Immunosuppressed Microenvironment – An Emerging Target in Prostate Cancer Management

European Oncology & Haematology, 2014;10(1):51–7

Tasquinimod is an orally administered derivative of quinoline-3- carboxamide that targets the tumour microenvironment and inhibits the growth and metastasis of tumour cells by inhibiting angiogenesis and by enhancing the immune response (see Figure 4).71–73 In addition, it appears to modulate the accumulation and function of regulatory myeloid cells and promotes local tumour immunity by blocking the interaction between the S100A9 and pro-inflammatory receptors such as RAGE and TLR4.74 Tasquinimod has shown anti-tumour effects in several tumour models: including increasing the number of tumour infiltrating CD8+ T cells71 and reducing the accumulation of MDSC populations.75 Tasquinimod also has anti-angiogenic effects in prostate tumours, which may be mediated through histone acetylation of regulatory genes.76 It also increases tumour levels of thrombospondin-1 (TSP1), an endogenous anti-angiogenic agent that promotes the recruitment of M1 phenotype TAMs.77

In a phase II study of 206 men with minimally symptomatic mCRPC, tasquinimod significantly slowed progression and increased PFS: 69 % of tasquinimod-treated patients were progression free at 6 months compared with 37 % of the placebo group (p<0.001) and median PFS was increased from 3.3 to 7.6 months (p=0.0042) (see Figure 5).78 All AEs were in general, transient and manageable. Long-term follow-up data showed that OS after tasquinimod treatment was longer than previously reported in this patient group.79 A phase III clinical trial of patients with mCRPC is ongoing in a similar patient population. The primary endpoint is radiological PFS and the trial is powered to show an effect on OS.80 A phase II trial is also investigating the use of tasquinimod as maintenance therapy in mCRPC after chemotherapy with docetaxel.81 In addition, tasquinimod has demonstrated promise in preclinical studies when administered prior or subsequent to androgen deprivation therapy.82

Combination therapies targeting multiple tumour pathways represent an appealing strategy but confer the risk of additional toxicities. Since the inhibitory effects of MDSCs on innate anti-tumour immunity have presented a barrier to immunological approaches to prostate cancer, there is a strong rationale for combining tasquinimod with immunotherapy.83 Preclinical studies have demonstrated that tasquinimod in combination with tumour-targeted superantigens (TTS, an immunotherapy) confers enhanced anti-tumour effects.75 Tasquinimod may also be employed in combination with chemotherapy82 and radiation, though clinical data are missing at the moment.84 MDSCs have also been implicated as a mechanism of tumour resistance to anti-angiogenic therapies, providing a foundation for future research into combinations of tasquinimod with these agents.85

Other Potential for Targets for Therapeutic Intervention
Pro-angiogenesis Factors in the Tumour Microenvironment
Angiogenesis is essential for the development of tumours; without the development of new blood vessels, tumours are only able to grow to 1–2 mm3. As the tumour outgrows its blood supply, the tumour microenvironment becomes hypoxic86 and the HIF pathway is activated, mediated by the transcriptional regulators HIF-1a and HIF- 2a. This pathway facilitates tumour neovascularisation.62 Signals within in the tumour microenvironment stimulate myeloid cells to promote angiogenesis. Furthermore, certain populations of myeloid cells inhibit the response of tumours to anti-angiogenic agents.87 Inhibition of tumour angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) signalling pathway, therefore provides a promising therapeutic target. However, clinical trials investigating bevacizumab,88,89 sunitinib,90 sorafenib91 and imatinib92 have demonstrated limited efficacy and significant toxicities.

