Inhibiting the PD-L1 Pathway may help restore Antitumor Immune Response

PD-L1 and PD-1 play different roles in immune regulation and T-cell activation

The major histocompatibility complex (MHC) on tumor cells must also present antigens to T-cell receptors to activate T cells.1

PD-L1 may be expressed on both antigen-presenting immune cells and tumor cells within the tumor microenvironment.2-4

  • Antigen Presenting Cell – T Cell: Inhibiting the PD-L1 to CD80 (B7.1) and PD-L1 to PD-1 interactions may help restore T-cell activity3,5

  • T-Cell – Tumor Cell: Inhibiting the PD-L1 to CD80 (B7.1) and PD-L1 to PD-1 interactions may help restore antitumor immune response2,5

Preventing PD-L1 binding to both CD80 (B7.1) and PD-1 may help restore T-cell activity3,5

Video: “Inhibiting PD-1/PD-L1 Pathway” Video: “Inhibiting PD-1/PD-L1 Pathway”

 

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Not all patients have the same likelihood of responding to PD-1/PD-L1 pathway inhibition10,11

PD-L1 expression status may help identify patients most likely to:

  • Respond to PD-1/PD-L1 pathway inhibition alone11,12

  • Respond to PD-1/PD-L1 pathway inhibition plus inhibition of another immuno-oncology (IO) pathway12-14

PD-L1 expression is being studied as a way to identify patients who may be eligible for alternate approaches to targeting different pathways12-18

High PD-L1 expressing patients may respond to PD-1/PD-L1 pathway inhibition alone

Clinical studies have shown that high PD-L1–expressing patients may demonstrate a higher likelihood of response through blockade of the PD-1/PD-L1 pathway15-17

Low PD-L1 expressing patients may respond to PD-1/PD-L1 pathway inhibition plus inhibition of another immuno-oncology pathway

Clinical studies are being conducted in bladder, SCCHN, and NSCLC to explore the role of PD-L1 expression in identifying patients who might respond to inhibition of the PD-1/PD-L1 pathway and the CTLA-4 pathway14,19-21

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Durvalumab (MEDI4736: Anti–PD-L1 Antibody)

Durvalumab (MEDI4736) blocks PD-L1 binding to PD-1 and CD80 (B7.1) and is being investigated alone and in combination with tremelimumab for its potential effects on non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), bladder cancer, and other tumor types.6,7

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References: 1. Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt's Essential Immunology. 13th ed. Chichester, West Sussex, UK: Wiley-Blackwell; 2017. 2. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450-461. 3. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25-39. 4. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10. 5. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit t cell responses. Immunity. 2007;27(1):111-122. 6. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299-308. 7. National Institutes of Health. ClinicalTrials.gov. Durvalumab with or without tremelimumab in advanced incurable solid malignancies given with or without standard chemotherapy regimens. https://clinicaltrials.gov/ct2/show/NCT02537418. Accessed May 1, 2017.