Clinical development of immunotherapy for prostate cancer

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1 International Journal of Urology (2017) doi: /iju Review Article Clinical development of immunotherapy for prostate cancer Masanori Noguchi, 1,2,3 Noriko Koga, 1 Tsukasa Igawa 2 and Kyogo Itoh 3 1 Clinical Research Division, Research Center for Innovative Cancer Therapy, 2 Department of Urology, and 3 Cancer Vaccine Center, Kurume University School of Medicine, Kurume, Japan Abbreviations & Acronyms ADT = androgen deprivation therapy APC = antigen-presenting CAR-T = chimeric antigen receptor T CRPC = castration- prostate cancer CTL = cytotoxic T lymphocyte CTLA-4 = cytotoxic T lymphocyte antigen 4 DC = dendritic EMP = estramustine phosphate FDA = US Food and Drug Administration GM-CSF = granulocytemacrophage colony-stimulating factor HR = hazard ratio = metastatic castration prostate cancer MDSC = myeloid-derived suppressor MHC = major histocompatibility complex OS = overall survival PAP = prostatic acid phosphatase PBMC = peripheral blood mononuclear PD-1 = programmed death 1 PD-L1 = programmed death ligand 1 PFS = progression-free survival PPV = personalized peptide vaccine PSA = prostate-specific antigen TAA = tumor-associated antigen TCR = T- receptor Treg = regulatory T Correspondence: Masanori Noguchi M.D., Ph.D., Clinical Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, 67 Asahi-machi, Kurume , Japan. noguchi@med.kurume-u.ac.jp Received 26 January 2017; accepted 14 May Abstract: Prostate cancer is the most common cancer in men, and the second leading cause of cancer-related death in Western countries. Prostate cancer-related death occurs in patients with metastatic castration- prostate cancer. Although several new drugs for castration- prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed. Key words: cancer vaccine, chimeric antigen receptor T s, immunotherapy, prostate cancer, tumor microenvironment. Introduction Although prostate cancer patients with metastatic disease treated with ADT alone usually respond well, ultimately, most patients fail ADT. Progressive status despite ADT is recognized as CRPC, and most prostate cancer-related deaths occur in patients with. Recently, four new drugs, abiraterone acetate, enzalutamide, cabazitaxel and radium-223, for CRPC patients have been approved by the FDA. These new drugs showed OS benefits in phase 3 studies. 1 5 Despite the approval of these new drugs for CRPC patients, each of these has prolonged survival by just a few months. Treatments that can provide durable disease control and long-term survival benefits are still required. In the past few decades, immunotherapy has become an important part of treating some types of cancer. Recent trials showed that immunotherapy can increase survival for patients with CRPC, metastatic melanoma and other malignancies using sipuleucel-t, CTLA-4 and PD-1 blockade, respectively. 1,6,7 Newer types of immune treatments are now being studied, and will impact how we treat cancer in the future. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are summarized and the future clinical development of immunotherapy for prostate cancer is discussed. Mechanism of immunotherapy for cancer Antigen-specific immune s mediated adoptive immunity for systemic antitumor immunity. There are several types that recognize and destroy tumor s, such as macrophages, APCs, CD8 + CTL s and natural killer s. Presentation of tumor antigens to T s by APCs including monocytes and DCs is required to stimulate adaptive immunity. Proliferation and generation of antitumor effects are stimulated by antigen-specific T s through cytokines, and direct killing by CTL. However, tumor s are developing pathways to suppress immune responses and escape from the immune system, and clinical progression. 8 Most investigated mechanisms of escape from the immune system include the modulation of immune-inhibitory (checkpoint) pathways to suppress T- activity, and the disruption of antigen processing and presentation. 9 s can also recruit and promote 2017 The Japanese Urological Association 1

