT00450619
Hormonal therapy
RT alone (n = 11) RT + monthly rPSA (n = 19); RT given during 4th and 6th rPSA +GM-CSF 100 µg/day, days 1–4 +IL‑2 4 MIU/M2 days 8–12
Treatment arms
RT ± rPSA n = 30 hormonePhase II naive patients with Gulley et al. localized PC (2005) NCT00005916
RT
Study/Phase/ Patients study (year)/ Clinicaltrials. gov identifier
Table 1. Phase I/II studies combining PROSTVAC ® or its precursors (rPSA)† with other antineoplastic treatment modalities.
[44,45]
[46]
[47]
[24]
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n = 28 metastatic CRPC with increasing PSA or disease progression
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Monthly P + escalating dose of IPI with vaccine boosts (1, 3, 5, and 10 mg) + GM-CSF 100 μg/day × 4 days
rPSA monthly alone (n = 14) vs rPSA+ weekly docetaxel + dexamethasone (n = 14) + GM-CSF 100 μg/day × 4 days
E 160 mg daily vs E + P days 1, 15, 29, + 4 monthly boosts, then boosts every 3 months
PFS: 3.9 months; OS: 34.4 months
TTP: rPSA = 1.8 months rPSA + docetaxel = 3.2 months 11 rPSA crossed over to receive docetaxel; TTP = 6.1 months vs 3.7 months for historical control
NR 1°: TTP; 2°: OS
6/9 PSA-specific T-cell response + antigen cascade to MUC-1
Median increase of 3.33× for both treatment arms Antigen spreading observed
Local grade 1 and 2 injection site reactions; no dose-limiting toxicity and immune-related events similar to IPI alone
rPSA: Grade 1 or 2 toxicity rPSA+ docetaxel: grade 3 lymphopenia in two patients; one had arthralgias, hyperglycemia and infection with neutropenia
NR NR Planned to include lymphocyte subsets, regulatory T cells, cytokines, naive thymic emigrants
rPSA well tolerated with grade 2 or less toxicity
Immune response § Safety
4/8 rPSA increased TTP: nilutamide = 7.6 months vs ≥2× rPSA = 9.9 months 8/21 nilutamide patients added rPSA and gained 5.2 months for 15.9 months overall 12/21 rPSA patients added nilutamide and gained 13.9 months for 25.9 months overall from rPSA start Median OS for all patients = 4.4 years with trend favoring rPSA then nilutamide (5.1 vs 3.4; p = 0.13)
Clinical response‡
§
‡
†
rV-PSA + rB7.1 followed by rF-PSA; results with PROSTVAC that include the TRICOM of multiple costimulatory molecules are generally more robust [20]. Increase in PSA or evidence of disease progression. Immune response defined as an increase in PSA-specific T cells measured by ELISPOT. ADT: Androgen deprivation therapy; CRPC: Castration-resistant prostate cancer; IPI: Ipilimumab; NCT: National Clinical Trials; NR: Not reported; OS: Overall survival; P: PROSTVAC®; PFS: Progression-free survival; PSA: Prostate-specific antigen; rPSA: PROSTVAC precursors; RT: Radiation therapy; TAA: Tumor-associated antigen; TBD: To be determined; TTP: Time to progression.
n = 30 metastatic PROSTVAC CRPC with IPI Phase I Madan et al. (2012) NCT00113984
Immune checkpoint inhibitors
rPSA ± docetaxel Phase II Arlen et al. (2006) NCT01145508
Chemotherapy
1) n = 72 minimally symptomatic metastatic CRPC, chemotherapy naive 2) n = 34 nonmetastatic castration-sensitive PC
Nilutamide 300 mg/day × 1 month, 150 mg/day (n = 21) vs monthly rPSA (n = 21) After 6 months, patients with rising PSA could receive combination therapy
n = 42 Nilutamide ± rPSA Phase nonmetastatic CRPC II Arlen et al. with rising PSA (2005) Madan et al. (2008) NCT00020254
Enzalutamide (E) ± PROSTVAC (P) 2 Phase II Singh et al. (2013) NCT01867333 NCT01875250
Treatment arms
Study/Phase/ Patients study (year)/ Clinicaltrials. gov identifier
Table 1. Phase I/II studies combining PROSTVAC ® or its precursors (rPSA)† with other antineoplastic treatment modalities (cont.).
[49]
[25]
[48]
[44,45]
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Drug Evaluation Shore the treatment of advanced melanoma. In a Phase I trial of 30 patients with metastatic CRPC, the addition of PROSTVAC to ipilimumab did not increase safety concerns and the median OS was 34.4 months [49] . These positive results provide rationale for combining PROSTVAC with other immunotherapies, including monoclonal antibodies against PD-1, an immune checkpoint inhibitor with potentially fewer toxic effects than ipilimumab. Overall, these Phase I/II combination studies indicate that PROSTVAC can be safely combined with other cancer therapies. Efficacy was generally enhanced by the use of immunotherapy without significant changes to the safety profile of the cancer therapy. The availability of immunotherapy options for metastatic CRPC raise questions about optimal sequencing strategies [52,53] . The use of immunotherapy in the adjuvant setting has potential advantages to offer relatively nontoxic therapy at the point of lowest disease burden [53] and Phase II trials have been conducted with PROSTVAC to explore efficacy in earlier disease settings [24,36] . Potential sequencing opportunities for PROSTVAC include use after ADT failure or after failure of secondary hormonal therapy, and prior to docetaxel or other
chemotherapy. Yet, preclinical research also supports the concept of introducing immunotherapy even prior to androgen ablation [54] , such as in patients currently being managed with watchful waiting. The effects of immunotherapy may continue after treatment has stopped because the immune system has been activated against the tumor cells. Thus, the use of other anticancer modalities after immunotherapies may actually offer a combined therapy approach [39] . The use of immunotherapies after docetaxel therapy (or other drugs that require use of corticosteroids) remains controversial [52,55] . The current Phase III clinical trial of PROSTVAC requires a 28-day washout between corticosteroids and vaccine to limit any antagonistic effects of the corticosteroid on the immune system [33] . Conclusion PROSTVAC represents a novel treatment opportunity for patients with metastatic CRPC, with the potential to extend the lives of men with this disease. PROSTVAC works by stimulating the immune system to specifically target prostate cancer cells. PROSTVAC immunotherapy is well tolerated, with grade 2 or less injection site reactions being most common.
