PROSTATE DISEASE 28

Immunotherapy for prostate cancer: the next step?

HANNAH RUSH, CLARE GILSON AND SIMON CHOWDHURY

Immunotherapy is showing great promise in the treatment of a wide range of cancers. Using the body’s own immune system to attack tumours is an attractive proposition that has the advantage of being selective with reduced toxicity. In this article the authors provide a comprehensive overview of the current approaches being tested in the treatment of prostate cancer. Immunotherapy involves stimulating the body’s adaptive immune response against tumour cells. It has the potential to be more targeted and less toxic than cytotoxic chemotherapy (© Steve Gschmeissner/Science Photo Library) rostate cancer is the most common with CRPC, including the cytotoxic agent Pcancer among men worldwide and one cabazitaxel (Jevtana), anti-androgen drugs of the leading causes of cancer-related abiraterone (Zytiga) and enzalutamide mortality. When diagnosed early, it can (Xtandi), and sipuleucel-T, the first cellular be treated effectively with surgery or immunotherapy to receive a licence radiotherapy. However, 5% of patients for solid tumour oncology.1 Although present with metastatic disease. Despite sipuleucel-T was approved by the American recent advances in treatment, the average Food and Drug Administration (FDA) in life expectancy for these patients is only 2010, following an appraisal in 2015, the 3.5 years. National Institute for Health and Care Excellence (NICE) has not recommended its Androgen deprivation therapy (ADT) use within the NHS in the UK, largely on has traditionally been the lynchpin of the grounds of cost.2 Hannah Rush, Clinical Fellow in Medical first-line management of metastatic Oncology; Clare Gilson, Clinical Fellow disease. Eventually, all patients treated for Recent advances in immunotherapy have in Medical Oncology; Simon Chowdhury, metastatic disease will develop castration- been practice-changing in the treatment of Consultant Medical Oncologist; resistant prostate cancer (CRPC). Over the melanoma, renal cell carcinoma and lung Department of Medical Oncology, last five years, a range of new agents have cancer. It is an exciting therapeutic option, Guy’s Hospital, London been found to improve survival in patients offering the potential for significant

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improvement in patient outcomes, coupled Immune markers Prognosis with a more favourable side-effect profile than traditional cytotoxic agents. This Protective immune response Presence of effector T cells specific to TAAs, review will outline some of the immuno- including epitopes on the androgen receptor therapeutic approaches currently being Presence of antibodies against NY-ESO-1, a TAA evaluated in trials. NK cell tumour infiltration

WHAT IS IMMUNOTHERAPY? Poor prognosis Increased level of circulating and tumour- Preclinical data support the role of infiltrating immunosuppressive Tregs immunotherapy in the treatment of prostate Mutations of TGF-β cancer. Studies show that prostate cancer Increased risk of recurrence Infiltration of macrophages after ADT stimulates an immune response and that infiltration of certain immune cells within TAA, tumour-associated antigens; NK cell, natural killer cell; Tregs, T regulating cells; a tumour correlates with patient survival,3 TGF-β, transforming growth factor beta. suggesting the immune system’s key role in Table 1. Immune markers of prognosis in prostate cancer4 controlling cancer growth (Table 1). of current therapies and support the of progression-free survival (PFS), a Immunotherapy involves stimulating the development of novel approaches capable significant 4.3-month median survival body’s adaptive immune response against of exploiting this further. difference favoured treatment.10 tumour cells, a slower process than the effect of cytotoxic agents. As prostate IMMUNOTHERAPY AGENTS Subsequently, the IMPACT study, a double- cancer is relatively slow-growing, there Currently, there are two main strategies blind, placebo-controlled trial, assessing the is sufficient time for immunotherapy to for harnessing immunotherapy in prostate efficacy of sipuleucel-T in 512 patients with produce a response. One advantage in cancer: and checkpoint metastatic CRPC, was designed with overall harnessing the immune system in prostate blockade. In the context of treating cancer, survival (OS) as the primary endpoint.11 A cancer is that the prostate is not a vital therapeutic aim to stimulate significant improvement in median OS of organ. Well described tumour-associated immune cells to recognise malignant cells 4.1 months was seen, with a 3-year survival antigens (TAAs) have been studied, including as foreign, thus initiating an immune of 31% versus 23% with placebo. As in the prostate-specific antigen (PSA), prostate- attack. Tumours employ inhibitory initial trials, the PFS did not differ between specific membrane antigen (PSMA), prostate checkpoint signals to prevent stimulating the two groups. Sipuleucel-T was generally acid phosphatase (PAP) and prostate stem T-cell activation, thus checkpoint blockade well tolerated, with 99% of the patients able cell antigen (PSCA). No perfect prostate enables the immune response to proceed to complete the treatment course. The most cancer TAA has yet been discovered. uninterrupted against tumour cells.8 common side-effects reported were chills, fever and headache. A subgroup analysis In addition to the understood mechanism Autologous vaccines demonstrated the greatest effect was seen in of their therapeutic effect, some established Sipuleucel-T is an autologous dendritic patients with a lower baseline PSA, suggesting prostate cancer treatments also activate cell infusion. Following leukophoresis, the treatment may be most beneficial in those the immune system. ADT enhances immune the cells are primed with a fusion with less advanced disease.12 response against tumour cells, improving protein of the tumour-associated T-cell activation and homing to sites of antigen PAP and granulocyte macrophage One criticism of the trial design was that disease.5 Chemotherapy has traditionally colony-stimulating factor (GM-CSF), cells were harvested in both arms of been thought of as impairing immune before being infused back into the the trial – approximately 90% of each response due to lysis of leucocytes; however, patient. The primed dendritic cells activate patient’s circulating mononuclear cells were there is some suggestion that it may facilitate antigen-specific cytotoxic T cells, which harvested – yet in the control arm these induction of anti-tumour immunity. For target PAP-expressing tumour cells.9 cells were not re-infused. Cell depletion may example, docetaxel has been reported to therefore account for poorer survival in the increase the production of pro-inflammatory Two phase 3, randomised, placebo- control arm.13 cytokines6 and doxorubicin to enhance controlled trials were initially conducted cytotoxic T-cell anti-tumour immunity.7 with a total of 225 patients with Viral vector-based vaccines These data suggest that immune activation metastatic CRPC. Although there was PROSTVAC-VF comprises two recombinant may play a part in the effectiveness no difference in the primary endpoint viral vectors, each encoding transgenes

