Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Grasso, Catherine S.; Tsoi, Jennifer; Onyshchenko, Mykola; Abril-Rodríguez, Gabriel; Ross‐Macdonald, Petra; Wind‐Rotolo, Megan; Champhekar, Ameya S.; Medina, Egmidio; Torrejon, Davis Y.; Shin, Daniel Sanghoon; Tran, Phuong; Kim, Yeon Joo; Puig-Saus, Cristina; Campbell, Katie M.; Vega-Crespo, Agustin; Quist, Michael J.; Martignier, Christophe; Luke, Jason J.; Wolchok, Jedd D.; Johnson, Douglas B.; Chmielowski, Bartosz; Hodi, F. Stephen; Bhatia, Shailender; Sharfman, William H.; Urba, Walter J.; Slingluff, Craig L.; Diab, Adi; Haanen, John B.A.G.; Algarra, Salvador Martín; Pardoll, Drew M.; Anagnostou, Valsamo; Topalian, Suzanne L.; Velculescu, Victor E.; Speiser, Daniel E.; Kalbasi, Anusha; Ribas, Antoni

doi:10.1016/j.ccell.2020.08.005

Cited by 257 publications

(189 citation statements)

References 60 publications

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“…Similarly response rates to anti-PD1/L1 for desmoplastic melanomas have been described as approximately 70% versus~40% for cutaneous melanomas more broadly [1]. The strongest predictors of response to anti-PD1 in melanoma include PD-L1 expression, interferon-g associated gene expression, and high TMB (4,5). This melanoma demonstrated 0% PD-L1 expression but an extremely high TMB emphasizing the limited interaction between these biomarkers and the importance of neoantigenicity.…”

Section: Discussionmentioning

confidence: 76%

Case Report: Single Dose Anti-PD1 in a Patient With Metastatic Melanoma and Cardiac Allograft

Goodman

Karapetyan²,

Pugliano‐Mauro³

et al. 2021

Front. Immunol.

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BackgroundImmune-checkpoint inhibition has improved outcomes in metastatic melanoma. However, limited data describes the safety and efficacy of this treatment in the setting of cardiac allograft. Emerging translational and clinical evidence suggests that the majority of the benefit from these therapies is driven by the initial dose(s), and that attenuated dosing schedules may be as effective as continuous treatment.Case presentationWe present a case vignette of a cardiac transplant recipient with metastatic melanoma who experienced six months of clinical benefit after one dose of pembrolizumab and did not suffer allograft rejection.ConclusionThis case adds to the current available literature on the administration of checkpoint inhibitors in patients with cardiac allografts. Further, it explores potential markers of immunotherapy response and supports the potential of shorter or individualized immune-checkpoint blockade dosing strategies.

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Section: Discussionmentioning

confidence: 76%

Case Report: Single Dose Anti-PD1 in a Patient With Metastatic Melanoma and Cardiac Allograft

Goodman

Karapetyan²,

Pugliano‐Mauro³

et al. 2021

Front. Immunol.

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“…On the contrary, as a characteristic of host immune cell profiles in responders, a high frequency of CD4 and CD8+ T cells [35,38], NK cells [39], Th9 [40], central memory cells [41], and effector memory T cells [42] has been observed. IFN-γ is also observed in responders [43,44]. PD-1 expression on immune cells and PD-L1 expression on macrophages are increased in responders [35].…”

Section: Discussionmentioning

confidence: 92%

Immune Profile Analysis in Peripheral Blood and Tumor in Patients with Malignant Melanoma

Saito

Sawada

Nakamura

2021

IJMS

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Melanoma is a severe and life-threatening malignancy derived from melanocytes. The traditional treatment for melanoma could not sustain satisfactory outcomes long term; however, the recent immune checkpoint treatment has made a breakthrough in these problems. Nivolumab is a representative immune checkpoint treatment, and this PD-1-targeted therapy has evolutionally developed and improved the clinical outcome in a recent decade. On the other hand, the clinical application of immune checkpoint treatment presents clinicians with novel questions, especially how to obtain additional efficacy and overcome the disadvantage by using this treatment. To answer these problems, we first investigated the distribution of PD-L1 in various organs to clarify the organs most affected by anti-PD-1 antibody treatment. Among various organs, lung, placenta, spleen, heart, and thyroid highly expressed PD-L1, while skin, thalamus, hippocampus, ovary, stomach, testis, and prostate showed lower expressions of PD-L1. Furthermore, the immune profiles were also examined in tumors and peripheral blood in patients with melanoma. PD-1 was highly expressed in CD8 and CD4 cells, and B cells also highly expressed PD-1 compared with NK cells. However, there was no significant difference in Th1/Th2/Th17 cytokines and inhibitory cytokine IL-10. Although nevus showed a low expression of PD-L1 compared with healthy skin, PD-L1 expression was increased in growth-phase melanoma. Finally, we analyzed the peripheral blood profiles in patients treated with nivolumab. PD-1-bearing dendritic cells (DCs) were increased during nivolumab treatment and Lin-CD11c+HLA-DR+ cells were highly increased during nivolumab treatment. These findings indicate a clue to answering the problems during nivolumab treatment and suggest to us the importance of multiple aspect observation during immune checkpoint treatment.

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“…Ongoing efforts to identify biomarkers are underway, including with gene-expression profiling, such as those signatures associated with IFNg (8,108). Until robust biomarkers are identified and then correlated with response to specific therapies, an all-comers approach must be utilized.…”

Section: Resultsmentioning

confidence: 99%

Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma

Rohatgi

Kirkwood

2021

Front. Oncol.

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The advent of first and second-generation immune checkpoint blockade (ICI) has resulted in improved survival of patients with metastatic melanoma over the past decade. However, the majority of patients ultimately progress despite these treatments, which has served as an impetus to consider a range of subsequent therapies. Many of the next generation of immunotherapeutic agents focus on modifying the immune system to overcome resistance to checkpoint blockade. ICI resistance can be understood as primary, or acquired—where the latter is the most common scenario. While there are several postulated mechanisms by which resistance, particularly acquired resistance, occurs, the predominant escape mechanisms include T cell exhaustion, upregulation of alternative inhibitory checkpoint receptors, and alteration of the tumor microenvironment (TME) into a more suppressive, anti-inflammatory state. Therapeutic agents in development are designed to work by combating one or more of these resistance mechanisms. These strategies face the added challenge of minimizing immune-related toxicities, while improving antitumor efficacy. This review focuses upon the following categories of novel therapeutics: 1) alternative inhibitory receptor pathways; 2) damage- or pathogen-associated molecular patterns (DAMPs/PAMPs); and 3) immune cell signaling mediators. We present the current state of these therapies, including preclinical and clinical data available for these targets under development.

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Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Cited by 257 publications

References 60 publications

Case Report: Single Dose Anti-PD1 in a Patient With Metastatic Melanoma and Cardiac Allograft

Case Report: Single Dose Anti-PD1 in a Patient With Metastatic Melanoma and Cardiac Allograft

Immune Profile Analysis in Peripheral Blood and Tumor in Patients with Malignant Melanoma

Beyond PD-1: The Next Frontier for Immunotherapy in Melanoma

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