PD-1 & PD-L1: biologa, funcin,

mecanismo de accin de los

inhibidores
Guillem Argils, MD
Gastrointestinal Malignancies Program
Early Drug Development Program
Vall dHebron University Hospital
INTRODUCING ANTITUMOR
IMMUNE RESPONSE
Immune-surveillance of tumors:
Cancer-immunity cycle

Blood vessel

Lymph node

Tumor

1. Release of cancer
cell antigens
 Cancer-immunity cycle

Blood vessel
2. Cancer antigen
presentation
Lymph node

Tumor

1. Release of cancer
cell antigens
Cancer-immunity cycle

3. Priming and activation

2. Cancer antigen Blood vessel

presentation
Lymph node

Tumor

1. Release of cancer
cell antigens
Cancer-immunity cycle
4. Trafficking of T cells to
tumors

3. Priming and activation

2. Cancer antigen Blood vessel

presentation
Lymph node

Tumor

1. Release of cancer
cell antigens
Cancer-immunity cycle
4. Trafficking of T cells to
tumors

3. Priming and activation

5. Infiltration of T cells into

tumors

2. Cancer antigen Blood vessel

presentation
Lymph node

Tumor

1. Release of cancer
cell antigens
Cancer-immunity cycle
4. Trafficking of T cells to
tumors

3. Priming and activation

5. Infiltration of T cells into

tumors

2. Cancer antigen Blood vessel

presentation
Lymph node
6. Recognition of cancer
cells by T cells

Tumor

1. Release of cancer
cell antigens
Cancer-immunity cycle
4. Trafficking of T cells to
tumors

3. Priming and activation

5. Infiltration of T cells into

tumors

2. Cancer antigen Blood vessel

presentation
Lymph node
6. Recognition of cancer
cells by T cells

Tumor

1. Release of cancer
cell antigens 7. Killing of cancer cells

Chen DS & Mellman I. Immunity 2013

Immunotherapies to induce anti-
tumor immunity
THE IMMUNE SYNAPSE
Immune synapse
INMUNE SYNAPSE (1)
PD1/PD-L1 AXIS AS THE MAIN
CONTROLLER IN EFFECTOR IMMUNE
SYNAPSE
PD-1/PD-L1 Axis main regulator
of tumor immune escape
PD-1/PD-L1/PD-L2 Expression:

PD-L1 expression PD-L2 expression

Normal cells Activated
Tumor cells dendritic cells
Activated Macrophages
dendritic cells Certain epithelial
Macrophages cells
T-REG PD-L2 expression
is controlled by IL-
T-lymphocytes 4 secretion
In tumor cells PD-L1 expression is constitutive in the rest
of cells is inducible upon inflammation.
When an activated T-Cell arrives to a tissue it secretes
IFN-gamma which induces PD-L1 expression in normal
cells and inflammatory cells
PD-1/PD-L1/PD-L2 functions:
-PD-1 activation block the main effectors of
the activated TCR complex and CD26.

-ZAP70
-LAC
-PI3K-AKT path
-MAPK path

-PD-1 activation disassembles immune

synapse

-PD-1 activation increase T-CELL motility

PD-1 Axis activation is able itself to cancel

T-CELL responses.
PD1/PD-L1 AXIS THERAPEUTICS
PD-1/PD-L1 Blockade
ANTI-PD1/PD-L1 antibodies:
ANTI-PD1 VS ANTI-PD-L1
ANTI-PD1

ANTI-PD-L1
 ANTI-PD-L1 MERCK Y ADCC
Drug Target AB ADCC
isotype

MEDI0680 PD-1 IgG4 NO

Nivolumab PD-1 IgG4 NO
Pembrolizumab PD-1 IgG4 NO
Clula tumoral
Pidilizumab PD-1 IgG1 mod NO Linfocito
Celula presentadora
BMS-936559 PD-L1 igG4 NO de Ag

MEDI4736 PD-L1 IgG1 mod NO

Atezolizumab PD-L1 IgG1 mod NO
Avelumab PD-L1 IgG1 YES
PD1/PD-L1 drug development
Nivolumab and pembrolizumab are both
approved for treatment of refractory and
unresectable melanoma by the FDA
Nivolumab is als approved by the FDA for the
treatment of refractory and unresectable
NSCLC (Squamous)
The rest of the compounds are on phase 1,2
and 3 single agent or in combinations
PD1/PD-L1 drug development
Anti-PD-1/PD-L1 are being tested in
combination with other chemotherapy
Platinum-based chemotherapy
Antracyclines
Alkylating agents
Taxanes
Anti-PD-1/PD-L1 are being tested in
combination radiotherapy
PD1/PD-L1 drug development
Anti-PD-1/PD-L1 are being tested in
combination with other inmune-checkpoints
Anti-CTLA-4
OX40 agonist
CD40 agonist
Anti-LAG3
Other inmune-modifiers
PD1/PD-L1 drug development
Anti-PD-1/PD-L1 are being tested in
combination with other targeted therapies
MEK inhibitors
BRAF inhibitors
Pi3k inhibitors
TGF-beta inhibitors
TAKE HOME MESSAGES
PD-1 signaling is one of the most potent
mechanisms used by the tumor for overpass the
immune system
PD-1 Axis therapeutics are one of the big hits in
immune-oncology
Combinational therapeutics with, other immune-
checkpoint inhibitors, chemo or radiotherapy as
well as other targeted agents will conform the
future of immune therapeutics in oncology.