2 M NOGUCHI ET AL. the developing immunosuppressive s, such as Tregs and MDSCs. 10 In addition, the release of immunosuppressive factors, such as transforming growth factor-b, interleukin-6 and interleukin-10, might be directly or indirectly mediated by tumors. These factors contribute to the development of the immunosuppressive microenvironment of the tumor. 11,12 Figure 1 shows the targets of immunotherapy in the tumor microenvironment. The cancer immunotherapies currently under investigation can be classified into four strategies for cancer treatment according to their target. The first strategy is designed to augment the frequency of T s in a patient, specific for one or more tumor-associated antigens. The second strategy is T- checkpoint blockade, such as CTLA-4, PD-1 or PD-L1. The third strategy is the use of T s engineered to express a CAR. The last strategy of immunotherapy is to disrupt or Antigen peptides (a) Memory T TCR Activate and proliferation CTL MHC class I + antigen Peptide Antigen peptides (b) B7 B7 Activation Memory T CTL CD28 CTLA 4 CTLA 4 antibody Antibody blocked negative signal PD-1 PD-1 antibody PD-L1 PD-L1 antibody (c) Antigen specific transduced CTR Antigen specific CAR CAR T (d) Memory T Treg Suppress Suppressed T MDSC Fig. 1 Targets of immunotherapy. (a) Antigen peptides are presented by APCs, such as monocytes and DCs, to T s, and antigenspecific T s are stimulated to proliferate and generate antitumor effects through cytokines, and direct killing by CTL. (b) Immune checkpoint inhibitors, including CTLA4, PD-1 and PD-L1 antibodies, block negative signals to T- cytotoxicity. (c) Engineered or modified CAR- T s permit recognition of a -surface antigen without MHC restriction, and have antitumor activity. (d) Tregs and MDSCs suppress the activation of T s in the tumor microenvironment The Japanese Urological Association

3 Immunotherapy for prostate cancer otherwise modify the immunosuppressive tumor microenvironment. Cancer vaccines The four main types of vaccine-based immunotherapies investigated in prostate cancer can be classified as autologous, -based, viral-based or peptide-based vaccines. The important clinical trials of immunotherapy for prostate cancer are summarized in Table 1. Prostate cancer is a disease for which cancer vaccines have shown survival benefits, with sipuleucel-t being the first cancer vaccine to receive FDA approval for the treatment of any malignancy. This autologous dendritic- vaccine consists of PAP and GM-CSF. 13,14 Three phase 3 clinical trials of sipuleucel-t for prostate cancer reported promising findings for this autologous vaccine. In the first two studies, there was no difference in time to tumor progression, but there was a significant increase in OS (25.9 months vs 21.4 months and 19.0 months vs 15.7 months). 15,16 A third phase 3 clinical trial, known as the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial, showed a 4.1-month improvement in median OS. 1 This provided the first solid evidence that cancer vaccines could provide a real benefit in clinical outcome for patients with prostate cancer. One early clinical investigation of cancer vaccines for prostate cancer was with GVAX. This vaccine is a based vaccine derived from LNCaP and PC3 lines genetically modified to secrete GM-CSF. Although the results of phase 1/2 trials for patients with metastatic prostate cancer were a safety profile, PSA decrease and stabilization, and a median OS time of 35.0 months with highdose treatment, 17 two phase 3 trials (VITAL-1 and VITAL- 2) were closed prematurely due to the lack of superior clinical efficacy compared with chemotherapy in VITAL-1 and an increase in patient mortality observed in VITAL Despite these failure of phase 3 studies, GVAX continues to be explored in combination regimens and for other tumor types. 19 Other investigators have explored different vaccine strategies and target antigens. One anticipated vaccine for prostate cancer is PROSTVAC (PSA-TRICOM), which is a PSA-targeted poxvirus-based vaccine consisting of a heterologous prime-boost (vaccinia or fowlpox virus vector) and three costimulatory molecules (TRICOM; B7.1, ICAM-1 and LFA-3) serving to increase the PSA-specific immune response. 20 -specific CTL responses and prolonged OS in CRPC patients are suggested in a multicenter phase 2 clinical trial of PROSTAVAC. 21 Subsequently, a phase 3 randomized, placebo-controlled trial of PROSTAVAC (NCT ) is currently enrolling 1200 patients with. Patients are randomized to receive PROSTAVAC with GM-CSF, PROS- TAVAC with placebo GM-CSF or double placebo, with OS as the primary end-point. Another new concept of vaccine for prostate cancer is PPV. 22 In this personalized cancer vaccine strategy, appropriate peptide antigens for vaccination are screened based on pre-existing host immunity, and up to four peptides are selected from a list of vaccine candidates in each patient. Previous phase 1 studies of PPV for CRPC showed that PPV was well tolerated, and ular or humoral immune responses, and decreases in the PSA levels in some patients have been reported In a randomized phase 2 study, the combination treatment of PPV with low-dose EMP for CRPC patients showed a longer survival than that of standard dose EMP. 26 Another combination treatment of PPV with low-dose dexamethasone for patients with chemotherapy-na ıve CRPC also showed longer PSA progression-free survival and median survival time. 27 In addition, another phase 2 study suggested that the OS of docetaxel- CRPC patients treated with PPV (n = 20) was longer than that of historical controls (n = 17) (17.8 months vs 10.5 months, P = 0.166). 