Checkpoint Inhibitors in Urothelial Cancer: Biomarkers and
Treatment Strategies
Daniel P. Petrylak , MD Professor of Medicine and Urology
Director, Genitourinary DART Co-Director, Signal Transduction Program
Smilow Cancer Center Yale University School of medicine
August 12, 2016
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 2
Efficacy Responses to Atezolizumab by PD-L1 IC Subgroup
• Responses were seen in all IC subgroups, but ORR was enriched with higher PD-L1 status • Complete responses accounted for nearly half of the observed responses
– CRs were observed in all PD-L1 subgroups, with the highest rate in IC2/3 patients • ORRs per immune-modified RECIST were concordant
a Includes 46 patients with missing/unevaluable responses. b CR + PR + SD ≥ 24-wk rate per IRF RECIST v1.1. Treated patients had measurable disease at baseline per investigator-assessed RECIST v1.1. Data cutoff: Mar. 14, 2016.
IC2/3 n = 100
IC1/2/3 n = 207
Alla N = 310
ORR: confirmed IRF RECIST v1.1 (95% CI)
28% (19, 38)
19% (14, 25)
16% (12, 20)
CR rate: confirmed IRF RECIST v1.1 (95% CI)
15% (9, 24)
9% (6, 14)
7% (4, 10)
IC1 n = 107
IC0 n = 103
11% (6, 19)
9% (4, 16)
4% (1, 9)
2% (0, 7)
2
Dreicer R, et al. IMvigor210: Atezolizumab in platinum-treated mUC. ASCO 2016
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 3
• Longer OS observed in patients with higher PD-L1 IC status • 12-mo OS compares favorably with historic estimates of ≈ 20%1
• NE, not estimable. a 1 prior line of therapy for mUC and no (neo)adjuvant therapy. Data
cutoff: Mar. 14, 2016. 1. Agarwal Clin Genitourin Cancer 2014.
3
Median follow-up (range): All pts: 17.5 mo (0.2 to 21.1+ mo) 2L only: 17.3 mo (0.5 to 21.1+ mo)
Ove
rall
Sur
viva
l
100
80
60
40
20
0
Time, months 6 8 10 2 4 0 12 14 16 18 20
▮ All Patients + Censored Subgroup
12-mo OS (95% CI)
IC2/3 IC0/1 All All pts (N = 310)
50% (40, 60)
31% (24, 37)
37% (31, 42)
2L only (n = 120)
61% (44, 77)
29% (19, 39)
38% (29, 47)
Subgroup
Median OS (95% CI)
IC2/3 IC0/1 All All pts (N = 310)
11.9 mo (9.0, 17.9)
6.7 mo (5.4, 8.0)
7.9 mo (6.7, 9.3)
2L only (n = 120)
NE (10.9, NE)
7.1 mo (5.0, 9.2)
9.0 mo (7.2, 11.3)
Efficacy Overall Survival
# at Risk: All pts: 310 265 203 176 146 126 110 97 82 35 5
2L only: 120 101 83 72 61 54 44 34 29 11 2
Dreicer R, et al. IMvigor210: Atezolizumab in platinum-treated mUC. ASCO 2016
All Pts and 2L only
▮ All Patients ▮ 2L only + Censored
Control Targeted therapies Immune checkpoint blockade Combinations/sequencing/biomarker selection
Surv
ival
Time Su
rviv
al
Time
Where we are now
Salvati M, 3rd Intl Symp in Lung Ca, 2014; Ribas A, WCM, 2013; Ribas A, et al. Clin Cancer Res 2012; Drake CG. Ann Oncol 2012 Friends Brookings Conference 2013
Could Biopsies and Biomarkers help?
Where we want to be
T-‐cells • How many? • What type? • Recognize tumor an:gens? • Breadth of an:gen recogni:on (one, a
few, many) • Affinity of TCR for pep:de-‐MHC complex • Func:onal state • Differen:ated state • Expression of inhibitory receptors • Metabolic state and access to glucose • Where located?
