Download Tumor cell

Licia Rivoltini, MD
Unit of Immunotherapy of Human Tumors
The complex network of anti-tumor immunity
Innate
immunity
First line
defense
Tumor
cell
Adaptive
immunity
Specificity
& memory
Kidd et al., Nature Biotech 2015
CD8+ T cells: key players in tumor rejection
B cell depleted
CD8+ T cell depleted
Adoptive immune cell transfer
CD8+ T cells
CD8+ T cell depleted
CD4+ T cells
NK cells
B cells
B cell depleted
Fox et al., J clin Invest 2015
CD8+ T cells: clonal expansion and immune memory
Expansion of
tumor-specific effector cells
Tumor (?)
(optimal priming, adequate cytokines
and growth factors contexture)
Induction of
immune memory
(central and effector memory
cells for long-term protection)
CD8+ T cells: selective and potent tumor killers
Cytotoxic
granules
(perforin, granzyme B)
HLA/Antigen
complex
TCR
FasL
Fas
Immunological
synapse
Activated CD8+
cytotoxic T cells
(CTL)
Tumor
cell
Cell
apoptosis
Tumor antigens
A
Tumor
killing
A
A
Initial tumor
elimination
by NK cells
T cell
exhaustion
Homing of
cytotoxic
CD8+ T cells
to tumor site
A
A
A
A
Lymph
node
A
Dendritic
cells
Process and
present Ag
to specific
T cells
Clonal expansion
of cytotoxic antitumor CD8+ T
cells
generation of
memory cells
Peripheral
blood
Immune checkpoints
• Stop of proliferation
• Reduced glucose consumption
• Inhibition of cytotoxicity and
cytokine release
• Blocking of antibody production
In a reversible fashion
Immune checkpoint
(CTLA4, PD1)
anti-PDL-1
Nguyen et al., Nature Rev Immunol 2015
Immune checkpoint
(CTLA4, PD1)
pAKT/PI3K
anti-PDL-1
Nguyen et al., Nature Rev Immunol 2015
Predictive factors of response?
30-40%
15%
Patrick A. Ott et al. Clin Cancer Res 2013;19:5300-5309
T cell
Tumor cell
T cell
Neo
antigen
Tumor cell
level of tumor antigens
T cell
level of T cell infiltrate
level of PD-1 expression
in T cells
PD-1
Neo
antigen
Tumor cell
level of tumor antigens
T cell
level of T cell infiltrate
level of PD-1 expression
in T cells
PD-1
PDL-1
Neo
antigen
level of PD-L1 expression
in tumor cells (and stroma)
Tumor cell
level of tumor antigens
Tissu antigens
Muc1,MART-1,
PSMA..)
Unique mutated antigens or
NEO-ANTIGENS
(non-synonimous mutations
due to genetic instability)
Unique mutated antigens or
NEO-ANTIGENS
Tissu antigens
Muc1,MART-1,
PSMA..)
(non-synonimous mutations
due to genetic instability)
Melanoma
NSCLC
High mutations
High mutations
Low mutations
Low mutations
Lysis of: autologous tumor, common tumors
same histotye, common tumor different histotype
Rizvi et al. Science , 2015
McGranahan et a., Science 2016
Unique mutated antigens or
NEO-ANTIGENS
Tissu antigens
Muc1,MART-1,
PSMA..)
(non-synonimous mutations
due to genetic instability)
Melanoma
NSCLC
High mutations
High mutations
Low mutations
Low mutations
Lysis of: autologous tumor, common tumors
same histotye, common tumor different histotype
Rizvi et al. Science , 2015
McGranahan et a., Science 2016
Mohini Rajasagi et al. Blood 2014;124:453-462
DNA damage response gene mutations, mutational load, and sensitivity to
chemotherapy plus immune checkpoint blockade in urothelial cancer
DDR mutant UC is associated with
•
•
•
Higher mutational load
Higher CD8+ T cell infiltrate
Potentially higher sensitivity to CT+ICI
DNA damage response gene mutations, mutational load, and sensitivity to
chemotherapy plus immune checkpoint blockade in urothelial cancer
DDR mutant UC is associated with
•
•
•
Higher mutational load
Higher CD8+ T cell infiltrate
Potentially higher sensitivity to CT+ICI
small cell neuroendocrine carcinoma
of the urinary bladder.
