programed death ligand 1 is a target for cancer immunotherapy

1. Programed
Death Ligand 1

2. OUTLINE
Introduction
PD-L1 DISTRIBUTION
PD-L1 on Tumor Cells
PD-1/PD-L1 Based Cancer Immunotherapy
Silencing & Regulating PD-L1 Expression in Tumor Cells
 Application of PD-L1 antibodies in cancer combination
therapy

3. Introduction
• Programmed death-ligand 1 (PD-L1) also known as CD274 or
B7-H1 is encoded by the CD274 gene
• PD-L1 is type 1 transmembrane protein
• ligand for the inhibitory receptor PD-1
• typically expressed on immune cells so they don’t destroy each
other in inflammation
• expression can be detected in other non-immune cells, vascular
endothelium, tumor cells
• suppress the adaptive immune system during pregnancy, tissue
allografts, autoimmune disease and hepatitis.
• blockage of PD-L1 pathway provide a rationale for cancer
immunotherapy.
• Co-stimulate T-cell subsets that produce interleukin-10 (IL10)

4. cancer cell
PD-L1
lymphocyte
Placenta Tumor

5. https://www.proteinatlas.org/ENSG00000120217-CD274/tissue

6. • PD-L1 expressed in cancers like Urothelial carcinoma
and non-small cell lung cancer.
• The PD-L1 pathway help tumors to attenuate anti-
tumor immunity and escape destruction by the
immune system
• A number of checkpoint blockade inhibitors including
Atezolizumab and Avelumab have been developed
that target the PD1/PDL1 interaction in order to allow
T-cells to recognize tumor cells without being
deactivated by the tumor.

8. • Broad distribution of PD-L1 in different cellular
compartments can lead to deactivate of the CTLs
• mPD-L1 holds the structure integrity and can bind
to its receptor, PD-1, to modulate cancer cell
• The antibody has limited influence on
intracellular cPD-L1 and nPD-L1 which affect the
efficacy of therapy
• PD1/PD-L1 blockade achieved via three methods:
(1) antibody blockade
(2) gene silencing
(3) small-molecule pathway inhibition

9. • Three PD-L1 antibodies are approved by FDA
• Around half of patients with positive PD-L1 expression benefit from the treatment.
• Very interestingly, there was some responses to PD-L1 antibody in the PD-L1 negative, for uncertain
reasons
• The highlight of this treatment is the relative low rate of treatment related adverse events Compared to
conventional therapies such as docetaxel treatment
• the usage of PD-L1 antibodies brings immune-related adverse events (ir-AE) into safety consideration
• Pneumonitis is the most severe ir-AE, with relative lower rates that PD-1 antibodies
• PD-L1 antibodies respond very positively to blood cancers like leukemia and lymphoma

10. Experimental
•KN035
PD-L1 antibody with subcutaneous formulation, its under clinical evaluations in the US, China, and Japan[
•AUNP12
29-mer peptide the first peptic PD-1/PD-L1 inhibitor, evaluated in clinical trial
•CA-170
PD-L1 and VISTA antagonist, as a potent small molecule inhibitor in vitro. currently under phase I clinical trial over
mesothelioma patients.
•BMS-986189
•is a macrocyclic peptide pharmacokinetics, safety and tolerability is currently being studied on healthy subjects

11. • Single interfering RNA “switch off” the protein synthesis
• The intracellular nPD-L1 and cPD-L1, can directly respond to gene silencing, resulting in decreased
levels of mPD-L1
• cancer cells transfected with PD-L1 siRNA are more sensitive to T cell killing anticancer
• the first gene silencing based therapeutics, the liposomal miR-34a mimic, underwent Phase I clinical
trials, then halted
• PD-L1 expression is mainly regulated via MAPK (RAS/RAF/MEK/ERK) and PI3K/Akt pathways
• Chemical inhibitors PD-L1 based treatment Inhibiting these pathways downregulate cellular PD-L1
expression
• signaling pathway inhibition take time to reduce PD-L1 expression, this approach not as sufficient as
antibody at a very early stage, while still sufficient to regulate PD-L1 at the later stage

12. At present, 76% of the active trials are testing combination
regimens of PD-1/PD-L1 mAbs with other cancer therapies
Application of PD-L1 antibodies in cancer combination therapy in 2019.

13. Thank you

14. • Wu, Yilun, et al. "PD-L1 distribution and perspective for cancer immunotherapy–blockade,
knockdown, or inhibition." Frontiers in Immunology 10 (2019): 2022.
• Sau, Samaresh, et al. "PDL-1 antibody drug conjugate for selective chemo-guided immune modulation
of cancer." Cancers 11.2 (2019): 232.
• https://www.nature.com/articles/d42473-019-00048-0
• https://www.nature.com/articles/d41573-019-00182-w