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for PSA and three immune co-stimulatory ONY-P1 is another cell-based CTLA-4 targeting agent tremelimumab, a molecules. A -based vector is comprising three irradiated prostate cancer fully human IgG2 monoclonal antibody, used for the initial priming vaccination, cell lines. In a non-randomised phase 2 has undergone testing in a phase 1 followed by six planned fowlpox-based trial, 26 patients with metastatic CRPC trial of 11 patients with PSA recurrence. vector boosts. This is intended to activate received ONY-P1 intradermally, with bacilli Dose-limiting toxicities of diarrhoea host dendritic cells, which in turn activate Calmette-Guerin as a vaccine adjuvant and skin rash were observed; however, a T cells against PSA-expressing cells. for the first two doses. A significant delay prolongation of PSA doubling time in three in PSA velocity was observed in 11 of the patients suggests that further investigation A phase 2, randomised, double-blind, 26 patients.18 may be warranted.21 placebo-controlled study of 125 patients with minimally symptomatic CRPC Personalised peptide vaccines PD-1 checkpoint blockade found a significant 8.5-month (25.1 This approach screens a patient’s The immune regulatory inhibitor versus 16.6 months) survival advantage immune response against a panel of programmed cell death protein 1 (PD-1) is in patients treated with PROSTVAC-VF. 31 TAA-peptide epitopes known to be another suppressive immune checkpoint There was no difference in the primary potentially immunogenic in prostate receptor. Tumour cells can express endpoint of PFS. Common adverse cancer. A small panel of peptides is programmed death ligand 1 or 2 (PD-L1 events were fever, nausea, fatigue selected and the patient is vaccinated or PD-L2), which interact with PD-1 on and injection site reactions.14 It is not with them. One phase 2 study involving T cells, resulting in inhibition of T-cell yet clear at which stage of disease 42 patients with CRPC, of whom half activation against the cancer. In mouse PROSTVAC-VF will be most effective; were resistant and half sensitive to models, the absence of PD-1 has shown the results of studies evaluating its use docetaxel, found a non-significant trend to dramatically delay tumour growth and in non-metastatic hormone-sensitive towards improved survival amongst the increase cytotoxic T cells within tumour prostate cancer are awaited. docetaxel-resistant patients compared tissue.22 A study examining the tumour with historical controls (17.8 versus biopsies of seven patients with prostate Another viral vaccine in early development 10.8 months).19 cancer found that 90% of the infiltrating uses adenovirus type 5 vectors to deliver CD8+ T lymphocytes had upregulated cell tumour-associated antigen-coding genes. CTLA-4 checkpoint blockade surface expression of PD-1.23 In a phase 1 trial including 32 patients T-cell responses depend on a balance with metastatic CRPC, 48% had an between positive and negative co-regulatory Nivolumab is an anti-PD-1 monoclonal increase in PSA doubling time and 55% signals that are generated within the antibody that has recently been approved survived longer than predicted.15 T cell. Cytotoxic T-lymphocyte antigen 4 by the FDA for use in metastatic (CTLA-4) is an immune checkpoint melanoma. In a phase 1 trial of nivolumab, Cell-based vaccines receptor responsible for suppressing including 17 patients with metastatic GVAX is an allogenic, whole-cell vaccine T-cell activation. Ipilimumab is a fully CRPC, no objective response was seen consisting of two prostate cancer cell human monoclonal antibody that binds amongst the prostate cancer patients.24 lines transduced with GM-CSF. Two large to and inhibits CTLA-4 ligand-driven 42 patients in the trial, with a mix of solid phase 2 trials, VITAL-1 and VITAL-2, have activation. By overcoming the CTLA-4 tumour types, had biopsies assessed for been conducted. VITAL-1, comparing mediated suppression, T cells are activated PD-L1 expression. Whilst none of the GVAX with docetaxel and prednisone, was with the potential to ‘take them off patients with negative PD-L1 biopsies had terminated early due to a futility analysis the leash’, allowing TAA recognition a response, 36% of patients with evidence that suggested a low probability of the trial and elimination. of PD-L1 expression had an objective reaching the primary endpoint.16 VITAL-2, response to treatment. PD-L1 was the only which compared docetaxel and GVAX A phase 3 trial of 799 patients with biomarker to have a significant correlation with docetaxel alone, was terminated due advanced CRPC that had progressed with response to nivolumab.25 to high mortality in the treatment arm.17 after docetaxel compared radiotherapy The increased death rate in the treatment and ipilimumab with radiotherapy and CONCLUSION group was not clearly related to increased placebo. There was no significant survival Immunotherapy is an exciting and toxicity. Recent evidence has suggested difference (11.2 versus 10.0 months).20 rapidly advancing field that is enjoying that GVAX may have a role when given Ongoing studies are investigating the renewed interest and some success in in combination with ADT for hormone- use of ipilimumab in earlier stages of prostate cancer. Sipuleucel-T continues to sensitive prostate cancer. prostate cancer. demonstrate durable and well-tolerated

