immunotherapy in solid tumors Licia Rivoltini MD Unit of Immunotherapy of Human Tumors Fondazione IRCCS Istituto Nazionale dei Tumori Milano Perspectives in Lung Cancer ID: 805904
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Slide1
Biological
basis for immunotherapyin solid tumorsLicia Rivoltini, MDUnit of Immunotherapy of Human TumorsFondazione IRCCS Istituto Nazionale dei TumoriMilano
Perspectives
in
Lung
Cancer
:
16th
European
Congress
Torino, March 6-7, 2015
Slide2Immune system in infectious diseaseReferenze: A, Richard L. et al. PNAS, 2010 , vol. 107; B. Dr. Volker Brinkmann, Max Planck Institute for Infection Biology; C. http://pathmicro.med.sc.edu/ghaffar/innate.htm
;D.
,
http://www.lbl.gov/Science-Articles/Archive/PBD-immune-system.html
; E.
B cell Analytical Imaging Facility of the Albert Einstein College of Medicine and the NCI cancer center support grant (P30CA013330).
B
lymphocytes
T
lymphocytes
phagocytes
natural
killer
cells
Slide3Cancer
Immunosurveillance
Tumor
cells
CD8+
phagocytes
CD4+
B
cells
NK
cells
The immune
system
recognition
and
targeting
of
tumor
cells
Slide4Cancer Immunology(ImmunOncology)Understanding cancer immune evasion and researching avenues to
help the immune system
controlling
tumor growth
Slide5Innate
immunityRapid, first-linenon specific immune response
Slide6Innate
immunity
NK
cells
recognize
infected
target
cells
Infected
cells
Phagocytes
(
macrophages
,
dendritic
cells
)
engulf
pathogens
and
dying
infected
cells
Slide7Adaptive
immunitySpecific immune responseImmunological memory
Slide8ANTIGEN
PRESENTIG CELLS(dendritic cells)presentantigens from pathogensAdaptive immunity
MHC-I
Slide9Activated
CD8+
cytotoxic
T
cells
ANTIGEN
PRESENTIG CELLS
(
dendritic
cells
)
present
antigens
from
pathogens
Adaptive
immunity
MHC-I
TCR
Slide10Infected
host cells
Activated
CD8+
cytotoxic
T
cells
ANTIGEN
PRESENTIG CELLS
(
dendritic
cells
)
present
antigens
from
pathogens
Adaptive
immunity
MHC-I
TCR
Slide11Infected
host cells
Activated
CD8+
cytotoxic
T
cells
ANTIGEN
PRESENTIG CELLS
(
dendritic
cells
)
present
antigens
from
pathogens
Activated
B
cells
Adaptive
immunity
MHC-I
TCR
T
helper
cells
Cytokines
Slide12Infected
host cells
Activated
CD8+
cytotoxic
T
cells
ANTIGEN
PRESENTIG CELLS
(
dendritic
cells
)
present
antigens
from
pathogens
Activated
B
cells
Adaptive
immunity
MHC-I
TCR
T
helper
cells
Cytokines
Antibodies
against
the
pathogen
Slide13Immunological
memory
Pathogen
clearance
Slide14Immunological
memory
Pathogen
clearance
Activation
of
negative
feedback
pathways
to
shut
down immune
response
Immune
suppressive
cells
Negative
checkpoints
Regulatory
T
cells
Myeloid
derived
suppressor
cells
CTLA4
PD1
Slide15Immunological
memory
Pathogen
clearance
Memory T
cells
and Ab
Immune
suppressive
cells
Negative
checkpoints
Regulatory
T
cells
Myeloid
derived
suppressor
cells
CTLA4
PD1
Activation
of
negative
feedback
pathways
to
shut
down immune
response
Slide16Tumor
cells express ANTIGENS that can be recognized by T cells
Infected
host
cells
CD8
+ T
cells
Tumor
cells
CD8
+ T
cells
Pathogen
proteins
Proteins
associated
with
cancer
transformation
T cell
receptor
MHC
class
I
Slide17Tumor
Associated Antigens(TAA)
Tissue
antigens
(MUC1, EPCAM,
PSA
, PSMA,
Mart-1,
CEA….…
)
Unique
mutated
antigens
(
cancer
genetic
instability
)
Embryonic
antigens
(
MAGE3,
NY-ESO1, PRAME….)