Tumor • An:gens/neo-‐an:gens • Density of pep:de/MHC complexes • Expression of inhibitory ligands • Expression of s:mulatory ligands • Produc:on of inhibitory cytokines • Produc:on of other inhibitory
substances • Expression of chemokines • Innate resistance to ly:c
mechanisms
Stroma/Other Immune Cells • Treg • MDSC • Monocytes/macrophages/APC • B-‐cells • NK and NKT cells • Tumor Vasculature • Fibroblasts
Host gene:cs Life:me environmental exposures TCR repertoire
Carcinogenesis: Muta:ons Altered gene expression Chronic inflamma:on
Tumor evolu:on Metastases Evolu:on of Tumor-‐Host immune rela:onship
Immune Interven:on Outcome
Pa:ent Presen:ng for Treatment
Tumor microenvironment and Host An:-‐tumor immune response
Issues with the PD-L1 Biomarker
• Heterogeneity – multiple tumors and multiple passes within a tumor
• Interval between biopsy and treatment • Primary versus metastatic disease • Antibody and staining conditions
• Defining a positive result (cut-offs): o Cell type expressing PD-L1 (immune cell
versus tumor or both) o Location of expression – cell surface versus
intracellular versus stromal o Intensity, percent of cells ‘positive’ o Distribution - patchy versus diffuse, intratumoral
versus peripheral
E1L3N SP142
Neg
ativ
e P
ositi
ve
1 mm
H&E
Immunofluorescence shows stroma and epithelial staining are often concordant and adjacent Green = Cytokeratin Blue = Nuclei Red = PD-L1 (SP142)
McLaughlin (Rimm) et al., JAMA Oncology. 2016 Jan 1;2(1):46-54
• PD-L1 localized with macrophages, dendritic cells and T cells, but not B cells
PD-L1 Expression in Immune Cells and Tumor Cells by Immunofluorescence
PD-L1 / CD163 (macrophage) PD-L1 / CD11c (dendritic cells)
PD-L1 / CD3 (T cells) PD-L1 / CK (tumor)
IC, tumor-infiltrating immune cell; TC, tumor cell. Markers of ICs: CD3, T cells; CD11b, dendritic cells; CD163, macrophages. Marker of TCs: CK, cytokeratin. Red: PD-L1 staining; Green: IC and TC markers; Blue: DAPI staining. Herbst RS et al. Nature 2014;515: 563-567.
Role of sequencing in anti-cancer immunotherapy
Tumor cells: -Mutation load -Neoantigens
-Genomic instability -Mutation
immune mol -Resistance
Immune cells: -TCR seq
-Amount/clones -Specificity -Antigens
Mutation load and change with therapies Class I and Class II neoantigens
Allelic frequency and expression of neoantigens Association with genetic makeup and oncogenic signaling
Expression of immune inhibitory targets Clonal TCR selection and affinity
PD-L1-/TIL- PD-L1-/TIL+ PD-L1+/TIL+ PD-L1+/TIL-
45% Type I
17% Type II
26% Type III
12% Type IV
Four Categories of Tumors Based on Presence of PD-L1 and TILS
Proposed mechanisms associated with NSCLC resistance to anti-PD-1/B7-H1 therapySubgroup
Type Tumor Distribution
Possible Resistance Mechanism(s) Analysis
B7-H1 TIL
- - I 45%Poor priming of general T cell responses
Peripheral CD4+ and CD8+ T cell responses to autologous tumor cells
Lack of inflammatory cell recruitment
Chemokine expression in biopsy or FFPE samples
+ + II 17%Incomplete PD-1/B7-H1 pathway blockade and activation of alternate immune suppressive pathways
CD80 expression on TILs, expression of alternate suppressive pathways in TME
- + III 26% Alternate immune suppressive pathways
Expression of select molecules in pathways with roles in evasion of NSCLC immunity
+ - IV 12% Intrinsic induction of B7-H1 by oncogenes
Expression of molecules triggering aberrant signaling events
Velcheti (Rimm) et al. Lab Invest. 2014 Jan;94(1):107-16.; Chen L. Unpublished 450 samples analyzed
Biomarker Analyses for PD-L1 Treatment Mechanistic studies using pre and post biopsies
Herbst RS et al. Nature 2014;515: 563-567;
Biomarker Analyses Defining the Profile of Non-responders
• Three distinct patterns of nonresponse were observed • Most patients who progressed failed to show up-regulation of PD-L1 or
evidence of activated T cells • These results provide evidence for the “inflamed tumor” hypothesis
CD8 CD8 CD8
CD8 CD8 CD8
Pre
-trea
tmen
t
Pre
-trea
tmen
t
Pre
-trea
tmen
t
On-
treat
men
t wee
k 9
On-
treat
men
t wee
k 6
On-
treat
men
t wee
k 6
Immunologic ignorance Non-functional
immune response Excluded infiltrate
Herbst RS et al. Nature 2014;515: 563-567;
Herbst RS et al. Nature 2014;515: 563-567;
Summary of Responses to MPDL3280A in Paired Biopsies
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 13
PD-L1 IC status
CD
8A
GZM
A
GZM
B
IFN
G
CX
CL9
CX
CL1
0
PR
F1
TBX
21
IC3 IC2 IC1 IC0
High PD-L1 IC Staining Is Associated With Preexisting Teff Activation
• Activated T cells are characterized by expression of CD8, granzymes, perforin, cytokines and other factors
• This Teff gene signature was associated with PD-L1 IC status
– 2 IFNγ-inducible Th1 chemokines (CXCL9 and CXCL10) notably correlated with IC status (P < 0.0001)
– CD8+ T-cell infiltration also correlated with IC status (P < 0.001)1
• CXCL, chemokine (C-X-C motif) ligand; GZM, granzyme, INFG, interferon γ; PRF1, perforin 1; Th1, T helper 1; TBX21, T-box 21. a RNAseq data. Data cutoff: March 14, 2016. 1. Rosenberg Lancet 2016.