Pal et al., Foundation Medicine Boston
T cell
level of T cell infiltrate
level of PD-1 expression
in T cells
PD-1
PDL-1
Neo
antigen
level of PD-L1 expression
in tumor cells (and stroma)
Tumor cell
level of tumor antigens
ADAPTIVE IMMUNE
RESPONSE
(activated CD8+ T cells)
PD-L1 in tumor cells
Inducible expression due to
local inflammation
• cytokines and chemokines
• IFN produced by T cells
PD-L1 in
LN, blood and BM
ADAPTIVE IMMUNE
RESPONSE
(activated CD8+ T cells)
PD-L1 in tumor infiltrating
stroma (myeloid) cells
PD-L1 in tumor cells
Inducible expression due to
local inflammation
• cytokines and chemokines
• IFN produced by T cells
PD-L1 in
LN, blood and BM
ADAPTIVE IMMUNE
RESPONSE
(activated CD8+ T cells)
PD-L1 in tumor infiltrating
stroma (myeloid) cells
Surrogated
by CD80
PD-L1 in tumor cells
Inducible expression due to
local inflammation
• cytokines and chemokines
• IFN produced by T cells
Constitutive expression due
to oncogenic pathways
• HIF1a-hypoxia
• VHL
• EGFR activation
• AP-1 signaling
• PTEN loss
• PI3K/AKT/mTOR
Impact of immune checkpoint protein expression in tumor cells nd tumor
infiltrating CD8+ T cells on clinical benefit from PD-1 blockade in mRCC
Expression of either PDL-1
or PD-L2 on tumor cells
and low infiltration by T
cells expressing multiple
IC are associated with
better response to ICI
hot
hot
PD-1 blockade
HOT TUMORS
COLD TUMORS
cold
Lizotte et al , J Clin Invest 2016
Daud et al , J Clin Invest 2016
T cell
LOW level of T cell infiltrate
LOW level of PD-1 in T cells
LOW level of PD-L1
in tumor cells (and stroma)
LOW level of tumor
antigens (neo-antigens)
Tumor cell
T cell
Immunosuppressive
immune components
Myeloid-derived
suppressor cells
LOW level of T cell infiltrate
LOW level of PD-1 in T cells
Tumor associated
macrophages
LOW level of PD-L1
in tumor cells (and stroma)
Regulatory
T cells
LOW level of tumor
antigens (neo-antigens)
Tumor cell
Myeloid derived suppressor cells
Monocytic MDSC
Granulocytic MDSC
(activated neutrophil-like cells)
CD33+CD15+CD11b+LDG
(immature monocyte-like cells)
CD33+CD11b+CD14+HLA-DRneg
STAT
ROS
Arginase-1
TGFb
iNOS
PD-L1
Myeloid derived suppressor cells
Monocytic MDSC
Granulocytic MDSC
(activated neutrophil-like cells)
CD33+CD15+CD11b+LDG
(immature monocyte-like cells)
CD33+CD11b+CD14+HLA-DRneg
STAT
ROS
Arginase-1
TGFb
iNOS
Systemic effect
Local effect
PD-L1
Immune
suppression
Stroma
remodelling
Neoangiogenesis
Mesenchymal
transition
Pre-metastatic
niche
Bone
metastases
An immunosuppressive protumoral microenviroment
defines intrinsic resistance to
anti-PD-1 therapy
Genes involved in mesenchymal transition,
cell adhesion,
extracellular matrix remodeling,
angiogenesis, wound healing and myeloid
derived suppressor cells
(IPRES signature)
Hugo et al., Cell 2016
Myeloid Index Score
Rivoltini et al., manuscript in prep
Monocytic MDCS
Sade-Feldman et al., Clin Cancer Res 2016
Absolute neutrophil count
Myeloid Index Score
Monocytic MDCS
Neutrophil to lymphocyte ratio
Rivoltini et al., manuscript in prep
Sade-Feldman et al., Clin Cancer Res 2016
Ferrucci et al., Ann Oncol 2015
Neutrophil lymphocyte ratio (NLR) as a clinical biomarker predictive of
outcomes with immune checkpoint inhibition therapy in genitourinary cancers
Evaluation of monocytic myeloid-derived suppressor cell (m-MDSC)
frequency in patients with metastatic urothelial carcinoma
How to improve efficacy?
30-40%
15%
Patrick A. Ott et al. Clin Cancer Res 2013;19:5300-5309
Mechanisms of tumor cell death in “local” therapies
Cryoablation
Cryoablation
Radiotherapy
Radioembolization
Chemoembolization
Cryoablation
Radiotherapy
Radioembolization
Chemoembolization
Katrina F. Chu & Damian E. Dupuy Nature Rev Cancer 2014
(presurgery) Ablative therapy to induce local and systemic immune changes
in patients with metastatic RCC
Intratumor:
•Increase of PD1+ T cells
•Higher expression of immune gene signatures
Blood:
•Decrease of Treg cells and IL-6 levels (transient window)
Clinical pilot study of anti-CTLA4 +/- cryoablation in mRCC patients
(presurgery) Ablative therapy to induce local and systemic immune changes
in patients with metastatic RCC
Intratumor:
•Increase of PD1+ T cells
•Higher expression of immune gene signatures
Blood:
•Decrease of Treg cells and IL-6 levels (transient window)
Clinical pilot study of anti-CTLA4 +/- cryoablation in mRCC patients
HCC patients treated
with TARE (transarterial
radio-embolization)
display a window of
systemic immune
modulation
(Rivoltini and Mazzaferro,
in preparation)
Pembrolizumab plus low dose ipilimumab for patients with advanced renal
carcinoma: phase I KEYNOTE-029 study
Managble toxicity and significant activity
(disease control rate 50%)
Choueiri et al.
