Atezolizumab, an Anti–Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study

McDermott, David F.; Sosman, Jeffrey A.; Sznol, Mario; Massard, Christophe; Gordon, Michael; Hamid, Omid; Powderly, John D.; Infante, Jeffrey R.; Fassò, Marcella; Wang, Yan V.; Zou, Wei; Hegde, Priti S.; Fine, Gregg; Powles, Thomas

doi:10.1200/jco.2015.63.7421

Cited by 518 publications

(353 citation statements)

References 46 publications

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“…46 However, more recent preclinical and clinical studies indicate that host cell-derived PD-L1, in particular that produced by dendritic cells and macrophages, could also contribute to PD-1/PD-L1 pathway-targeting immuno-checkpoint blockade. 47–53 Our current studies strongly implicate adipose PD-L1 expression, which is tightly associated with adipogenic differentiation, in therapeutic efficacy of these immunotherapy antibodies. This adipocyte PD-L1-dependent immunomodulatory activity represents a previously unrecognized role of adipose tissue in cancer immunopathogenesis (Figure 7), in addition to a variety of well-documented endocrine and paracrine mechanisms by which adiposity promotes cancer progression.…”

Section: Discussionmentioning

confidence: 77%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.

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Section: Discussionmentioning

confidence: 77%

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Sun

Gupta

et al. 2018

OncoImmunology

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“…However, the relevance of these markers remains more controversial. 21,23,41 In addition, correlations have been previously reported between the biomarkers tested in our study and other potential predictive parameters, which mitigate this bias. Indeed, a positive association was found between patients belonging to the group with PD-L1-expressing tumors and CD8 C T cell infiltration and those harboring high mutational load and in silico predicted mutant neoantigens.…”

Section: Cd8mentioning

confidence: 56%

“…14,18 Furthermore, the pre-existence of CD8-positive tumor-infiltrating lymphocytes, whether or not they express PD-1, has been correlated with the benefit of anti-PD-1 therapy in melanoma, 19 MicroSatellite Instability (MSI)-high colorectal carcinomas 11 and urothelial tumors, 12 but this association has not been confirmed by other groups in melanoma 20,21 or in other tumors. 22,23 Activated CD8 C T cells identified by their PD-L1 expression or the detection of PD-1 by immune cells have also been correlated with clinical response to anti-PD-1. 19,22 In the light of these results, composite biomarkers integrating various components of host-tumor interaction combined in a "tumor-immune signature" may be more relevant to guide the selection of potential responding patients to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy

et al. 2017

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Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the ALK gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. CD8C T cells was also observed in ALK-positive lung cancer patients compared with EGFR-mutated (p D 0.03) or WT patients (p D 0.012). These results strongly suggest that a subgroup of ALK-positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies.

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“…Lastly, assays measuring PD-L1 in tumors have yet to establish a clear threshold of expression that defines what is considered "PD-L1-positive." For instance, the FDA-approved Ventana PD-L1 assay defines ≥5% PD-L1-positive cells in bladder cancer tissue to be associated with higher clinical response rates to atezolizumab [38]. However, alternative PD-L1 assays used in various other clinical trials of nivolumab or pembrolizumab have wide variability in PD-L1 expression analysis methodologies.…”

Section: Predictive Biomarkers For Ctla-4 and Pd-1/pd-l1 Blockersmentioning

confidence: 99%

Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer

Wong¹,

Cameron²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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The clinical success of immune checkpoint blockers is a pivotal advancement for treating an increasing number of cancer types. However, immune checkpoint blockers still rarely induce complete remission and show little to no therapeutic efficacy in a significant percentage of cancer patients. Efforts are now underway to identify biomarkers that accurately predict which patients benefit from immune checkpoint blockers. Moreover, adaptive immune resistance can develop in tumors during treatment with immune checkpoint blockers. These adaptive resistance mechanisms in tumors might be disrupted by combining adjunctive immunotherapies, which could potentially improve the therapeutic efficacy of immune checkpoint blockers. This chapter discusses the mechanism of action of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1/ programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint blockers and biomarkers that might predict clinical responses to these drugs. Lastly, ongoing research on mechanisms of tumor adaptive resistance could facilitate rationale design of adjunctive immunotherapies that can be synergistically combined with immune checkpoint blockers to more effectively treat cancer.

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Atezolizumab, an Anti–Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study

Abstract: Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.

Cited by 518 publications

References 46 publications

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy

Immune Checkpoint Blockade and Adaptive Immune Resistance in Cancer

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