13
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
10
5
0
-5
Log 2
RN
A E
xpre
ssio
na
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 14
PD-L1 IC Status Is Associated With Multiple Immune Inhibitory Regulators
• Negative regulators of the immune system, such as immune checkpoint proteins and regulatory T cells can dampen the anti-cancer immune response
• These data suggest that pre-existing adaptive immune response may be suppressed in these patients
• PD-L1 expression is associated with an activated but potentially suppressed immune response
• CTLA4, cytotoxic T-lymphocyte–associated antigen; FOXP3, forkhead box P3; HAVCR2, hepatitis A virus cellular receptor 2; IDO1, indoleamine 2,3-dioxygenase 1; LAG3, lymphocyte activation gene 3; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains.
• a RNAseq data. Data cutoff: March 14, 2016.
14
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
PD
-L1
LAG
3
HA
VC
R2
CTL
A4
TIG
IT
IDO
1
FOX
P3
CD
244
Log 2
RN
A E
xpre
ssio
na
PD-L1 IC status
10
5
0
-5
IC3 IC2 IC1 IC0
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 15
Teff IFNγ-Induced Gene Expression is Associated With Response
• Higher baseline IFNγ response genes were observed in atezolizumab responders
• These data are consistent with Th1 and CTL immune responses
• IFNγ-inducible MHC-I antigen processing and transport genes were also associated with response
• CTL, cytotoxic T lymphocyte; IRF1, interferon regulatory factor 1; MHC-I, major histocompatibility complex I; PSMB, proteasome subunit β; STAT1, signal transducer and activator of transcription 1; TAP, transporter. a RNAseq data. Data cutoff: March 14, 2016.
15
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Log 2
RN
A E
xpre
ssio
na
-4
0
4
8
12
Log 2
RN
A E
xpre
ssio
na
0.0
2.5
5.0
7.5
10.0
PD SD PR CR
RECIST v1.1 response
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 16
Luminal
Basal
Urothelium
TCGA Subtype II Is Associated With Higher ORR
• Gene expression data used to classify IMvigor210 tumor samples recapitulated TCGA subtypes1,2
• Responses occurred in all subtypes, but ORR was significantly higher in luminal II vs other subtypes (P = 0.0072)
• TCGA, The Cancer Genome Atlas. Data cutoff: March 14, 2016. 1. Cancer Genome Atlas Research Network Nature 2014. 2. Rosenberg Lancet 2016.
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
PD SD PR CR
RECIST v1.1 response
16
0
25
50
75
100
OR
R, %
I II III IV
n = 73 n = 52 n = 38 n = 36
Luminal Basal
Courtesy of Macmillan Publishers Ltd: Choi W, et al. Nat Rev Urol. 2014;11(7):400-410, copyright 2014.
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 17
TCGA Subtype II Is Associated With Higher ORR
• Gene expression data used to classify IMvigor210 tumor samples recapitulated TCGA subtypes1,2
• Responses occurred in all subtypes, but ORR was significantly higher in luminal II vs other subtypes (P = 0.0072)
• What might be the drivers of this subtype-specific response?
• TCGA, The Cancer Genome Atlas. Data cutoff: March 14, 2016. 1. Cancer Genome Atlas Research Network Nature 2014. 2. Rosenberg Lancet 2016.
