Prostate cancer as a model for tumour immunotherapy

Drake, Charles G.

doi:10.1038/nri2817

Cited by 314 publications

(285 citation statements)

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“…Biologically, using cancer immunotherapy earlier is logical because immunotherapy may be more effective when tumor burden is low (26) and the immune system is more intact (27). As tumors progress, the microenvironment becomes increasingly resistant to an immune response (28).…”

Section: Discussionmentioning

confidence: 99%

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Investigators

2017

Clinical Cancer Research

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Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time 12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T!ADT versus ADT!sipuleucel-T (P ¼ 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T!ADT versus ADT!sipuleucel-T (P ¼ 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P ¼ 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08-0.67; P ¼ 0.007). Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-T!ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation.

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Section: Discussionmentioning

confidence: 99%

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Investigators

2017

Clinical Cancer Research

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“…Studies have suggested close links among certain infections of the prostate, chronic inflammation, and the development of inflammation-associated prostatic diseases (5)(6)(7)(8)(9)(10). It has been proposed that certain infections of the prostate contribute to the development of chronic inflammation and regenerative "risk factor" lesions, referred to as proliferative inflammatory atrophy, contribute to the development of prostate cancer (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

Ponomareva

Liu

Duan

et al. 2013

Molecular Cancer Research

102

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Close links have been noted between chronic inflammation of the prostate and the development of human prostatic diseases such as benign prostate hyperplasia (BPH) and prostate cancer. However, the molecular mechanisms that contribute to prostatic inflammation remain largely unexplored. Recent studies have indicated that the IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes. Upon sensing DNA, AIM2 recruits the adaptor ASC and pro-CASP1 to assemble the AIM2 inflammasome. Activation of the AIM2 inflammasome cleaves pro-interleukin (IL)-1b and pro-IL-18 and promotes the secretion of IL-1b and IL-18 proinflammatory cytokines. Given that human prostatic infections are associated with chronic inflammation, the development of BPH is associated with an accumulation of senescent cells with a proinflammatory phenotype, and the development of prostate cancer is associated with the loss of IFN signaling, the role of AIM2 in mediating the formation of prostatic diseases was investigated. It was determined that IFNs (a, b, or g) induced AIM2 expression in human prostate epithelial cells and cytosolic DNA activated the AIM2 inflammasome. Steady-state levels of the AIM2 mRNA were higher in BPH than in normal prostate tissue. However, the levels of AIM2 mRNA were significantly lower in clinical tumor specimens. Accordingly, constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells as compared with BPH cells. Further, the cytosolic DNA activated the AIM2 inflammasome in the androgen receptor-negative PC3 prostate cancer cell line, suggesting that AIM2-mediated events are independent of androgen receptor status.

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“…5). 23 In the coming years, as the results of studies currently underway with the newly approved therapies become available, our understanding of where these treatments fall into place should become clearer.…”

Section: Resultsmentioning

confidence: 99%

“…2). 23 Although this drug has only recently been made available in the United States, it had been an active area of research for quite some time. Two randomized, placebo-controlled, phase III trials were carried out (D9901 24 and D9902A 25 ).…”

Section: Immune Therapymentioning

confidence: 99%

Emerging novel therapies in the treatment of castrate-resistant prostate cancer

Abdulla

Kapoor

2013

CUAJ

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The treatment options for patients with castration-resistant prostate cancer (CRPC), until very recently, only included docetaxel. In the past 10 months, newly Federal Drug Administration (FDA) approved agents in the United States have shown survival benefit for patients with CRPC. This review takes a closer look at these newer agents: sipuleucel-T (immune therapy) and cabazitaxel (cytotoxic therapy). We also review the evidence supporting the FDA's approval of denosumab (bone-targeted therapy) as a treatment option for men with CRPC and bony metastases. Newer agents currently being investigated in phase III clinical trials for their potential role in metastatic CRPC are also reviewed. These agents include abiraterone (hormonal therapy), TAK-700 (hormonal therapy), MDV3100 (hormonal therapy), ipilimumab (immune therapy), zibotentan (endothelin-A receptor antagonist) and dasatinib (tyrosine kinase inhibitor). As ongoing studies using all the aforementioned agents continue to evolve, our understanding of how and where these agents fit into the treatment paradigm for patients with CRPC will become clearer. RésuméLes options thérapeutiques des patients atteints d'un cancer de la prostate résistant à la castration (CPRC), jusqu'à tout récemment, ne comprenaient que le docetaxel. Au cours des 10 derniers mois, de nouveaux agents approuvés par la Food and Drug Administration (FDA) des États-Unis ont montré un avantage lié à la survie chez les patients atteints d'un CPRC. Nous examinons ici plus étroite-ment ces nouveaux agents : le sipuleucel-T (immunothérapie) et le cabazitaxel (traitement cytotoxique). Nous passons aussi en revue les données étayant l'approbation par la FDA du dénosumab (traitement ciblant les cellules osseuses) comme option thérapeutique chez les hommes atteints d'un cancer de la prostate résistant à la castration avec métastases osseuses. Les nouveaux agents en cours d'études cliniques de phase III en raison de leur rôle potentiel dans le traitement du CPRC métastatique sont aussi examinés. Ces agents incluent l'abiratérone (hormonothérapie), le TAK-700 (hormonothérapie), le MDV3100 (hormonothérapie), l'ipilimumab (immunothérapie), le zibotentan (antagoniste des récepteurs de l'endothéline-A) et le dasatinib (inhibiteur de la tyrosine-kinase). À mesure que les études en cours sur ces agents continuent de progresser, notre compréhen-sion du rôle et de l'usage de ces agents dans le paradigme théra-peutique des patients atteints de CPRC s'approfondira.

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Prostate cancer as a model for tumour immunotherapy

Cited by 314 publications

References 132 publications

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

Emerging novel therapies in the treatment of castrate-resistant prostate cancer

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