28 Based on these results, a phase 3, randomized, placebo-controlled trial of PPV (UMIN ) for docetaxel- CRPC patients with OS as the primary end-point was carried out in Japan. This clinical trial has completed enrolling 333 patients, and is currently under investigation. T- checkpoint inhibitors Mechanisms of T- checkpoint inhibitors include interference with molecules on T s that regulate their expansion and function, known as immune checkpoints. CTLA-4, was identified as the first of these T- molecules showing high inhibition of cytolytic antitumor T- responses, 29 and an antibody of CTLA-4 (ipilimumab) was approved for the treatment of patients with metastatic melanoma by the FDA in Subsequent investigation has identified many other checkpoint molecules, such as PD-1 and PD-L1. Antibodies blocking PD-1 have recently received FDA approval for the treatment of melanoma, non-small lung cancer and renal cancer This treatment is expected to be a more active immunotherapeutic strategy than other immunotherapies. Ipilimumab has been evaluated in several phase 1, 2 and 3 clinical trials. A phase 1/2 clinical trial of ipilimumab for patients with showed safety, tolerability and a synergistic activity with radiotherapy. 33 However, a randomized, double-blind phase 3 clinical trial comparing ipilimumab with placebo after radiotherapy in 799 patients in whom docetaxel chemotherapy failed did not confirm an OS benefit. 34 Furthermore, a phase 1 clinical trial of PD-1 blockade with nivolumab in solid malignancies showed no objective responses in 17 men with. 35 Results to date examining either CTLA-4 or PD-1 blockade alone have suggested little role for these treatments as monotherapy for patients with However, effectiveness of T- checkpoint inhibitors with other combination is still investigated. 37 CAR-T s T s with engineered or modified CAR have recently emerged as promising tools for treating tumors. Recent studies have shown marked antitumor activity using CAR-T s that permit recognition of a -surface protein using an antibody recognition domain fused to the TCR signaling domain. 38 CAR-T s targeting CD19 have led to complete responses in some B- malignancies. 39 Although the 2017 The Japanese Urological Association 3

4 M NOGUCHI ET AL. Table 1 Important clinical trials of immunotherapy for CRPC Category Agent (trial ID/ref) Phase n Setting Target Platform Comparison treatment PFS OS Cancer vaccine Sipuleucel-T 1 FDA approved Asymptomatic Cancer vaccine GVAX Asymptomatic Cancer vaccine GVAX plus docetaxel Symptomatic Cancer vaccine PROSTAVAC-VF Minimally Cancer vaccine PROSTAVAC + GM-CSF (NCT ) symptomatic Asymptomatic or minimally symptomatic PAP/GM-CSF fusion Cultured autologous PBMCs Allogeneic tumor lines Allogeneic tumor lines GM-CSF transduced lines GM-CSF transduced lines Placebo (autologous s) Docetaxel plus prednisone 14.6 weeks vs 14.4 weeks (HR 0.95, P = 0.63) 25.8 months vs 21.7 months (HR 0.775, P = 0.032) NA 20.7 months vs 21.7 months (HR 1.03, P = 0.78) Docetaxel NA 12.2 months vs 14.1 months (HR 1.70, P = 0.008) PSA Vaccine-fowl pox Control vector 3.8 months vs 3.7 months (HR 0.884, P = 0.6) PSA Vaccine-fowl pox Placebo GM-CSF Ongoing Ongoing Cancer vaccine PPV plus low-dose EMP CRPC Several TAAs Multiple peptides EMP 8.5 months vs 2.8 months (HR 0.28, P = 0.001) Cancer vaccine PPV plus dexamethasone Chemotherapy naive CRPC Cancer vaccine PPV Docetaxel Cancer vaccine PPV (UMIN ) Docetaxel Check point inhibitor Ipilimumab Docetaxel after radiation CAR-T CAR-T Prostate-specific membrane antigen microenvironment disruptor microenvironment disruptor Snitinib Docetaxel Tasquinimod Chemotherapyna ıve Several TAAs Multiple peptides Dexamethasone 22.0 months vs 7.0 months (HR 0.39, P < 0.001) 25.1 months vs 16.6 months (HR 0.56, P = 0.006) Undefined vs 16.1 months (HR 0.3, P = 0.033) 73.9 months vs 34.9 months (HR 0.41, P < 0.001) Several TAAs Multiple peptides Historical control NA 17.8 months vs 10.5 months (P = 0.166) Several TAAs Multiple peptides Placebo Ongoing Ongoing CTLA-4 Antibody Placebo NA 11.2 months vs 10.0 months (P = 0.053) Angiogenesis and MDSC Angiogenesis and MDSC CAR-T NA NA (2PR with PSA declines of 50%) Tyrosine kinase Placebo 5.6 months vs 4.1 months (HR 0.725, P < 0.001) Oral immunotherapy Placebo 7 months vs 4.4 months (HR 0.64, P < 0.001) NA 13.1 months vs 11.8 months (HR 0.9, P = 0.17) 21.3 months vs 23 months (HR 1.1, P = 0.25) The Japanese Urological Association

