PD-1/PD-L1 inhibitors

Sunshine, Joel C.; Taube, Janis M.

doi:10.1016/j.coph.2015.05.011

Cited by 525 publications

(387 citation statements)

References 52 publications

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“…As an additional difficulty, the expression of PD-L1 may vary within the tumor and can be induced by previous therapies (21). That being said, patients with low tumor expression of PD-L1 do not respond as well as those with high expression, not only in melanoma, but also across different tumor types (22). In an analysis of melanoma patients treated with pembrolizumab, response rate varied between 57% when melanoma had a high PD-L1 expression, and 8% when there was not PD-L1 expression (23).…”

Section: Pd-l1 Expressionmentioning

confidence: 99%

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

et al. 2017

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Immunotherapy has become a key element in the treatment of several tumors, such as lung carcinoma and melanoma. Immunotherapy, unlike classical chemotherapy and targeted drugs, may yield long-term survival, even in patients who stop treatment due to toxicity. This fact has generated considerable excitement and a real shift in the paradigm of cancer treatment. However, only a small subset of patients benefit from immunotherapy. Survival curves show that most patients have progression of the disease in the first months after starting immunotherapy, followed by a slower decrease over the first 3 years, until curves reach a plateau. This early progression suggests the presence of mechanisms for primary resistance.In addition, some patients have tumor relapse after years of response, suggesting that there is also acquired resistance in a small subset of patients. Resistance mechanisms are now being elucidated. PD-L1 expression in tumor and immune cells correlates with higher chances of response, but melanoma patients with PD-L1 negative tumors can also respond. Several studies have demonstrated an increased probability of clinical benefit when tumors are infiltrated by CD8 T cells, have a high mutation burden or have an interferon gamma signature. But none of these factors has been implemented in the clinical practice, since more studies confirming their value are needed, as well as the development of standardized techniques.

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Section: Pd-l1 Expressionmentioning

confidence: 99%

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

et al. 2017

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“…Indeed, patients whose tumors are PD-L1(+) may not respond, while ~15% of patients with PD-L1(−) tumors demonstrate an antitumor response to therapy. 1 While tumor cell PD-L1 expression varied among melanoma subtypes, we found that when present, it was geographically associated with CD8+ T-cells, similar to most conventional cutaneous melanomas. Previous studies have supported the presence of a possible IFN-γ-mediated adaptive mechanism of PD-L1 display in uveal melanoma cell lines.…”

Section: Discussionmentioning

confidence: 57%

“…[1][2][3][4] Studies from our group and others indicate that the major mechanism driving melanoma tumor cell PD-L1 expression is an association with tumor-infiltrating lymphocytes (TIL), consistent with an endogenous antitumor immune response that may be unleashed with anti-PD-1/PD-L1 therapies. 5 Such adaptive PD-L1 expression by melanoma is not dependent on BRAF, NRAS, or c-KIT mutational status.…”

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confidence: 99%

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Kaunitz¹,

Cottrell²,

Lilo³

et al. 2017

Journal of Investigative Dermatology

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PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13Correspondence: Dr JM Taube, MD, Division of Dermatopathology, Johns Hopkins Hospital, Blalock 907, 600N. Wolfe Street, Baltimore, MD 21287, USA. jtaube1@jhmi.edu. CONFLICT OF INTEREST:The remaining authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P = 0.0002) and higher in CSD (P = 0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P = 0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.Increased objective response rates (ORRs) to anti-PD-1/PD-L1 monotherapy as well as improved progression-free survival and overall survival have been linked to PD-L1 expression in the tumor microenvironment (TME) in some studies. [1][2][3][4] Studies from our group and others indicate that the major mechanism driving melanoma tumor cell PD-L1 expression is an association with tumor-infiltrating lymphocytes (TIL), consistent with an endogenous antitumor immune response that may be unleashed with anti-PD-1/PD-L1 therapies. 5 Such adaptive PD-L1 expression by melanoma is...

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“…PD-L2 has been demonstrated in B-cell lymphomas, and Hodgkin's disease (12) . PD-L1 is expressed in multiple normal tissues, and malignant cells while PD-L2 is essentially expressed from antigenpresenting cells (13)(14)(15) . Different from traditional cytotoxic chemotherapies or target treatments, evaluation of the effectiveness of immunotherapy poses some difficulties due to different reasons.…”

Section: Identification and Role Of Pd-1 And Its Ligands In Cancer Evmentioning

confidence: 99%

Blockade of the Checkpoint as New Target of the Immunotherapy in the Treatment of Cancer.

Yaşin¹,

Eliyatkın²

2018

Terh

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In the treatment of cancer, immunotherapy is applied to retrieve more precisely targeted activities from the components of immune systems via development of treatments mimicking immune system. To this end investigators in the field of oncology have conducted many studies concerning immunotherapy. Cancer cells lead a relatively more independent, and uncontrolled life with their ability to evade from immune system when compared with normal cells. Blockade of the checkpoint has opened the way for a new targeted oncological treatment modalities . In this paper we will briefly review potential position of anti-PD-1, and anti-PD-L1 as novel, and very popular treatment approaches in cancer.Key words: PD-L1, PD-1, blockade of checkpoint, cancer, immunotherapy ÖZKanser tedavisinde, immünoterapi, bağışıklık sistemini taklit eden tedavilerin gelişti-rilmesi yoluyla bağışıklık sistemi elemanlarından daha kesin hedefleri olan aktivite elde etmek için uygulanır. Bu nedenle kanser araştırmacıları tarafından son yıllarda, immunoterapi konusunda çok sayıda çalışma yapılmıştır. Kanser hücreleri, immün sistemden kaçabilme yeteneği ile normal hücrelerden daha bağımsız ve kontrolsüz bir yaşam sürer. Kontrol noktası blokajı kanser tedavisinde yeni bir hedefe yönelik tedavinin önünü açmıştır. Bu makalede, kanserde yeni ve çok popüler olan bir yaklaşım modalitesi olarak anti-PD-1 ve anti-PD-L1 gibi ajanların bugünkü ve gelecekteki olası durumlarını kısaca gözden geçireceğiz.

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PD-1/PD-L1 inhibitors

Cited by 525 publications

References 52 publications

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Blockade of the Checkpoint as New Target of the Immunotherapy in the Treatment of Cancer.

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