A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

Heidegger, Isabel; Necchi, Andrea; Pircher, Andreas; Tsaur, Igor; Marra, Giancarlo; Kasivisvanathan, Veeru; Kretschmer, Alexander; Mathiéu, Romain; Ceci, Francesco; Bergh, Roderick C.N. van den; Thibault, Constance; Tilki, Derya; Valério, Massimo; Surcel, C.; Gandaglia, Giorgio

doi:10.1016/j.euo.2020.10.010

Cited by 23 publications

(17 citation statements)

References 56 publications

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“…After radiotherapy, patients were randomly allocated to receive ipilimumab or placebo until progression or intolerable side effects. The study found SITAR led to an improvement in OS at 2 years (25.2% vs 16.6%), 3 years (15.3% vs 7.9%), 4 years (10.1% vs 3.3%), and 5 years (7.9% vs 2.7%) 26,51,52 …”

Section: Introductionmentioning

confidence: 91%

“…The study found SITAR led to an improvement in OS at 2 years (25.2% vs 16.6%), 3 years (15.3% vs 7.9%), 4 years (10.1% vs 3.3%), and 5 years (7.9% vs 2.7%). 26,51,52 Avelumab with stereotactic ablative body radiotherapy (SABR) was tested in a prospective phase 2 study called the ICE-PAC trial, which enrolled 31 men with progressive metastatic castrate-resistant prostate cancer (mCRPC) after at least one prior androgen receptor directed therapy. 21 Avelumab was administered every 2 weeks for 12 cycles.…”

Section: Prostate Cancermentioning

confidence: 99%

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Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

et al. 2022

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Previous preclinical and clinical trials have shown promising antitumour activity and toxicity profile when employing the 'Synergy between Immunotherapy and Radiotherapy' (SITAR) strategy. Approximately, one in seven radiation therapy studies currently recruiting is investigating SITAR. This article reviews the range of cancers known to respond to immunotherapy and publications analysing SITAR. It sets the background for work that needs to be done in future clinical trials. It also reviews the potential toxicities of immunotherapy and discusses areas where caution is required when combining treatments.

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Section: Introductionmentioning

confidence: 91%

Section: Prostate Cancermentioning

confidence: 99%

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

et al. 2022

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“…For example, pre- and postmenopausal breast cancer patients have differential efficacy to zoledronic acid, which is linked to immunomodulatory effects of anti-estrogen treatment [ 160 ]. Similarly, prostate cancer patients are treated with many concomitant therapies, such as androgen deprivation therapy and glucocorticoids that also have immunomodulatory effects, and therefore, it becomes questionable whether combinations with immunotherapies show clinical benefit [ 198 ]. Importantly, bone-modifying agents are used in many clinical trials in combination with immunotherapies, though their use may not be equivalent and comparable.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis

Kähkönen¹,

Halleen²,

Bernoulli

2021

Cells

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Immunotherapies provide a potential treatment option for currently incurable bone metastases. Bone marrow is an important secondary lymphoid organ with a unique immune contexture. Even at non-disease state immune cells and bone cells interact with each other, bone cells supporting the development of immune cells and immune cells regulating bone turnover. In cancer, tumor cells interfere with this homeostatic process starting from formation of pre-metastatic niche and later supporting growth of bone metastases. In this review, we introduce a novel concept osteoimmuno-oncology (OIO), which refers to interactions between bone, immune and tumor cells in bone metastatic microenvironment. We also discuss therapeutic opportunities of targeting immune cells in bone metastases, and associated efficacy and safety concerns.

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“…The TME orchestrates cancer progression and modification of TME components has proven clinical efficacy in several cancers like renal cell cancer or non-small cell lung cancer (NSCLC) [ 1 , 3 , 38 ]. However, in PCa, the most common cancer in men, TME modifying therapies like anti-angiogenic drugs or immune-checkpoint inhibitors did not show relevant clinical activity yet [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive characterization of the prostate tumor microenvironment identifies CXCR4/CXCL12 crosstalk as a novel antiangiogenic therapeutic target in prostate cancer

et al. 2022

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Background Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME. Methods TEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell–cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model. Results Compared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro. Conclusions Overall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa. Graphical Abstract

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A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

Cited by 23 publications

References 56 publications

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

Osteoimmuno-Oncology: Therapeutic Opportunities for Targeting Immune Cells in Bone Metastasis

Comprehensive characterization of the prostate tumor microenvironment identifies CXCR4/CXCL12 crosstalk as a novel antiangiogenic therapeutic target in prostate cancer

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