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responses in prostate cancer; studies to associated comorbidities. Immunotherapy changes in how immune-related responses determine if the impressive results seen could potentially be more effective when are assessed.26,27 with checkpoint inhibitors in other solid administered early in the course of the tumours can be replicated in prostate disease; many current trials are focused on Studies have assessed whether genetic cancer are ongoing. Questions remain this possibility (Table 2). analysis of tumour cells can provide clues as regarding the efficacy of newer treatments, to who will respond to immunotherapy. New what constitute optimum sequencing We need to better understand the natural peripheral biomarkers are also being sought and the potential benefits of combination history of changes within tumours treated to aid in the prediction and measurement therapy (see Table 2 for a summary of with immunotherapy. According to current of response to treatment, as well as markers ongoing trials). methods of measuring PFS, most patients that would enable the prediction of toxicity. show no response to immunotherapy, yet This would allow targeted therapy for To date, immunotherapy has been there is often significant improvement individuals most likely to benefit from investigated predominantly in advanced in OS. The Prostate Cancer Clinical immunotherapy, providing a rationale disease, where the immune system may Trials Working Group has proposed for the use of such high cost treatments have been suppressed and impaired by new criteria for evaluating cytotoxic and and a basis on which truly individualised previous treatments, disease burden and non-cytotoxic agents, which include treatment plans could be formulated.

No. of Agents Population Phase Primary outcome Trial number patients Sipuleucel-T and Metastatic CRPC 100 2 Evaluate peripheral NCT01981122 enzalutamide immune response Sipuleucel-T and ADT Non-metastatic 68 2 Measure change in NCT01431391 prostate cancer with immune response rising PSA Sipuleucel-T and Refractory metastatic 50 2 Immune response to NCT01560923 indoximod prostate cancer sipuleucel-T

PROSTVAC and GM-CSF Metastatic prostate 1298 3 Overall survival NCT01322490 cancer PROSTVAC and Non-metastatic 26 2 Decrease in tumour NCT01875250 enzalutamide hormone-sensitive regrowth rate prostate cancer PROSTVAC and Metastatic CRPC 76 2 Progression-free survival NCT01867333 enzalutamide Localised prostate 711 3 Disease-free survival NCT01436968 ProstAtak as adjuvant cancer with radiotherapy GVAX and ADT with Localised prostate 29 1 and 2 Assess CD-8 infiltration NCT01696877 cyclophosphamide cancer into prostate cells Ipilimumab and Pre-chemotherapy 54 2 Impact of the timing of NCT01804465 sipuleucel-T metastatic CRPC ipilimumab on immune reponse created by sipuleucel-T Pidilizumab and Advanced CRPC 57 2 Feasibility and immune NCT01420965 sipuleucel-T with efficacy cyclophosphamide Table 2. Ongoing trials of immunotherapy agents in prostate cancer

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