Evaluation of clinical activity of IPI and NIVO in patients with NIVO-refractory
metastatic urothelial cancer
IPI and NIVO is active in UC patients who failed NIVO
Callahan et al.
Pembrolizumab plus low dose ipilimumab for patients with advanced renal
carcinoma: phase I KEYNOTE-029 study
Managble toxicity and significant activity
(disease control rate 50%)
Choueiri et al.
Evaluation of clinical activity of IPI and NIVO in patients with NIVO-refractory
metastatic urothelial cancer
IPI and NIVO is active in UC patients who failed NIVO
Callahan et al.
•
•
•
• Cell transition and DNA
replication
• Cell cycle
• CDK cyclins
• Differentiation and
expansion of T cells
Pei-Ling Chen et al. Cancer Discov 2016;6:827-837
•
Effector T cells
NK cell function
IL-12/IFNgamma response
Differentiation and clonal expansion
of CD8+ T cells
Granzyme B/perforin lytic machinery
Distinct but synergistic effects of CTLA-4 and PD-1 blockade
Lymph node
Tumor lysis by innate cells (or cancer
therapies) and antigen relase
Antigen up-take, process
presentation by dendritic cells
CTLA-4
Effect of blockade
and
• Resques dendritic cell tolerance
• Improves T cell priming by dendritic cells
• Reduces immunosuppression by Treg
• Increases T cell proliferation and function
Priming of antigen-specific T cells by
dendritic cells
T cell clonal expansion and
trafficking from regional lymph
nodes to tumor site
Tumor infiiltration by specific T cells
Tumor lysis
by xx
tumor
infiltrating T cells
• Potentiates T cell effector functions
• Increases T cell proliferation
• Rescuses T cells from inhibition by
PD-L1+ myeloid-derived suppressive cells
Effect of blockade
PD-1
Tumor site
Outcomes of PD-1/PD-L1 responders who discontinued therapy for immune
related adverse events (irAEs): results of a cohort of patients with mRCC
In 9 patients, long-term responses after only
a median duration therapy of 5 mo (4-15).
Induction of Immune memory?
Im et al., Nature 2016
Outcomes of PD-1/PD-L1 responders who discontinued therapy for immune
related adverse events (irAEs): results of a cohort of patients with mRCC
In 9 patients, long-term responses after only
a median duration therapy of 5 mo (4-15).
Induction of Immune memory?
Chronic immune stimulation induces memory responses that are blocked by PD-1
a-PD-1
control
Utzschneider et al., Immunity 2016
Im et al., Nature 2016
Impact of antibiotics on outcome in patients with mRCC treated with ICI
Antibiotic therapy before or during ICI is
associated with poor PFS and OS during
ICI therapy (n=80)
Impact of antibiotics on outcome in patients with mRCC treated with ICI
Antibiotic therapy before or during ICI is
associated with poor PFS and OS during
ICI therapy (n=80)
ICI responding patients
expand a microbiota cluster
Transplant of the C cluster
reverts ICI resistance
in mice
Vétizou et al,Science 2015
To summarize
o Strong scientific rational of GU tumors’ sensitivity to Immune
checkpoint inhibitors
o “Immunogenic tumors” (more neoantigens, more
mutations, more mutational load, more infiltrating T cells,
more PD-1/PDL-1, 2 expression) are more likely to respond
o “Myeloid-enriched tumors” (microenvironmentally or
systemically) are more likely to fail responding to
ICI(preconditioning required?)
o Combinations (ablation, multiple ICI…) should be more
effective…. But avoid antibiotics (?)
o Potential long-term immune memory with PD-1 blockade
(like with a-CTLA4)
Thank you
Mutation burden as a biomarker of response to immune checkpoint in
nine solid cancers: the new concept of iCAM
iCAM: mutation burden threshold, a gene expression signature of a blocked immune response
of robust CD8+ T cell response and up-regulation of immune checkpoints
Using data from 10,745 tumors from 33
solid cancer type in TGCA, iCAM is expressed in
Melanoma
Lung cancer
Colon cancer
Endometrial
Gastric adenocarcinoma
Serous ovarian
Bladder urothelial
Cervical
Her2+ breast cancer
iCAM represents a clinically useful mutation
burden threshold