Slide18Tumor
draining
lymph
node
Tumor
site
Tumor
cell
debris
(ANTIGENS)
Mechanisms
leading
to
spontaneous
tumor
immunity
Dendritic
cells
Cytokines
Chemokines
NK
cells
- PRIMING PHASE -
CD8+
T
cells
cytokines
Y
Y
Y
Y
Y
Y
B
cells
CD4+
T
cells
cytokines
Antibodies
Y
Y
Y
Peripheral
blood
Y
Y
Y
Tumor
growth
control
- EFFECTOR PHASE -
Tumor
Immunity
Cycle
Slide19Tumor
cell
Activated
CD8+
cytotoxic
T
cells
(CTL)
Cytotoxic
granules
(
perforin
,
granzyme
B)
FasL
Fas
Pathways
of
tumor
cell
killing
by CD8+ T
cells
TCR
MHC/Ag
Slide20Immunosurveillance
in cancer patientsPresence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer
patients
Slide21Immunosurveillance
in cancer patientsPresence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer
patients
Tumor
T
cell
infiltrate often associates with
better
prognosis
Slide22Immunosurveillance
in cancer patientsPresence of antigen-specific T cells and antibodies at tumor site, draining LN and peripheral blood of cancer
patients
Tumor
T
cell
infiltrate often associates with
better
prognosis
Immunosuppressive pathways
increase with disease progression
Slide23Correlation with improved overall or progression-free survival, disease stage, or therapy outcome;
type of lymphocyte dictates where there is a correlation with improved outcome
Figures adapted from Zhang L, et al. N
Engl
J Med 2003;348(3):203–213, Copyright ©2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
1. Zhang L, et al. N
Engl
J Med 2003;348(3):203–213; 2.
Hiraoka
K, et al. Br J Cancer 2006;94(2):275–280; 3.
Galon J, et al. Science 2006;313(5795):1960–1964; 4. Mahmoud SM, et al. J Clin
Oncol 2011;29(15):1949–1955; 5. Loi S, et al. J Clin
Oncol
2013;31(7):860–867; 6.
Piras F, et al. Cancer 2005;104(6):1246–1254; 7.
Azimi F, et al. J Clin
Oncol 2012;30(21):2678–
2683 8.
Siddiqui SA, et al. Clin
Cancer Res 2007;13(7):2075–2081; 9. Donskov
F, et al. Br J Cancer 2002;87(2):194–201; 10. Flammiger A, et al. APMIS 2012;120(11):901–908 11.
