Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study

Slovin, Susan F.; Higano, Celestia S.; Hamid, Omid; Tejwani, Sheela; Harzstark, Andrea L.; Alumkal, Joshi J.; Scher, Howard I.; Chin, Kevin M.; Gagnier, Paul; McHenry, M. Brent; Beer, Tomasz M.

doi:10.1093/annonc/mdt107

Cited by 489 publications

(348 citation statements)

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“…58 Seventy patients with metastatic, castrate-resistant prostate cancer enrolled on that trial, and 41 received RT. The delivery of palliative-dose RT before ipilimumab was identified as safe; and all AEs, including irAEs, were unchanged with the combination therapy at both 3 mg/kg and 10 mg/kg of ipilimumab.…”

Section: Ctla-4 Inhibition With or Without Single-fraction Palliativmentioning

confidence: 99%

Irradiation and immunotherapy: From concept to the clinic

Salama

Postow

Salama

2016

Cancer

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In recent years, an increased understanding of T‐cell–regulatory mechanisms has led to the development of a novel class of immune‐checkpoint inhibitors that have robust clinical activity against a broad array of malignancies—even those that historically were not believed to be sensitive to immune therapy. With this, there has been renewed interest in the potential for synergy with more traditional forms of anticancer therapy like radiation therapy (RT). The role of RT in palliation or as definitive treatment for certain malignancies has been well established. Yet, in recent years, the concept has come to light that RT could be an attractive partner for use in combination with other immunotherapies. The effects of RT include not only control of an irradiated tumor but also multiple immunomodulatory effects on both the tumor and the microenvironment, priming tumors for an immune‐mediated response. Herein, the authors summarize relevant preclinical data and rationale supporting the synergy of combined RT and immunotherapy and highlight recent clinical work on promising combination strategies. Cancer 2016;122:1659‐71. © 2016 American Cancer Society.

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Section: Ctla-4 Inhibition With or Without Single-fraction Palliativmentioning

confidence: 99%

Irradiation and immunotherapy: From concept to the clinic

Salama

Postow

Salama

2016

Cancer

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“…35 Subsequent case reports and phase II studies have further increased the research interest, with these initial results suggesting that RT in combination with immunoregulatory agents may lead to "abscopal" responses in some patients, providing optimism that RT can enhance the systemic antiimmune response. 36,37 The underlying principle is that local RTinduced ICD and antitumour immune responses need to be augmented with the addition of immunoregulatory agents which enhance the local and systemic immune response by overcoming the immunosuppressive nature of the local tumour environment, leading to systemic specific antitumour immunity and increasing the possibility of abscopal effects (Figure 1). …”

Section: Enhancing the Immunogenic Potential Of Stereotactic Ablativementioning

confidence: 99%

Stereotactic ablative radiotherapy and immunotherapy combinations: turning the future into systemic therapy?

Walshaw¹,

Honeychurch²,

Illidge³

2016

BJR

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Radiotherapy (RT) is effective at cytoreducing tumours and until relatively recently the focus in radiobiology has been on the direct effects of RT on the tumour. Increasingly, however, the effect of RT on the tumour vasculature, tumour stroma and immune system are recognized as important to the overall outcome. RT is known to lead to the induction of immunogenic cell death (ICD), which can generate tumour-specific immunity. However, systemic immunity leading to "abscopal effects" resulting in tumour shrinkage outside of the RT treatment field is rare, which is thought to be caused by the immunosuppressive nature of the tumour microenvironment. Recent advances in understanding the nature of this immunosuppression and therapeutics targeting immune checkpoints such as programmed death 1 has led to durable clinical responses in a range of cancer types including malignant melanoma and non-small-cell lung cancer. The effects of RT dose and fraction on the generation of ICD and systemic immunity are largely unknown and are currently under investigation. Stereotactic ablative radiotherapy (SABR) provides an opportunity to deliver single or hypofractionated large doses of RT and potentially increase the amount of ICD and the generation of systemic immunity. Here, we review the interplay of RT and the tumour microenvironment and the rationale for combining SABR with immunomodulatory agents to generate systemic immunity and improve outcomes. THE INTERPLAY OF RADIOTHERAPY WITH THE TUMOUR MICROENVIRONMENTIt is estimated that radiotherapy (RT) is required in the treatment of over 50% of all patients with cancer. 1,2 The focus of radiobiology over previous decades has been on the direct cytoreductive effect that RT exerts on cancer cells by inducing DNA damage and only relatively recently have the effects of RT on tumour vasculature, stroma and the immune system received more attention. RT is known to have a number of effects on the generation of tumour-specific immunity, which include enhanced antigen release, expression of Natural killer receptor G2D (NKG2D) ligands, production of Type I Interferon (IFN) and complement, increased major histocompatibility complex and neoantigen expression and the induction of immunogenic cell death (ICD). [3][4][5][6][7][8][9]

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“…CTLA-4 has been shown to be up regulated upon T cell activation, in order to diminish this response. In the mCRPC setting, ipilimumab was tested in a phase I/II trial, where patients received ipilimumab in several dosing schedules plus radiation to a single bone metastasis (24). Results of this trial showed that ipilimumab has antitumor activity with tumor control and manageable toxicities.…”

Section: Immune Checkpoint Inhibitionmentioning

confidence: 99%