Integrins
In addition to the accumulation of macrophages and fibroblasts, the tumour microenvironment also includes a group of cell surface receptors called integrins, which are involved in activation and expression of proteases that aid in extracellular matrix (ECM) degradation, in the cell–cell adhesions that must be broken for migration to occur, as well as transferring information between cells and the ECM.93 Integrins, in particular the avß3- and a5ß1-integrins, also play an important role in angiogenesis. The manipulation of integrin signalling may provide a target for therapeutic intervention. Antibodies targeting integrin are in clinical development for prostate cancer.94 Cilengitide has, to date, demonstrated only modest clinical efficacy in mCRPC.95

The Bone Microenvironment
The bone microenvironment is an important therapeutic target in mCRPC since it is estimated that 90 % of prostate cancer patients experience bone metastases.96 Numerous molecular events in the bone microenvironment are involved in bone metastasis in mCRPC.97 Recent research indicates that stromal elements of the bone microenvironment mediate the development of bone metastasis in mCRPC.22,98 Denosumab is a fully human mAb that inhibits normal and tumour-associated bone lysis by preventing RANKL-mediated formation and activation of multinucleated osteoclasts or giant cells from RANK-positive mononuclear preosteoclasts and macrophages, with demonstrated impact on ongoing osteolysis in randomised phase II trials.99,100

In a phase III trial conducted in 1,904 patients with bone metastases from CRPC, denosumab was compared with zoledronic acid. Median time to first on-study skeletal-related event (SRE) was 20.7 months (95 % CI 18.8–24.9) with denosumab compared with 17.1 months (15.0–19.4) with zoledronic acid (HR 0.82, 95 % CI 0.71–0.95; p=0.008 for superiority).101 In a second randomised phase III trial, denosumab also significantly prevented the onset of bone metastases in patients with CRPC though the benefit was moderate and mostly considered non-clinically relevant, except perhaps for specific high-risk subgroups102 (median metastasisfree survival: 29.5 [95 % CI 25.4–33.3] versus 25.2 [22.2–29.5] months; HR 0.85, 95 % CI 0.73–0.98; p=0.028).103

Radium-223 chloride (Ra-223) is an alpha-emitting radioisotope that targets osteoblastic metastasis. In a recently reported randomised phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, 922 patients were randomised to Ra-223 (n=615) or placebo (n=307). In a planned interim analysis (n=809), Ra-223 significantly improved OS (median 14.0 months versus 11.2 months placebo; p=0.00185; HR=0.695; 95 % CI 0.552–0.875). A rate of SREs was lower in the Ra-223 group, and the time to the first SRE was significantly delayed (median time to SRE 13.6 months versus 8.4 months, respectively; p=0.00046; HR=0.610; 95 % CI 0.461–0.807).104,105 The treatment also demonstrated a favourable safety profile and, as a result, the FDA and European Medicines Agency (EMA) approved Ra-223 for the treatment of mCRPC that has metastasised to bones in 2013.

In a phase II trial, the tyrosine kinase inhibitor cabozantinib caused bone metastases to partially or completely resolve in 85 % of patients with CRPC.106,107 Studies are now exploring the relationship the bone microenvironment and prostate cancer in epithelial tissue and the ability of the cancer to migrate from its origin in the prostate.108

Summary and Concluding Remarks
Treatment approaches successfully employed in many cancers have not proved successful in the management of mCRPC, suggesting that new paradigms are required. The main role of the tumour microenvironment in the development and progression of prostate cancer provides novel targets for therapeutic intervention. Many cellular and molecular components of the immunosuppressed tumour microenvironment have been identified as potential therapeutic targets, including MDSCs, TAMs and the pro-inflammatory protein S100A9. Immunotherapies such as sipuleucel-T and ipilimumab are novel therapeutic strategies with great potential in mCRPC.109 Tasquinimod has demonstrated an ability to modulate the tumour microenvironment in preclinical models, and clinical studies to date have demonstrated promising efficacy and safety in patients with prostate cancer. In addition, preclinical studies indicate that it may enhance the effect of other therapies such as androgen deprivation therapy and chemotherapy. Further preclinical and clinical testing will fully exploit its therapeutic potential as a novel agent targeting the tumour microenvironment rather than direct action on tumour cells. The bone microenvironment is also a promising therapeutic target, with denosumab and Ra-223 proving promising treatment options. Further investigation of components of the tumour environment should help expand the treatment armamentarium for mCRPC.

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Keywords: Castrate-resistant prostate cancer, immunosuppression, ipilimumab, tumour microenvironment, myeloid-derived suppressor cells, S100A9, tumour-associated macrophages, radium-223, sipuleucel T, tasquinimod