Executive summary • The growth kinetics of prostate cancer and its generation of prostate-specific antigen (PSA) make it a rational target for immunotherapy. • PROSTVAC® contains transgenes for PSA and three costimuatory molecules (called TRICOM). • PROSTVAC combines two poxviruses – vaccinia vector for effective priming of the immune system and fowlpox for subsequent boosts. • The prime–boost concept elicits a robust and prolonged immune response by exposing the immune system to the same antigens while using different viral vectors. • The mechanism of action of PROSTVAC involves immune stimulation, specifically APCs and cytotoxic T lymphocytes to recognize and target cancer cells expressing PSA. • Antigen cascade also has been demonstrated against additional tumor antigens (such as MUC-1, PSMA and PAP) in some patients treated with PROSTVAC. • In a randomized, double-blind Phase II study of men with asymptomatic or minimally symptomatic metastatic CRPC, PROSTVAC provided a significant prolongation in median overall survival of 8.5 months. • A subset analysis of factors known to be prognostic for overall survival in metastatic CRPC consistently favored the PROSTVAC group over the control group, confirming the robustness of treatment effect across subgroups. • PROSPECT is an ongoing global, Phase III, multicenter, randomized, double-blind, placebo-controlled trial of PROSTVAC in 1200 patients with asymptomatic or minimally symptomatic metastatic CRPC with overall survival as the primary end point. • PROSTVAC has been well tolerated; the most common adverse events reported in the Phase II trial were injection site reactions, fatigue, fever and nausea. • No vaccinia-related serious adverse events or cases of unintentional transmission to caregivers or household contacts have been reported to date. • PROSTVAC is available as a subcutaneous injection that can be used off the shelf in various clinical practice settings. • PROSTVAC has been studied in combination with other cancer therapies, and efficacy has been generally enhanced without altering the safety profile of the cancer therapy. • A greater benefit of PROSTVAC immunotherapy may be realized in earlier stage disease and in patients with low-disease burden.
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Results of a randomized, double-blind, placebo-controlled Phase II trial demonstrated a median OS benefit of 8.5 months in patients with metastatic CRPC who received PROSTVAC compared with those who received control. A Phase III trial is ongoing to confirm these results in a larger population of patients with metastatic CRPC. The characteristics of PROSTVAC lend this targeted immunotherapy to use in combination with other cancer therapies, and initial Phase II trials show enhanced efficacy with no significant alteration in the known safety profile of the other modalities. The kinetics of the effect of PROSTVAC also suggest that it may be most beneficial in patients with low tumor burden and less aggressive disease, providing the rationale to study the immunotherapy in earlier stages of prostate cancer. PROSTVAC is administered subcutaneously, making it an easy and readily adaptable treatment for urology, radiation oncology and medical oncology practices. References Papers of special note have been highlighted as: of interest of considerable interest
Continued research into the mechanisms of immunotherapy will provide important information to optimize their use and establish a new paradigm in the treatment of advanced prostate cancer. Financial & competing interests disclosure ND Shore is a consultant to Bavarian Nordic, Inc., Dendreon, Astellas Pharma US, Inc., Algeta, Bayer, Janssen Pharmaceuticals, Inc., Pfizer, Inc., Sanofi-Aventis US, LLC, Medivation, Ferring Pharmaceuticals, Inc., and Millenium. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Support for third-party writing assistance was provided and funded by Bavarian Nordic, Inc. The author was fully responsible for all content and editorial decisions, contributed to the conception and design of the manuscript, and approved the final version for submission. 10
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PROSTVAC® targeted immunotherapy candidate for prostate cancer
Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostatespecific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.