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
17
PD SD PR CR
RECIST v1.1 response
0
25
50
75
100
OR
R, %
I II III IV
n = 73 n = 52 n = 38 n = 36
Luminal Basal
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 18
IMvigor210: TCGA Subtype in mUC
• CDKN2A, cyclin-dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; GATA3, GATA-binding protein 3.
• Data cutoff: March 14, 2016. • 1. Choi Nat Rev Urol 2014. 2.
Aine Sci Rep 2015. 3. The Cancer Genome Atlas Research Network Nature 2014.
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
TCGA Subtype
I II III IV
18
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 19
IMvigor210: TCGA Subtype in mUC
• CDKN2A, cyclin-dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; GATA3, GATA-binding protein 3.
• Data cutoff: March 14, 2016. • 1. Choi Nat Rev Urol 2014. 2.
Aine Sci Rep 2015. 3. The Cancer Genome Atlas Research Network Nature 2014.
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
TCGA Subtype
I II III IV
19
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 20
IMvigor210: TCGA Subtype in mUC
• CDKN2A, cyclin-dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; GATA3, GATA-binding protein 3.
• Data cutoff: March 14, 2016. • 1. Choi Nat Rev Urol 2014. 2.
Aine Sci Rep 2015. 3. The Cancer Genome Atlas Research Network Nature 2014.
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
TCGA Subtype
I II III IV
20
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 21
IMvigor210: TCGA Subtype in mUC
• Luminal and basal tumors are distinct subtypes with unique histology and gene expression1-3
• CDKN2A, cyclin-dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; FGFR3, fibroblast growth factor receptor 3; GATA3, GATA-binding protein 3.
• Data cutoff: March 14, 2016. • 1. Choi Nat Rev Urol 2014. 2.
Aine Sci Rep 2015. 3. The Cancer Genome Atlas Research Network Nature 2014.
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
TCGA Subtype
I II III IV
21
Luminal
Basal
Urothelium
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 22
IMvigor210: TCGA Subtype in mUC
• Luminal I patients have low Teff gene expression
22
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
CD8A
GZMB GZMA
IFNG CXCL9 CXCL10 PRF1 TBX21
TCGA Subtype
I II III IV
Teff
Mesenchymal
• Data cutoff: March 14, 2016.
Luminal
Basal
Urothelium
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 23
IMvigor210: TCGA Subtype in mUC
• Luminal I patients have low Teff gene expression
• In Luminal II patients with disease progression, a trend toward lower baseline Teff expression was seen, compared with Luminal II responders
23
Luminal Basal I II III IV
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
CD8A
GZMB GZMA
IFNG CXCL9 CXCL10 PRF1 TBX21
Teff
TCGA Subtype
• Data cutoff: March 14, 2016.
Luminal
Basal
Urothelium
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 24
IMvigor210: TCGA Subtype in mUC
• Stromal genes were also analyzed
24
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
CD8A
GZMB GZMA
IFNG CXCL9 CXCL10 PRF1 TBX21 COL4A1 COL4A2 PDGFRB BGN NUAK1
Stromal
Teff
TCGA Subtype
I II III IV Mesenchymal
• COL4A, collagen type IV α; PDGFRB, platelet-derived growth factor β. Data cutoff: March 14, 2016.
Luminal
Basal
Urothelium
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 25
IMvigor210: TCGA Subtype in mUC
• Subtype II patients tended to have lower stromal gene expression
25
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
CD8A
GZMB GZMA
IFNG CXCL9 CXCL10 PRF1 TBX21 COL4A1 COL4A2 PDGFRB BGN NUAK1
Stromal
Teff
TCGA Subtype
I II III IV
• Data cutoff: March 14, 2016.
Luminal
Basal
Urothelium
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 26
IMvigor210: TCGA Subtype in mUC
• Luminal I tumors have low Teff expression
• Luminal II tumors have high Teff and low stromal gene expression
• Basal tumors have high Teff and high stromal gene expression
26
Luminal Basal
Papillary like Squamous
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
Response IC status TC status
FGFR3 CDKN2A KRT5
EGFR GATA3 FOXA1 ERBB2
KRT14
Mesenchymal
CD8A
GZMB GZMA
IFNG CXCL9 CXCL10 PRF1 TBX21 COL4A1 COL4A2 PDGFRB BGN NUAK1
Stromal
Teff
TCGA Subtype
I II III IV
• Data cutoff: March 14, 2016.