Badoual
C, et al. Clin
Cancer Res 2006;12(2):465–472; 12. Piersma SJ, et al. Cancer Res 2007;67(1):354–361 , 13. Azimi et al., J Clin
Oncol 2012
Al-
Shibli
et al.,
Clin
Cancer
Res 2008
Angell
and
Galon
,
Current
Opin
Immunol
2013
IMMUNOSCORE
T
cell
infiltrate
is
positive
prognostic
factor
in
several
cancer
histologies
Adaptive
immunity
in
cancer
patients
-
role
of T
cell
infiltrate
-
NSCLC
Slide24Anti-
tumor immune responseTumor growth
Subclinical
pre-diagnosis
phase
ELIMINATION
Of
tumor
cells(partial or complete)
Tumor
immunity
: a
dynamic
interaction
Slide25Anti-
tumor immune responseTumor growth
Subclinical
pre-diagnosis
phase
ELIMINATION
Of
tumor
cells(partial or complete)
EQUILIBRIUMbetween immune responseand
tumor growth
Immunoselection
/editing
Tumor
immunity
: a
dynamic
interaction
Slide26Anti-
tumor immune responseTumor growth
Subclinical
pre-diagnosis
phase
Clinical
phase
ELIMINATION
Of
tumor
cells
(partial or complete)
EQUILIBRIUM
between immune response
and tumor growth
ESCAPEof
tumor cells from immune control
Immunoselection
/editing
Tumor
immunity
: a
dynamic
interaction
Slide27T
umor
cells
Down-
modulation
of MHC or
antigen
expression
Tumor
immune
escape
mechanisms
:
tumor
cells
counterattack
Slide28Down-
modulation
of MHC or
antigen
expression
T
umor
cells
Up-
regulation
of
pro-
apoptotic
molecules
(
FasL
, TRAIL)
Tumor
immune
escape
mechanisms
:
tumor
cells
counterattack
Slide29Down-
modulation
of MHC or
antigen
expression
T
umor
cells
Up-
regulation
of
pro-
apoptotic
molecules
(
FasL
, TRAIL)
Tumor
immune
escape
mechanisms
:
tumor
cells
counterattack
Release of immune
suppressive
factors
(
TGFb
, PG2,
iNOS
…)
Expression
of
inhibitory
checkpoints
(PDL1)
Ineffective
T
cells
Slide30tumor
cellsT cells
Regulatory
T
cells
Myeloid-derived
suppressor
cells
Immune
suppression
Release of
TGFb
,
iNOS
, IDO
Expression
of
inhibitory
checkpoints
(CTLA4, PD1, PDL1, LAG3,
TIM3, BLTA)
Tumor
immune
escape
mechanisms
:
switch
-off of immune
responses
Slide31To
summarize
Slide32To
summarizeSpontaneous tumor immunity does
occur
in
cancer
patients (
Tumor
Immunity
Circle)
Slide33To
summarizeSpontaneous
tumor
i
mmunity
does occur
in
cancer patients
(Tumor
Immunity Circle)
T cell
immunity
contribute
to better
prognosis (
Immunoscore
)
Slide34To
summarizeSpontaneous
tumor
i
mmunity
does occur
in
cancer patients
(Tumor
Immunity Circle)
T cell
immunity
contribute
to better
prognosis (
Immunoscore
)
Tumor
cells
acquire the ability
to evade immune
recognition
(Tumor Immune Escape
)
Slide35Anti-
tumor immune responseTumor growth
ELIMINATION
Of
tumor
cells
(
partial
or complete)
ESCAPEof tumor cells from immune control
EFFECTIVE
IMMUNOTHERAPY
CANCER IMMUNOTHERAPY:
tilt the balance to immune
tumor
control
Slide36Valeria Beretta
Chiara CastelliChiara CamisaschiAgata CovaPaola DehoPaola FratiSimona FrigerioFelicetta GiardinoGerman
Cancer Research
Center Heidelberg, Germany
Viktor
UmanskyAlexandra
Sevko
Unit of Melanoma
Surgery
Mario SantinamiRoberto
PatuzzoRoberta RuggeriAndrea
Maurichi
Francesco Gallino
Department
of
Pathology
Gabrina
Tragni
Antonello CabrasElena
Tamborini
Federica PerroneGiuseppe Pelosi
Unit of
Immunotherapy
of Human
Tumors
Aldo Bono
Elena
Tolomio
Daniele Moglia
Veronica Huber
Monica Rodolfo
Paola Squarcina
Marcella
Tazzari
Viviana VallacchiElisabetta Vergani
Medical Oncology Unit
INT Milan
Filippo de
Braud
Lorenza Di Guardo
Michele Del Vecchio
36
Acknowledgements
MIA
Consortium
,
University
of Milano Bicocca
Barbara
Vergani
Antonello Villa
Slide37Thank
you