Neal D Shore Carolina Urologic Research Center, 823 82nd Parkway, Myrtle Beach, SC 29572, USA Tel.: +1 843 449 1010 nshore@ gsuro.com
Keywords: biological therapy • cancer vaccine • immunotherapy • prostate cancer • PROSTVAC® • PSA-TRICOM • rilimogene-galvacirepvec
The treatment of advanced prostate cancer has evolved over the last several years and targeted immunotherapies represent a novel therapeutic approach in this evolution. Prostate cancer is a potential target for immunotherapy, as often times prostate cancer proliferates more slowly than other solid malignancies [1] . These growth kinetics allow the necessary time for an immunotherapeutic strategy to generate a targeted immune response, which is expected to translate into clinical benefit. In addition, prostate-specific antigen (PSA) is a unique marker of recurrent or early-stage disease that can be measured and tracked to obtain an estimate of tumor burden. Prostate cancer cells may also generate other unique gene products, or tumor-associated antigens (TAAs), that can be developed as potential immunotherapy targets. TAAs are often weakly immunogenic; thus, immunotherapy has been designed to enhance immune recognition in order to generate an immune response with tumorspecific T-cell-mediated destruction [2] . PSA, prostatic acid phosphatase (PAP) and prostate-
10.2217/IMT.13.176 © 2014 Future Medicine Ltd
specific membrane antigen (PSMA) are key TAAs that have been extensively studied and amply demonstrated to be overexpressed by prostate cancer cells [3–5] . The general process by which T cells mount an immune response to these TAAs is crucial to our understanding of how targeted immunotherapies demonstrate clinical benefit. An antitumor response is generated when the host immune system recognizes immunogenic antigens expressed on the surface of tumor cells. Antigen will bind to major histocompatibility complex (MHC) on APCs and be presented to T cells. This process also involves signalling through costimulatory molecules, such as B7.1, on APCs [6] . Following antigen stimulation, cytotoxic T lymphocytes (CTLs) become activated, proliferate within the local lymph nodes, and are released into the circulation to recognize the same antigens bound to MHC on tumor cells, resulting in lysis of tumor cells. However, tumors often develop tolerance to the immune system through
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Drug Evaluation Shore selection of nonimmunogenic tumor cell variants (a process also called immunoediting) [7] . Several processes have been identified that allow tumor cells to evade the immune system, including downregulation of MHC class I molecules [8] . Immunosuppressive cytokines are also produced in response to malignancies and include IL-4, IL-6, IL-10, TGF-β, VEGF and TNF. Immunosuppression may also occur as a result of an increase in regulatory T cells within the tumor microenvironment, as well as upregulation of checkpoint pathways that inhibit T-cell responses, including CTLA-4 and PD-1. Thus, the goal of immunotherapy is to enhance TAA presentation to the immune system and inhibit immunosuppressive pathways [2] . The ability to induce T-cell responses directed against a TAA and produce antitumor activity has been demonstrated with sipuleucel-T (Provenge; Dendreon Corp., WA, USA), an autologous cellular immunotherapy manufactured from a standard leukapheresis procedure to isolate peripheral blood mononuclear cells, including APCs, from the patients’ serum. The APCs are cultured ex vivo with PA2024, a fusion protein consisting of PAP linked to GM-CSF. The activated cells are infused back into the patient to induce an immune response against prostate cancer cells. Three Phase III trials of sipuleucel-T were conducted in 737 asymptomatic or minimally symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) [9–11] . In the first two trials, the primary end point, time to disease progression (TTP), did not reach statistical significance. Patients were followed for survival over 36 months as a secondary end point. Among patients who received sipuleucel-T, median overall survival (OS) was prolonged by 3.3–4.5 months compared with control [9] . The pivotal Phase III trial in 512 patients employed OS as the primary end point and identified a prolongation of 4.1 months versus control [10] . The safety profile of sipuleucel-T is mainly based on 601 prostate cancer patients who received at least one leukapheresis procedure [12] . Adverse events associated with sipuleucel-T include chills, fatigue, pyrexia, back pain, nausea, arthralgia and headache. Cerebrovascular events occurred more often in the sipuleucel-T group than in the control group (3.5 vs 2.6%). Classic biochemical (PSA) or radiological measures of disease progression have not been reliable markers of sipuleucel-T activity. Other agents recently approved for metastatic CRPC include the cytotoxic agent cabazitaxel (Jevtana®, Sanofi Aventis, Inc., NJ, USA), a microtubule inhibitor for use after docetaxel failure that was shown to provide an absolute improvement in median OS of 2.4 months [13] . Two oral antiandrogen agents, abiraterone
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acetate (Zytiga®, Janssen Biotech, Inc., PA, USA), an androgen biosynthesis inhibitor indicated in combination with prednisone therapy, and enzalutamide (Xtandi®, Astellas Pharma, US and Medivation, Inc., Tokyo, Japan and CA, USA), an androgen receptor inhibitor indicated after failure of docetaxel therapy, provided OS benefits of 4.6 and 4.8 months, respectively [14,15] . Radium-223 dichloride (Xofigo®, Bayer Healthcare Pharmaceuticals and Algeta ASA, NJ, USA) was recently approved for use in CRPC patients with painful bone metastases based on an improvement in median OS of 3.6 months [16] . Development of PROSTVAC® The initial development of immunotherapies for prostate cancer patients included poxvirus immunotherapies [17,18] . Poxviruses have several biological advantages when used as vehicles for cancer immunotherapy including the large size of their genomes enabling them to carry various inserted genes encoding for tumor antigens and immune costimulatory molecules. Presentation of tumor antigens within the poxviral context is highly immunogenic [2] . In addition, poxviral replication occurs in the cell cytoplasm and it does not integrate into host DNA, eliminating mutational risks [6] . PROSTVAC immunotherapy (also called PSA-triad of human T-cell costimulatory molecules [TRICOM]; generic name: rilimogene-galvacirepvec) is produced by inserting the transgenes for PSA