Antagonists of PD-1 and PD-L1 in Cancer Treatment

Lipson, Evan J.; Forde, Patrick M.; Hammers, Hans J.; Emens, Leisha A.; Taube, Janis M.; Topalian, Suzanne L.

doi:10.1053/j.seminoncol.2015.05.013

Cited by 276 publications

(208 citation statements)

References 69 publications

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“…11,51 Therapeutic blockade of PD-1 and PD-L1 induces dramatic and durable regression of melanoma and other cancers in patients, a finding that strongly supports this hypothesis. 12,[52][53][54] The contribution of PD-L1 expression in tumor progression without PD-1/PD-L1 blockade, however, remains unclear. Some studies reported negative impact of PD-L1 and PD-L2 expression on patient survival in pancreatic cancer 31 and renal cell cancer 55 in addition to an inverse relationship with tumor infiltrating CD8 C lymphocytes in esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8 C , CD45, CD4 C , CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.

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Section: Discussionmentioning

confidence: 99%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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“…Recent clinical trials showed that blockade of the PD-L1/PD-1 signaling with anti-PD-1 or anti-PD-L1 antibodies is effective in several malignancies and produces durable responses in a subset of patients (24,25). Clinical efficacy of PD-1-blocking antibodies has been demonstrated in patients with advanced melanoma, lung, and renal cancer (26)(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Anti–PD-1 Antibody REGN2810 and Its Antitumor Activity in HumanPD-1Knock-In Mice

Burova

Hermann

Waite

et al. 2017

Molecular Cancer Therapeutics

102

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The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and cancer cells, resulting in suppression of T-cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4 (S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cellbased assays, REGN2810 reverses PD-1-dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knockin mice were generated to express a hybrid protein containing the extracellular domain of human PD-1, and transmembrane and intracellular domains of mouse PD-1. In these mice, REGN2810 binds the humanized PD-1 receptor and inhibits growth of MC38 murine tumors. As REGN2810 binds to cynomolgus monkey PD-1 with high affinity, pharmacokinetic and toxicologic assessment of REGN2810 was performed in cynomolgus monkeys. High doses of REGN2810 were well tolerated, without adverse immune-related effects. These preclinical studies validate REGN2810 as a potent and promising candidate for cancer immunotherapy.

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“…Furthermore, adoptive transfer of autologous T-cells resulted in clinical objective responses in half of the treated melanoma patients [6,7]. Moreover, cancer regression and improved survival has been achieved in melanoma and lung cancer patients using antibodies to coinhibitory molecules, including anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4; ipilumimab, tremelimumab) antibodies [8,9], antiprogrammed cell death protein 1 (anti-PD-1; nivolumab, pembrolizumab) antibodies [10][11][12][13] and antiprogrammed death-ligand 1 (anti-PD-L1; avelumab, atezolizumab; durvalumab) antibodies [14][15][16][17]. Clinical success has also been achieved using targeted therapies aiming to inhibit molecular pathways that are important for tumor growth and maintenance, either as a single therapy or in combination with immunotherapeutic strategies [18].…”

Section: Introductionmentioning

confidence: 99%

The importance of correctly timing cancer immunotherapy

Nejad

Welters

Arens

et al. 2016

Expert Opinion on Biological Therapy

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Introduction:The treatment options for cancer-surgery, radiotherapy and chemotherapy-are now supplemented with immunotherapy. Previously underappreciated but now gaining strong interest are the immune modulatory properties of the three conventional modalities. Moreover, there is a better understanding of the needs and potential of the different immune therapeutic platforms. Key to improved treatment will be the combinations of modalities that complete each other's shortcomings. Area covered: Tumor-specific T-cells are required for optimal immunotherapy. In this review, the authors focus on the correct timing of different types of chemotherapeutic agents or immune modulators and immunotherapeutic drugs, not only for the activation and expansion of tumor-specific Tcells but also to support and enhance their anti-tumor efficacy. Expert opinion: At an early phase of disease, clinical success can be obtained using single treatment modalities but at later disease stages, combinations of several modalities are required. The gain in success is determined by a thorough understanding of the direct and indirect immune effects of the modalities used. Profound knowledge of these effects requires optimal tuning of immunomonitoring. This will guide the appropriate combination of treatments and allow for correct sequencing the order and interval of the different therapeutic modalities. ARTICLE HISTORY

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Antagonists of PD-1 and PD-L1 in Cancer Treatment

Cited by 276 publications

References 69 publications

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

Characterization of the Anti–PD-1 Antibody REGN2810 and Its Antitumor Activity in HumanPD-1Knock-In Mice

The importance of correctly timing cancer immunotherapy

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