Luminal
Basal
Urothelium
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 27
IMvigor210: TCGA Subtype in mUC
• IMvigor210 subtypes have distinct tumor-immune landscapes that reflect responsiveness to atezolizumab
• TIL, tumor-infiltrating lymphocyte. a High myeloid, inflammatory, activated stromal/fibroblast markers. Data cutoff: March 14, 2016.
27
Immune desert Inflamed Immune suppresseda
Increased responses
Tumor cells
TIL/immune cells
Tumor stroma
Luminal Basal
Papillary like Squamous Response IC status TC status
Mesenchymal
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
I II III IV
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 28
Mutation Load Represented by FoundationOne Genes Correlates With Mutation Load in TCGA Whole-Exome Sequencing
• To estimate mutation load, we used a 315- gene FoundationOne panel that covers ≈ 3% of the exome1
• Whole-exome results correlated with the FoundationOne regions, indicating that the restricted target region was sufficient to rank patients based on mutation load
UC (bladder) Single-Nucleotide Variants
Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
28
protein altering total
1
10
100
10 1000 10 1000TCGA whole exome
Foun
datio
nOne
(F1)
cap
ture
pan
el
Zero captured:FALSE
TRUE
BLCA somatic mutations (SNVs)
ρ = 0.860a ρ = 0.870a
100
10
1
Foun
datio
nOne
G
enes
Onl
y
10 1000 10 1000 TCGA Whole Exome
• a Spearman ρ coefficient. Data cutoff: March 14, 2016.
1. Rosenberg Lancet 2016.
Petrylak DP, et al., Atezolizumab (MPDL3280A) in UBC 29
• mUC has a high mutation load and thus potential for neoantigen generation and recognition by the immune system1-3
• Median load was significantly higher in responders vs non-responders
– This relationship was statistically independent of other predictors of response
Mutation Load by FoundationOne and Response
• 1. Lawrence Nature 2013. 2. Cancer Genome Atlas Research Network Nature 2014. 3. Kandoth Nature 2013. Data cutoff: March 14, 2016. Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in mUC. ASCO 2016
29
II III Luminal Basal
IV All (n = 150)
Mut
atio
n Lo
ad/M
B
I 0
10 20
30
40
IC0/1 IC2/3
0
10 20
30
40
50
Mut
atio
n Lo
ad/M
B
responder non-responder
RECIST v1.1 response
Treg Anti-CCR4, anti-CTLA-4
Adenosine 2AR inhibitors Anti-CD39, anti-CD73
IDO inhibitors, Cox2 inhibitors
Inhibitory Cytokines
MDSC Type 2 macrophages
HDACi, MER-TKi, CCR2i, CSF-1Ri, CKITi, ibrutinib, Anti-CD47 (‘Don’t Eat Me Signals’ )
Checkpoint Inhibitors LAG3, TIM3, TIGIT, B7-H3, B7-H4, PD-1H (Vista), CD200, CEACAM1, KIR
Antibodies and small molecule inhibitors of TGF-beta or its receptors
Metabolic Inhibitors and Prostaglandins
Hypoxia/Adenosine
Activate with TCR-CD3 Constructs (CEA, gp100) Co-opt non-specific TIL
Adoptive Transfer: TIL CAR-T
Vaccines, T-VEC, Anti-CD40, FLT3 TLR agonists, CAR-T
STING agonists Epigenetic Modifiers
Create new tumor-specific T-cells or enhance in vivo Ag presentation
Cytokines and Modified Cytokines
Expansion and Increase Function of Ag-specific T cells
Disrupt tumor barriers to T-cell infiltration Anti-VEGF, anti-SEMA-4D, anti-CTLA-4
Co-stimulatory Agonists – 4-1BB, OX-40, GITR, ICOS, CD27
T-Cell Immune Checkpoints as Targets for Immunotherapy
Adapted from Mellman I et al. Nature. 2011;480:481–489.
CTLA-4
PD-1
TIM-3
BTLA
VISTA LAG-3 HVEM
CD27
CD137
GITR
OX40
CD28
T cell stimulation
Blocking antibodies
Agonistic antibodies
Inhibitory receptors
Activating receptors
T cell
B7-1
T cell
Targeted Therapy
Vaccines
Cell Therapies
Conclusions
• Luminal type II urothelial cancer appears to be the most responsive to immune checkpoint inhibition
• Current studies are limited by lack of consective biopsy specimens
Disease Aligned Research Team Retreat and Symposium
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