and three immune costimulatory molecules via recombinant plasmid into the vaccine viral vector [19] . As the virus enters a host cell, the viral core is released and reproduction within the cell creates a proportion of poxviruses containing the recombinant plasmid that can be identified by expression of markers inserted into the plasmid. The plasmid-containing poxviruses are selected and amplified for use as an immunotherapy. PROSTVAC is a combination of two different poxviruses, both engineered to express PSA, modified at amino acid 155 (I to L) to increase immunogenicity [19] . The first PROSTVAC administration uses the vaccinia vector (PROSTVAC-V), which results in an effective priming of the immune system in order to elicit antitumor response. The second and subsequent PROSTVAC boost doses are fowlpox-based (PROSTVAC-F) and nonreplicating, which prevents the development of viral-coated proteins and maintains the targeted immune response to PSA rather than the viral proteins. The prime–boost concept is an approach to optimize immunotherapy by exposing the immune system to the same antigens while using different viral vectors to minimize the amount of viral protein exposed to the immune system [6] . Preclinical and clinical studies
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have determined and validated that the prime–boost PROSTVAC regimen elicits a robust and prolonged immune response [20,21] . Activation of T cells requires antigen recognition and presentation, as well as costimulation. Thus, LFA‑3,(CD58), ICAM-1 (CD54) and B7.1 (CD80), also known as TRICOM, are encoded with each PROSTVAC dose, both prime and boosts. TRICOM has been shown to significantly enhance T-cell activation in comparison to the use of just one or two costimulatory molecules [20] . TRICOM also enhances the strength of the multiple-antigen binding sites, leading to enhanced T-cell-mediated lysis of tumor cells [19,22] . Expansion of tumor antigen-specific memory T cells and production of multiple cytokines also has been observed with TRICOM [23] . These findings suggest a benefit in sustaining the immune response as the memory T cells remain available to initiate an immune response in the future without the need for ongoing immunotherapy administration. PROSTVAC triggers a targeted immune response to prostate cancer cells that is mediated by APCs and CTLs (Figure 1) [19] . As PROSTVAC is delivered to immune cells, including APCs, the transgenes for PSA and T-cell costimulatory molecules are processed and expressed within the MHC on the surface of APCs. Within locoregional lymph nodes, these activated APCs subsequently lead to activation and proliferation of corresponding CTLs and memory T cells bearing the receptor for the corresponding TAA PSA. Once released from the lymphatic system into the general circulation, the CTLs recognize and destroy PSA-expressing tumor cells throughout the body. Antigen cascade is the development of an immune response to other TAAs found on the tumor cells but not in the vaccine [24] . Studies have found that the immune response generated by targeting PSA with PROSTVAC exposes the immune system to other TAAs released from dying tumor cells, including MUC-1, PSMA and PAP [24,25] . T-cell responses to TAAs that are not present in PROSTVAC argue against using the T-cell response to the TAA (PSA in the case of PROSTVAC) as the only surrogate for immunotherapy efficacy [26] . The possibility also exists for other cellular and molecular entities (such as natural killer T cells) of the immune system to contribute to the efficacy of PROSTVAC [27] . Clinical efficacy: key Phase I & II trials of PROSTVAC-VF A Phase I trial was conducted to evaluate the clinical safety of PROSTVAC in combination with GM‑CSF in patients with metastatic CRPC [28] . Immunologic and clinical responses and kinetics of vaccinia virus
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clearance were also evaluated. In total 15 patients were enrolled and PSA-specific immune responses were observed in four out of six patients who were HLA-A2 positive. Decreases in serum PSA velocity were observed in nine out of 15 patients. No toxicity exceeded grade 2. Results of this trial provided rationale for a Phase II study in patients with less advanced prostate cancer. A double-blind, randomized, multicenter US Phase II trial enrolled 125 subjects with chemotherapy-naive, asymptomatic or minimally symptomatic metastatic CRPC with Gleason scores of 7 or less and no visceral metastases. A total of 122 patients received PROSTVAC (n = 82) or control (n = 40) in a 2:1 ratio [29] . A priming dose of PROSTVAC-V was administered subcutaneously (sc.) on day 1 followed by six booster sc. doses of PROSTVAC-F on days 14, 28, 56, 84, 112 and 140. GM-CSF 100 µg was coadministered with each PROSTVAC administration and for three consecutive days after each administration. Progression-free survival (PFS) was similar among the two treatment groups (3.8 months for PROSTVAC and 3.7 months for control; estimated hazard ratio: 0.88; p = 0.6); however, a significant prolongation in median OS of 8.5 months was observed in the PROSTVAC group (25.1 months) compared with the control group (16.6 months; estimated hazard ratio: 0.56; p = 0.006) (Figure 2) . More patients in the PROSTVAC group were alive at 3 years (30.5%) compared with the control group (17.5%). PSA responses were infrequent and no detectable antibody responses to PSA were observed. All patients developed antibodies to vaccinia vector and all but one patient to fowlpox vector, but there was no correlation between antivector antibodies and OS. To confirm the effect of PROSTVAC on OS, a subset analysis of factors known to be prognostic for OS in metastatic CRPC (e.g., PSA, alkaline phosphatase, lactate dehydrogenase and Halabi-predicted survival [30]) was performed [29] . These analyses consistently favored the PROSTVAC arm over the control arm, confirming the robustness of treatment effect across subgroups. Although some baseline factors appeared to favor the PROSTVAC arm (e.g., age and Halabi-predicted OS), the magnitude of benefit in the PROSTVAC trial could not be attributed to these imbalances. In addition, although post-trial treatment data were not collected, docetaxel was the only chemotherapeutic drug approved at the time the study was conducted. The median improvement in OS with docetaxel was demonstrated to be 2.4 months in metastatic CRPC patients; thus, it is unlikely that differences in post-trial treatment could explain the survival benefit observed in the PROSTVAC trial.
