IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade

Ayers, Mark; Lunceford, Jared; Nebozhyn, Michael; Murphy, Erin; Loboda, Andrey; Kaufman, David R.; Albright, Andrew; Cheng, Jonathan D.; Kang, Shijun; Shankaran, Veena; Piha-Paul, Sarina A.; Yearley, Jennifer H.; Seiwert, Tanguy Y.; Ribas, Antoni; McClanahan, Terrill K.

doi:10.1172/jci91190

Cited by 2,841 publications

(2,956 citation statements)

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“…In fact, tumor mutational burden, known to enhance neoantigen formation, has been shown to be associated with increased response to ICBs, and in some cases improved OS as well, across tumor types such as melanoma [99,100], NSCLC [101], and UC [54,56,102]. Baseline gene expression profiling has also been correlated with response to ICBs; specifically, interferon gamma (IFNγ) signature, which is indicative of an inflammatory tumor microenvironment, is associated with responsiveness to ICBs in several tumor types, including melanoma [103], UC [32,54,104,105], NSCLC [58,106], HNSCC [103], and gastric cancer [103].…”

Section: Immunotherapeutics and Patient Selectionmentioning

confidence: 99%

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

et al. 2018

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Immune checkpoint blockers have revolutionized cancer treatment in recent years. These agents are now approved for the treatment of several malignancies, including melanoma, squamous and non-squamous non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck squamous cell carcinoma. Studies have demonstrated the significant impact of immunotherapy versus standard of care on patient outcomes, including durable response and extended survival. The use of immunotherapy-based combination therapy has been shown to further extend duration of response and survival. Immunotherapies function through modulation of the immune system, which can lead to immune-mediated adverse events (imAEs). These include a range of dermatologic, gastrointestinal, endocrine, and hepatic toxicities, as well as other less common inflammatory events. ImAEs are typically low grade and manageable when identified early and treated with appropriate measures. Identifying the right patient for the right therapy will become more important as new immunotherapies and immunotherapy-based combinations are approved and costs of cancer care continue to rise.

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Section: Immunotherapeutics and Patient Selectionmentioning

confidence: 99%

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

et al. 2018

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“…For example, the objective response rate to PD-1 antibodies in metastatic melanoma is 33-40% [6,7]. Correlative tissue analyses from clinical trials of PD-1 antibodies in metastatic melanoma patients have suggested that resistance or nonresponse to PD-1 antibodies may be seen in tumors with inadequate antitumor T helper type 1 (Th1) immune responses as shown by a reduced IFN-γ signature [11], inadequate expression of inflammatory signals, poor infiltration with effector T cells [12] or high levels of intratumoral regulatory cells [13].…”

Section: Immunotherapy In Cancermentioning

confidence: 99%

“…A third Investigators were requested to maintain one untreated lesion for the duration of the trial to enable the assessment of systemic antitumor immune responses. PD-L1 expression and expression of an IFN-γ gene signature, which has been associated with increased PD-L1 expression, have been identified as positive predictor of response to PD-1 and PD-L1 antibody therapy [11,63,64]. IT-Tavo-EP has been shown to increase IFN-γ gene expression potentially priming less inflamed tumors to respond to PD-1 and PD-L1 antibodies.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

Canton¹,

Shirley²,

Wright³

et al. 2017

Immunotherapy

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Tumors evade detection and/or clearance by the immune system via multiple mechanisms. IL-12 is a potent immunomodulatory cytokine that plays a central role in immune priming. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. We developed an electroporation technique to produce highly localized IL-12 expression within tumors leading to regression of both treated and untreated lesions in animal models and in patients with a favorable safety profile. Furthermore, intratumoral tavokinogene telseplasmid electroporation can drive cellular immune responses, converting ‘cold’ tumors into ‘hot’ tumors. Clinical trials are ongoing to determine whether intratumoral tavokinogene telseplasmid electroporation synergizes with checkpoint blockade therapy in immunologically cold tumors predicted not to respond to PD-1 antibody monotherapy.

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“…However, these gene expression features were necessary, but not always sufficient, for [predicting] clinical benefit (10). Secondly, the immune gene signatures identified in these studies as being associated with anti-PD-1 or PD-L1 therapy response or survival are part of the genes previously identified as the immunological constant of rejection (ICR)-related genes, such as CXCR3, CCR5 ligand genes and IFN-gamma signaling genes.…”

Section: Editorialmentioning

confidence: 99%

“…The authors also discussed similar findings in two additional recent studies evaluating the association of immune-related gene expression in patients with advanced melanoma (Ayers et al, Abstract presented at 30 th Annual Meeting of SITC 2015) and NSCLC (n=224) (9) with anti-PD-L1 or PD-1. A research article in 2017 J Clin Invest by Ayers and colleagues (10) reported that the T cell-inflamed gene expression profile contained IFN-gamma-responsive…”

mentioning

confidence: 99%