5 Immunotherapy for prostate cancer availability of tissue-specific antigens has limited the development of this approach for prostate cancer, some investigators are exploring targeting prostate-specific membrane antigen and prostate stem antigen using the CAR-T approach CAR-modified T s directed toward prostate tissue-specific antigens might be a better treatment choice. microenvironment disruptors -associated immunosuppression contributes significantly to tumor progression and resistance to immunotherapies. 43 It has been recognized that Tregs suppress the activation of T s. Tregs are increased in the PBMCs, tumor microenvironment, lymph node drainage of patients with prostate cancer, 44,45 other solid tumors and hematological malignancies. 49 MDSCs are associated with immunosuppression with several mechanisms, such as defective dendritic function and activation of Tregs. 50 Circulating MDSCs are also increased in some malignancies, and are correlated with advanced clinical stages. 51 In animal studies, sunitinib, one anti-angiogenic agent with tyrosine kinase inhibitor activity, results in increased tumor-infiltrating lymphocytes infiltration, DC maturation and decreased infiltration of MDSCs into the tumor Subsequently, several phase 2 trials were carried out to examine sunitinib as monotherapy for patients with. 55,56 These trials showed signs of efficacy, PSA declines and objective responses. Although a phase 3 trial of sunitinib in patients with showed that sunitinib increased PFS, sunitinib did not impact OS compared with the placebo (13.1 months for sunitinib and 11.8 months for placebo, P = 0.17). 57 Another agent that targets the tumor microenvironment in prostate cancer is tasquinimod. Tasquinimod is an oral immunotherapeutic agent with reported effects on the tumor microenvironment by counteracting tumor growth with decreasing MDSCs and angiogenesis In a randomized, placebo-controlled phase 2 study of men with, tasquinimod significantly improved PFS (7.6 months for tasquinimod and 3.3 months for placebo, P<0.01). 61 However, an international, double-blind, placebo-controlled, phase 3 trial of chemotherapy-na ıve men with showed no significant OS benefit (21.3 months for tasquinimod and 24 months for placebo, P = 0.25). 62 Despite these results, there remains interest in the use of tumor microenvironment disruptors in combination with other immunotherapies. Conclusion Since sipuleucel-t became the first cancer vaccine to receive approval for patients with CRPC, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. Several strategies to enhance the immune response against prostate cancer s have been investigated. Recently, immune checkpoint inhibitors, such as CTLA-4 and PD-1 or PD-L1 antibodies, have generated excitement because they showed significant and durable responses in several malignancies including metastatic melanoma, renal, non-small lung and bladder cancer. Early clinical trials of CTLA-4 antibodies for patients with showed PSA modulation and objective responses in some cases. However, two phase 3 studies of anti-ctla-4 antibody in did not show improvement in OS. The results suggested that CTLA-4 blockade had little effect as monotherapy in patients with. Although there are several promising immunotherapeutic drugs under study, ongoing phase 3 trials for PROSTAVAC in the USA and PPV in Japan might soon broaden the scope of immunotherapies available to patients with CRPC. Current approaches are also investigating optimal combinations and sequencing of immunotherapies with other treatments. In addition, further investigation is required to predict patients with prostate cancer who would most benefit from immunotherapy. Conflict of interest MN has served as an advisory board consultant for Green Peptide Co. Ltd. KI has served as a consultant and received research funding from Taiho Pharmaceutical Company. NK and TI declare no competing interests. References 1 Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for castration- prostate cancer. N. Engl. J. Med. 2010; 363: de Bono JS, Oudard S, Ozguroglu M et al. 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