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PROSTVAC PSA
TRICOM† Tumor cell destruction
Subcutaneous injection
Clonal expansion of tumor-specific T cells
APC
Antigen processing
PSA antigen T-cell receptor MHC for PSA
CD80
CD28
Activated cytotoxic T cell T cell
Memory T cell
Immunotherapy © Future Science Group (2014) Figure 1. Mechanism of action of PROSTVAC®. The virus enters APCs, leading to expression of PSA and costimulatory molecules on the surface of APCs. CD80 (on APC) and CD28 (on T cells) are shown as an example of costimulation; LFA-3 (CD58) and ICAM-1 (CD54) also provide costimulation. These stimulated APCs activate T cells to express antigen and proliferate into CTLs and memory T cells. Activated T cells travel through the body and recognize PSA on tumor cells, leading to direct tumor cell lysis or triggering apoptosis. † TRICOM includes LFA-3 (CD58), blue; ICAM-1 (CD54), green; B7.1 (CD80), purple. CTL: Cytotoxic T lymphocyte; MHC: Major histocompatibility complex; PSA: Prostate-specific antigen; TRICOM: Triad of human T-cell costimulatory molecules.
A single-arm Phase II trial was conducted by the National Cancer Institute (NCI) in 32 patients with metastatic CRPC to investigate the effects of PROSTVAC with or without GM-CSF on immunologic and prognostic factors of median OS [26] . Patients with visceral metastases and any Gleason score were eligible for enrolment. The primary end point was immune response as measured by the ELISPOT assay for IFN-γ production, with TTP, objective response and OS as secondary end points. A total of 29 patients were evaluable for immune response, and of these, 13 patients (44.8%) demonstrated enhanced PSA-specific T-cell immune responses greater than or equal to twofold after PROSTVAC administration. Decreased
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PSA occurred in 12 out of 32 patients (37.5%) and five patients had decreases in PSA of 30% or more. The median OS was 26.6 months. The predicated survival by the Halabi nomogram for the study population was 17.4 months, providing a difference of 9.2 months. No differences in OS were observed for patients who received GM-CSF and those who did not. Patients with PSA-specific T-cell responses of greater than sixfold showed a trend toward prolonged survival (p = 0.055). Subgroup analysis of subjects by predicted survival indicated that those who had a predicted survival of greater than 18 months responded with an actual OS of 37 months or more (median was not reached at time of publication)
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Months Figure 2. Overall survival in Phase II trial of PROSTVAC® versus control in patients with metastatic castrationresistant prostate cancer using Kaplan–Meier estimates. The estimated median overall survival was 25.1 months for the PROSTVAC treatment group and 16.6 months for the control group. Reproduced with permission from [29] © 2010 American Society of Clinical Oncology. All rights reserved.
compared with those who had a predicted survival of less than 18 month; their actual median OS was 14.6 months. These results suggest that patients with a lower disease burden might derive particular benefit from immunotherapy, matching comparable observations recently reported for another immunotherapy (sipuleucel-T) in metastatic CRPC [31] . The safety, immunologic and tumor response effects of intraprostatic administration of
PROSTVAC were evaluated in a single-arm Phase II trial [32] . A total of 21 patients with locally recurrent hormone-naive prostate cancer after radiation were enrolled into five cohorts and received initial priming administration with subcutaneous PROSTVAC and booster administrations of intraprostatic PROSTVAC. Cohorts 3–5 also received intraprostatic GM-CSF. Cohort five received concurrent subcutaneous and intraprostatic boosters. Priming was given
Treatment
Asymptomatic/minimally symptomatic mCRPC patients
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Figure 3. PROSPECT study design. † Low-dose adjuvant (100 µg) subcutaneous administration, days 1–4 of each treatment [34] . mCRPC: Metastatic castration-resistant prostate cancer.
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Drug Evaluation Shore on day 1. Boosters were given on days 29, 57 and 85. During the study, stable or improved PSA was observed for 19 out of 21 patients (90.4%) and stable or improved PSA-DT occurred in nine out of 21 patients (42.9%). After administration, three out of nine (33%) evaluable HLA-A2 positive patients had immunological response to PSA by ELISPOT assay. Patients also developed a T-cell response to another prostate antigen, NGEP peptide, probably due to cross-priming of destroyed tumor cells. Overall, four out of nine patients (44%) evaluated had peripheral immune responses to either PSA or NGEP. Tumor immunologic infiltrates were tested in 13 biopsies before and after administration of PROSTVAC: CD3 + cells increased from 12.3 to 21.3 per highpower field (hpf; p = 0.0079), CD4 + cells increased from 1.7 to 12.3 per hfp (p = 0.0005) and CD8 + cells increased from 6.5 to 14.0 per hpf (p = 0.0007). One grade 3 toxicity (fever) occurred and the most common grade 2 adverse events were fever and injection site reactions. The authors concluded that intraprostatic PROSTVAC administration is safe, feasible and can generate a significant immune response [32] . Ongoing Phase III clinical trial Based on the median OS benefit of 8.5 months observed in the randomized Phase II trial [26,29] , a pivotal Phase III trial (PROSPECT) has been designed with OS as the primary end point. PROSPECT is a global, multicenter, randomized, double-blind, placebo-controlled Phase III trial of PROSTVAC in 1200 patients with asymptomatic or minimally symptomatic metastatic CRPC (ClinicalTrials.gov identifier: NCT01322490) [33] . Men are eligible if they have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, life expectancy of more than 1 year, and have not received prior chemotherapy. Patients requiring narcotics for cancer-related pain or metastases to organs other than lymph nodes or bone are excluded because these conditions would signify more advanced disease where the remaining survival might be too short to enable immunotherapy to exert its full therapeutic potential. Eligible patients are randomized in a 1:1:1 ratio to one of two active treatment arms or placebo (Figure 3) . The primary end point is OS with and without GM-CSF (100 µg/ day for 4 days following PROSTVAC administration) compared with placebo. Secondary outcomes include the proportion of patients who remain event free (i.e., radiological or pain progression, initiation of chemotherapy or death) at 6 months, immune response to TAAs and characterization of T-cell populations. Enrolment is ongoing and additional information is available at www.continueyourfight.com.
