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PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations

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Science Translational Medicine  02 Mar 2016:
Vol. 8, Issue 328, pp. 328rv4
DOI: 10.1126/scitranslmed.aad7118

Figures

  • Fig. 1. Mechanisms of action of the PD-L1 and PD-1 pathway.

    Cells that express high levels of PD-L1 may include tumor cells, APCs (DCs, macrophages, MDSCs, and B cells), T lymphocytes, epithelial cells, fibroblasts, and others. Engagement of PD-L1 by PD-L1+ cells induces T cell apoptosis, anergy, functional exhaustion, or IL-10 production.

  • Fig. 2. Proposed potential response biomarkers of PD pathway blockade.

    Several biomarkers, including high levels of PD-L1 expression, TH1-type chemokines, infiltrating T cells, mutations, low levels of immunosuppressive elements, and EMT/stem-like features, may be associated with an active response to PD pathway blockade.

  • Fig. 3. Mechanisms of poor tumor T cell infiltration.

    Active tumor β-catenin inhibits CCL4 expression and limits CD103+ DC recruitment and CD8+ T cell activation. TH1-type chemokines CXCL9 and CXCL10 are repressed by EZH2 and DNMT-mediated epigenetic silencing. Consequently, CD8+ T cells poorly infiltrate tumor. Therefore, suppressing β-catenin or epigenetic reprogramming could increase CD8+ T cell tumor infiltration.

  • Fig. 4. Scientific rationales of potential therapeutic combinations with PD pathway blockade.

    Multiple layers of immunosuppressive mechanisms, weak T cell activation, and tumor-intrinsic biological pathways contribute to cancer progression and therapy resistance. The different combinations with PD pathway blockade may yield a synergistic or additive clinical response.

Tables

  • Table 1. Examples of clinical trials with PD-1 and PD-L1 blockade.

    Clinical trials with less than 20 cases or published after 1 October 2015 were not included in the table. CRC, colorectal cancer; HSCT, hematopoietic stem cell transplantation.

    Target and drug informationClinical response rate in different cancer typesPhaseCasesReferences
    Target: PD-1
    Name: Nivolumab, Opdivo, BMS-936558,
    MDX-1106, ONO-4538
    Isotype: Humanized IgG4a
    Source: Bristol-Myers Squibb,
    Ono Pharmaceuticals
    12.8% in treatment-refractory metastatic melanoma,
    castrate-resistant prostate cancer, RCC, NSCLC, or CRC
    139(50)
    28% in advanced melanoma, 18% in NSCLC, 27% in RCC1296(51)
    40% in melanoma treated with nivolumab + ipilimumab,
    20% in nivolumab followed by ipilimumab
    186(58)
    87% in relapsed or refractory Hodgkin’s lymphoma123(56)
    14.5% in refractory NSCLC2117(70)
    31.7% in advanced melanoma progressed after
    anti–CTLA-4
    3405(65)
    40% in previously untreated melanoma without
    BRAF mutation
    3418(64)
    17% in previously treated advanced NSCLC2129(69)
    29% in previously treated advanced RCC134(71)
    20% in advanced squamous-cell NSCLC3272(68)
    57.6% (nivolumab + ipilimumab) versus 19% (ipilimumab)
    versus 43.7% (nivolumab) in untreated stage III or
    IV melanoma
    3945(63)
    Target: PD-1
    Name: Pembrolizumab, Keytruda,
    MK-3475, lambrolizumab
    Isotype: Humanized IgG4κ
    Source: Merck
    38% in melanoma1135(57)
    26% in ipilimumab-refractory advanced melanoma1173(61)
    63% versus 0% in stage IV NSCLC patients with high
    and low nonsynonymous mutation burden
    129(67)
    19.4% in advanced NSCLC1495(66)
    40% and 0% in mismatch repair–deficient/proficient CRC241(53)
    33% (pembrolizumab) and 11.9% (ipilimumab) in
    advanced melanoma
    3834(62)
    Target: PD-1
    Name: Pidilizumab or CT-011
    Isotype: Humanized IgG1
    Source: CureTech Ltd.
    51% in diffuse large B cell lymphoma (after HSCT)266(54)
    66% in relapsed follicular lymphoma232(55)
    Target: PD-L1
    Name: MPDL3280A, RG7446
    Isotype: Fc-modified human IgG1b
    Source: Genentech/Roche
    21% overall response rate in advanced incurable cancer NSCLC,
    SCLC, melanoma, RCC, CRC, gastric cancer, head and neck
    squamous cell carcinoma, breast cancer, ovarian, pancreatic
    cancer, uterine cancer, sarcoma, pancreaticoduodenal cancer
    1277(49)
    52% in metastatic bladder cancer168(47)
    Target: PD-L1
    Name: BMS-936559, MDX-1105
    Isotype: Fully human IgG4a
    Source: Bristol-Myers Squibb
    17.3% in melanoma, 11.7% in RCC, 10.2% in NSCLC, 5.9%
    in ovarian cancer
    1207(48)

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