Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

By Roy S. Herbst, J. Soria, M. Kowanetz, G. Fine, O. Hamid, M. Gordon, Jeffery A. Sosman, David F. McDermott, J. Powderly, S. Gettinger and 12 more. Nature, 2014

4,940 citations recorded by the source corpus.

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the ‘cancer immunity cycle’ by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/5dd77f44ab66bf790ff40893f880eed95c72f90d

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In Immunology

1. D. Pardoll
2. Lieping Chen
3. J. Wolchok
4. E. Wherry
5. W. Zou
6. Antoni Ribas
7. Kristen E. Pauken
8. G. Freeman

In Oncology

1. Lieping Chen
2. J. Wolchok
3. D. Pardoll
4. E. Wherry
5. W. Zou
6. Antoni Ribas
7. Kristen E. Pauken
8. G. Freeman

Citations in the corpus

• Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. (2015, background): “Atezolizumab Herbst (2014) [33] I Multiple solid tumors + hematologic malignancies 277 0.”
• Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. (2016, background): “In addition to PD-L1 expression, it is possible that response to PD-1 or PD-L1 blockade depends on a critical threshold of TILs at the start of therapy (50).”
• Systemic Immunity is Required for Effective Cancer Immunotherapy (2017, neutral): “For specific immunotherapies, individual cell subsets have been examined for mechanistic roles, and features have been correlated with responsiveness (Herbst et al., 2014).”
• Oncolytic viruses: a new class of immunotherapy drugs (2015, background): “Studies suggest that patients with tumours expressing high levels of programmed cell death 1 ligand 1 (PDL1) may have an improved response to T cell checkpoint inhibitors 180 .”
• Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance (2017, neutral): “Recent clinical studies revealed that the success of PD1/PD-L1 blockade correlates with PD-L1 expression levels in tumor cells 6,7 .”
• PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity (2017, background): “In cancer patients, clinical responses to PD-1 immunotherapy positively correlate with tumor PD-L1 expression, along with other predictive biomarkers such as preexisting CD8 T cell infiltration and mutational/neoantigen burden (Herbst et al., 2014; Tumeh et al., 2014).”
• Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures (2016, neutral): “sponsive [20–23].”