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Safety & tolerability In the randomized, double-blind Phase II trial, PROSTVAC was well tolerated; the most common adverse events reported were injection site reactions, fatigue, fever and nausea [29] . The majority of these adverse reactions were mild to moderate, with only one grade 3 injection site reaction of cellulitis. The safety of poxviral vaccines containing PSA, either alone or with costimulatory molecules, has been recently summarized by Kim et al. for 297 patients enrolled in nine clinical trials at the US NCI [35] . A total of 1793 poxviral injections were administered, with grade 2 adverse events in 32% and grade 3 adverse events in 1%; one patient experienced serious grade 4 myocardial infarction and thrombotic thrombocytopenic purpura. Overall, 77% of these events were local injection site reactions and none were serious. No vaccinia-related serious adverse events or cases of unintentional transmission to caregivers or household contacts have been reported to date. There has been no indication of immune-related side effects (e.g., autoimmune disorders). PROSTVAC offers advantages over current treatments as a more practical option that can be used ‘off the shelf’. Sipuleucel-T requires patients to undergo apheresis and wait 3 days for the processing of the product at a dedicated facility followed by intravenous administration in a hospital or specialized setting [12] . The PROSTVAC manufacturing process is less complex, and the subcutaneous route of administration allows for use in various clinical practice settings, including urology, radiation oncology and medical oncology. Treatment considerations for PROSTVAC immunotherapy GM-CSF
Immune system adjuvants have been used to enhance the immune response to therapeutic cancer vaccines. In animal models, GM-CSF facilitated recruitment of APCs leading to T-cell activation, and increased the production of multiple cytokines including IL-1, TNF and IL-6 that promote T-cell differentiation [34] . Despite the scientific rationale, the role of GM‑CSF as an immune adjuvant in clinical trials is less clear [19] . In the NCI Phase II trial of 32 patients with metastatic CRPC, the addition of GM-CSF to PROSTVAC did not appear to increase immune responses or OS [26] . The ongoing PROSPECT Phase III trial will clarify the need for GM-CSF as an immune adjunct to PROSTVAC [33] . IL-2 also has been used as an immune adjuvant. The cytokine is a T-cell growth factor that has antitumor effects against advanced melanoma and renal cell carcinoma [6] . However, its use is limited by significant toxicity and dose reductions are often required.
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PROSTVAC® targeted immunotherapy candidate for prostate cancer
Growth rate concept
Clinical studies of active immunotherapy have identified a consistent pattern regarding the timing and type of clinical response. Antitumor activity from immunotherapy occurs over a longer time period and lacks the immediate cytotoxicity and subsequent reduction in tumor size and serum tumor markers (PSA) frequently observed with traditional hormonal therapies, chemotherapy or radiation therapy [10,29] . As a result, the slower tumor growth rate translates into improved OS with no significant effssect on TTP or PSA responses [2,36,37] . With specific regard to PROSTVAC, prolonged tumor growth rates were observed within 3 months based on improved PSA kinetics, including PSA levels and PSA doubling time (DT) [36,37] . Similar findings have been reported for other immunotherapies, including sipuleucel-T and ipilimumab, an immune checkpoint inhibitor [10,38] . In the ipilimumab trial, patients with an apparently enlarging liver lesion on scans ultimately experienced significant tumor responses, suggesting that tumor infiltration with active immune cells can impair the ability to assess progression and may actually disguise an immune response as progressive disease [38,39] . Thus, OS remains the most reliable and objective end point for trials of immunotherapy [2] . A pooled analysis of five NCI-sponsored trials in patients with prostate cancer supports the kinetics of responses to immunotherapies and suggests the potential use of growth rates constants, which correlate with survival, as an intermediate efficacy end point for immunotherapies [40] . These findings also highlight important considerations for patient selection. The most appropriate candidates for immunotherapy of metastatic CRPC are likely those with newly diagnosed asymptomatic disease that does not require urgent treatment with chemotherapy to halt tumor growth. Patients with low disease burden and an uncompromised immune system (i.e., those patients who have not received substantial prior immunosuppressive therapy) may benefit most from activating immunotherapies [39] . Patients with more aggressive disease and a larger tumor burden (i.e., those with Halabi predicted survival of 3× p < 0.0005 6/8 had antigen cascade to other prostate TAAs
NR
rPSA well tolerated with grade 2 or less toxicity
TTP: flutamide alone = 85 days TBD (56–372) Flutamine + rPSA = 223 days (70–638)
TTP: nilutamide = 7.6 months vs rPSA 4/8 rPSA increased ≥2× = 9.9 months 8/21 nilutamide patients added rPSA and gained 5.2 months for 15.9 months overall 12/21 rPSA patients added nilutamide and gained 13.9 months for 25.9 months overall from rPSA start Median OS for all patients = 4.4 years with trend favoring rPSA then nilutamide (5.1 vs 3.4; p = 0.13)
Hematologic toxicities similar to Sm-153 alone
rPSA: grade 1 or 2 injection site reactions Grade 3 toxicities to IL-2 led to dose reduction
Immune response § Safety
PFS at 4 months: Sm-153 = 2/18 NR (11.1%) Sm-153 + P = 5/21 (23.8%) Median PFS days: 51 vs 112 (p = 0.045)
Biochemical failure: RT alone = 2/9 (22%) vs RT + rPSA = 2/17 (12%)
Clinical response‡
§
‡
rV-PSA + rB7.1 followed by rF-PSA; results with PROSTVAC that include the TRICOM of multiple costimulatory molecules are generally more robust [20]. Increase in PSA or evidence of disease progression. Immune response defined as an increase in PSA-specific T cells measured by ELISPOT. ADT: Androgen deprivation therapy; CRPC: Castration-resistant prostate cancer; IPI: Ipilimumab; NCT: National Clinical Trials; NR: Not reported; OS: Overall survival; P: PROSTVAC®; PFS: Progression-free survival; PSA: Prostate-specific antigen; rPSA: PROSTVAC precursors; RT: Radiation therapy; TAA: Tumor-associated antigen; TBD: To be determined; TTP: Time to progression.
†
Nilutamide ± n = 42 nonmetastatic CRPC rPSA with rising PSA Phase II Arlen et al. (2005) Madan et al. (2008) NCT00020254
Flutamide ± rPSA Phase II Bilusic et al. (2011) NCT00450463
Flutamide 400 mg TID alone (n = 13) Flutamide + monthly rPSA (n = 13)
Sm-153 1 mCi/kg on day 8 and every 12 weeks (n = 22) Sm-153 + PROSTVAC (n = 22) days 1,15, 29, then every 4 weeks +GM-CSF 100 μg/day × 4 days
Samarium-153 n = 44 metastatic CRPC after (Sm-153) ± PROSTVAC (P) docetaxel treatment Phase II Heery et al. (2013) NCT00450619
Hormonal therapy
RT alone (n = 11) RT + monthly rPSA (n = 19); RT given during 4th and 6th rPSA +GM-CSF 100 µg/day, days 1–4 +IL‑2 4 MIU/M2 days 8–12
Treatment arms
RT ± rPSA n = 30 hormonePhase II naive patients with Gulley et al. localized PC (2005) NCT00005916
RT
Study/Phase/ Patients study (year)/ Clinicaltrials. gov identifier
Table 1. Phase I/II studies combining PROSTVAC ® or its precursors (rPSA)† with other antineoplastic treatment modalities.
[44,45]
[46]
[47]
[24]
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n = 28 metastatic CRPC with increasing PSA or disease progression
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Monthly P + escalating dose of IPI with vaccine boosts (1, 3, 5, and 10 mg) + GM-CSF 100 μg/day × 4 days
rPSA monthly alone (n = 14) vs rPSA+ weekly docetaxel + dexamethasone (n = 14) + GM-CSF 100 μg/day × 4 days
E 160 mg daily vs E + P days 1, 15, 29, + 4 monthly boosts, then boosts every 3 months
PFS: 3.9 months; OS: 34.4 months
TTP: rPSA = 1.8 months rPSA + docetaxel = 3.2 months 11 rPSA crossed over to receive docetaxel; TTP = 6.1 months vs 3.7 months for historical control
NR 1°: TTP; 2°: OS
6/9 PSA-specific T-cell response + antigen cascade to MUC-1
Median increase of 3.33× for both treatment arms Antigen spreading observed
Local grade 1 and 2 injection site reactions; no dose-limiting toxicity and immune-related events similar to IPI alone
rPSA: Grade 1 or 2 toxicity rPSA+ docetaxel: grade 3 lymphopenia in two patients; one had arthralgias, hyperglycemia and infection with neutropenia
NR NR Planned to include lymphocyte subsets, regulatory T cells, cytokines, naive thymic emigrants
rPSA well tolerated with grade 2 or less toxicity
Immune response § Safety
4/8 rPSA increased TTP: nilutamide = 7.6 months vs ≥2× rPSA = 9.9 months 8/21 nilutamide patients added rPSA and gained 5.2 months for 15.9 months overall 12/21 rPSA patients added nilutamide and gained 13.9 months for 25.9 months overall from rPSA start Median OS for all patients = 4.4 years with trend favoring rPSA then nilutamide (5.1 vs 3.4; p = 0.13)
Clinical response‡
§
‡
†
rV-PSA + rB7.1 followed by rF-PSA; results with PROSTVAC that include the TRICOM of multiple costimulatory molecules are generally more robust [20]. Increase in PSA or evidence of disease progression. Immune response defined as an increase in PSA-specific T cells measured by ELISPOT. ADT: Androgen deprivation therapy; CRPC: Castration-resistant prostate cancer; IPI: Ipilimumab; NCT: National Clinical Trials; NR: Not reported; OS: Overall survival; P: PROSTVAC®; PFS: Progression-free survival; PSA: Prostate-specific antigen; rPSA: PROSTVAC precursors; RT: Radiation therapy; TAA: Tumor-associated antigen; TBD: To be determined; TTP: Time to progression.
n = 30 metastatic PROSTVAC CRPC with IPI Phase I Madan et al. (2012) NCT00113984
Immune checkpoint inhibitors
rPSA ± docetaxel Phase II Arlen et al. (2006) NCT01145508
Chemotherapy
1) n = 72 minimally symptomatic metastatic CRPC, chemotherapy naive 2) n = 34 nonmetastatic castration-sensitive PC
Nilutamide 300 mg/day × 1 month, 150 mg/day (n = 21) vs monthly rPSA (n = 21) After 6 months, patients with rising PSA could receive combination therapy
n = 42 Nilutamide ± rPSA Phase nonmetastatic CRPC II Arlen et al. with rising PSA (2005) Madan et al. (2008) NCT00020254
Enzalutamide (E) ± PROSTVAC (P) 2 Phase II Singh et al. (2013) NCT01867333 NCT01875250
Treatment arms
Study/Phase/ Patients study (year)/ Clinicaltrials. gov identifier
Table 1. Phase I/II studies combining PROSTVAC ® or its precursors (rPSA)† with other antineoplastic treatment modalities (cont.).
[49]
[25]
[48]
[44,45]
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Drug Evaluation Shore the treatment of advanced melanoma. In a Phase I trial of 30 patients with metastatic CRPC, the addition of PROSTVAC to ipilimumab did not increase safety concerns and the median OS was 34.4 months [49] . These positive results provide rationale for combining PROSTVAC with other immunotherapies, including monoclonal antibodies against PD-1, an immune checkpoint inhibitor with potentially fewer toxic effects than ipilimumab. Overall, these Phase I/II combination studies indicate that PROSTVAC can be safely combined with other cancer therapies. Efficacy was generally enhanced by the use of immunotherapy without significant changes to the safety profile of the cancer therapy. The availability of immunotherapy options for metastatic CRPC raise questions about optimal sequencing strategies [52,53] . The use of immunotherapy in the adjuvant setting has potential advantages to offer relatively nontoxic therapy at the point of lowest disease burden [53] and Phase II trials have been conducted with PROSTVAC to explore efficacy in earlier disease settings [24,36] . Potential sequencing opportunities for PROSTVAC include use after ADT failure or after failure of secondary hormonal therapy, and prior to docetaxel or other
chemotherapy. Yet, preclinical research also supports the concept of introducing immunotherapy even prior to androgen ablation [54] , such as in patients currently being managed with watchful waiting. The effects of immunotherapy may continue after treatment has stopped because the immune system has been activated against the tumor cells. Thus, the use of other anticancer modalities after immunotherapies may actually offer a combined therapy approach [39] . The use of immunotherapies after docetaxel therapy (or other drugs that require use of corticosteroids) remains controversial [52,55] . The current Phase III clinical trial of PROSTVAC requires a 28-day washout between corticosteroids and vaccine to limit any antagonistic effects of the corticosteroid on the immune system [33] . Conclusion PROSTVAC represents a novel treatment opportunity for patients with metastatic CRPC, with the potential to extend the lives of men with this disease. PROSTVAC works by stimulating the immune system to specifically target prostate cancer cells. PROSTVAC immunotherapy is well tolerated, with grade 2 or less injection site reactions being most common.
Executive summary • The growth kinetics of prostate cancer and its generation of prostate-specific antigen (PSA) make it a rational target for immunotherapy. • PROSTVAC® contains transgenes for PSA and three costimuatory molecules (called TRICOM). • PROSTVAC combines two poxviruses – vaccinia vector for effective priming of the immune system and fowlpox for subsequent boosts. • The prime–boost concept elicits a robust and prolonged immune response by exposing the immune system to the same antigens while using different viral vectors. • The mechanism of action of PROSTVAC involves immune stimulation, specifically APCs and cytotoxic T lymphocytes to recognize and target cancer cells expressing PSA. • Antigen cascade also has been demonstrated against additional tumor antigens (such as MUC-1, PSMA and PAP) in some patients treated with PROSTVAC. • In a randomized, double-blind Phase II study of men with asymptomatic or minimally symptomatic metastatic CRPC, PROSTVAC provided a significant prolongation in median overall survival of 8.5 months. • A subset analysis of factors known to be prognostic for overall survival in metastatic CRPC consistently favored the PROSTVAC group over the control group, confirming the robustness of treatment effect across subgroups. • PROSPECT is an ongoing global, Phase III, multicenter, randomized, double-blind, placebo-controlled trial of PROSTVAC in 1200 patients with asymptomatic or minimally symptomatic metastatic CRPC with overall survival as the primary end point. • PROSTVAC has been well tolerated; the most common adverse events reported in the Phase II trial were injection site reactions, fatigue, fever and nausea. • No vaccinia-related serious adverse events or cases of unintentional transmission to caregivers or household contacts have been reported to date. • PROSTVAC is available as a subcutaneous injection that can be used off the shelf in various clinical practice settings. • PROSTVAC has been studied in combination with other cancer therapies, and efficacy has been generally enhanced without altering the safety profile of the cancer therapy. • A greater benefit of PROSTVAC immunotherapy may be realized in earlier stage disease and in patients with low-disease burden.
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Results of a randomized, double-blind, placebo-controlled Phase II trial demonstrated a median OS benefit of 8.5 months in patients with metastatic CRPC who received PROSTVAC compared with those who received control. A Phase III trial is ongoing to confirm these results in a larger population of patients with metastatic CRPC. The characteristics of PROSTVAC lend this targeted immunotherapy to use in combination with other cancer therapies, and initial Phase II trials show enhanced efficacy with no significant alteration in the known safety profile of the other modalities. The kinetics of the effect of PROSTVAC also suggest that it may be most beneficial in patients with low tumor burden and less aggressive disease, providing the rationale to study the immunotherapy in earlier stages of prostate cancer. PROSTVAC is administered subcutaneously, making it an easy and readily adaptable treatment for urology, radiation oncology and medical oncology practices. References Papers of special note have been highlighted as: of interest of considerable interest
Continued research into the mechanisms of immunotherapy will provide important information to optimize their use and establish a new paradigm in the treatment of advanced prostate cancer. Financial & competing interests disclosure ND Shore is a consultant to Bavarian Nordic, Inc., Dendreon, Astellas Pharma US, Inc., Algeta, Bayer, Janssen Pharmaceuticals, Inc., Pfizer, Inc., Sanofi-Aventis US, LLC, Medivation, Ferring Pharmaceuticals, Inc., and Millenium. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Support for third-party writing assistance was provided and funded by Bavarian Nordic, Inc. The author was fully responsible for all content and editorial decisions, contributed to the conception and design of the manuscript, and approved the final version for submission. 10
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