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SITC workshop 2:50 pm - 3:10 pm
Clinical Trials: Provoking Immunity in the Tumor Microenvironment
Antoni Ribas, M.D., Ph.D.Professor of MedicineProfessor of Surgery
Professor of Molecular and Medical PharmacologyDirector, Tumor Immunology Program,
Jonsson Comprehensive Cancer Center (JCCC)University of California Los Angeles (UCLA)
Disclosure InformationAntoni Ribas
I have the following financial relationships to disclose:• Consultant for: Kite Pharma• Speaker’s Bureau for: None• Grant/Research support from: None• Stockholder in: Kite Pharma• Honoraria from: Amgen, Celgene, Genentech-Roche,
GSK, Millennium, Novartis, Prometheus • Employee of: None-and -• I will discuss the following off label use and/or
investigational use in my presentation: tremelimumab, nivolumab
Durable responses with anti-CTLA4 in approximately 10-15% of patients
CTLA4 response since 2004
CTLA4 response since 2003
How can CTLA4 blockade therapy be studied in humans?
CD4
CD4
CD4
CD8CD8
CD8CD8
CD8
CD8
CD8CD8CD8 CD8
CD8CD8
CD8
CD4
CD8CD8 CD4
CD4
CD8
CD4
CD4
CD8
CD8
CD8
CD4CD4
Anti-CTLA4 antibody
PK: Antibody levels in blood
Immune monitoring: Levels of blood immune cells
Tumor biopsies: Immune cells killing cancer cells
Studying where it counts: The Tumor
Tumor cells
DC
DC
B7CTLA4
MH
C
T cell
IL-2CD28
CTL
CTL
Treg
iDC
IDO
02/05
07/05
01/08
Anti-CTLA4 Antibodies Induce Dense Intratumoral Infiltrated by CD8+ CTLs in
Regressing Tumors
Exp1111MCEOS011806.011
FL1-H
010 110 210 310 410
FL2-
H
010
110
210
310
410 R40.06%160.09#45
PeripheralBlood
0.06%ByopsyMC101908.011
FL1-H
010 110 210 310 410
FL2-
H
010
110
210
310
410 R40.42%157.74 0.42%
Tumor
gp10
0 209
-217
Tetra
mer
CD8
10x
MART-1 CD8
Ribas, Comin-Anduix, Cochran et al. Clin Ca Res 2008
Treg Depletion with CTLA4 Blocking Monoclonal Antibodies
T cell
B7 CTLA4
Treg • Treg depletion in peripheral blood with anti-CTLA4 mAb: – Reuben et al. Cancer
2006
• No Treg depletion in peripheral blood with anti-CTLA4 mAb: – Maker et al. J Immunol
2005– Comin-Anduix et al.
iSBTc 2006
FoxP3
T cell
B7CTLA4
Anti-CTLA4 Treg
Anti-CTLA4
FoxP3
Patient PD: FoxP3 by IHC or ICS in TIL
ByBS_GHW012606.006
CD4
010 110 210 310 410
CD
25
010
110
210
310
410 0.47%CD4=CD25high0.47%CD4=CD25high
ByBS_GHW012606.006
FoxP3
010 110 210 310 410
Side
Sca
tter
0
256
512
768
1024FoxP3+92.66%#467
FoxP3 in TIL by ICS
CD
25+
CD4+ FoxP3+
S100
10x
FoxP3
FoxP3
40x
Post
92%
FoxP3 ICSCD4/CD25hi
FoxP3 in TIL by IHC
CD4
CD4
Begonya Comin-Anduix, PhDAlistair Cochran, MD
Inhibition of IDO by CTLA4 Blocking Monoclonal Antibodies
DC B7
Treg
IDOCTLA4
DC B7
Anti-CTLA4Treg
IDOCTLA4
Anti-CTLA4
• Grohmann, Fallarino et al. Nat Immunol. 3, 1097 (2002)
• Grohmann, Fallarino et al. Nat Immunol. 4, 1206 (2003)
• Munn, Mellor et al. J ClinInvest. 114, 280 (2004)
• Munn, Mellor et al. IntImmunol. 16, 1391 (2004)
Intratumoral FoxP3+ and IDO+ Cells
=
=
=
IDOChange
--
+ patchy+ patchy
+ patchy+ patchy
+ patchy++ diffuse
IDO
=
FoxP3Change
+ patchy+ patchy
++ patchy+ patchy
+ patchy0
+ patchy0
FoxP3
Post (1 mo/1 mo)
Progr4
pPR
PR
PR
Response
Pre
Post (9 mo/1 mo)
Pre3
Post (2 mo/1 mo)
Pre2
Post (3 mo/3mo)
Pre1
Timing of Biopsy
Pt No.
Phase 2 to Study the Mechanism of Action of Tremelimumab in Patients Using Repeated
Outpatient Tumor Biopsies
Tremelimumab-
1 30 60 90
-
Leukapheresis #1Tumor Biopsy #1PET CT Scan #1
[18F]FDG[18F]FLT
StandardRe-Staging
Exams
Tremelimumab
Leukapheresis #2Tumor Biopsy #2PET CT Scan #2
[18F]FDG[18F]FLT
Increase in TIL in most patients regardless of tumor response
GA18
Pre-Tx Biopsies Post-Tx Biopsies
GA12
GA14
GA29
No
tum
or re
spon
se
Huang… Cochran, Ribas Clinical Cancer Research 2011
40x CD8 IHC
With
tum
or re
spon
se
Intratumoral CD8 Infiltration
Pre Post
CD
8 C
ell D
ensi
ty
0
500
1000
1500
2000
2500
3000
Paired t-test p = 0.005
40x CD8 IHC
No difference in TIL activation or replicationHLA-DR+/CD45RO+ Activated T Cells
Pt w Response
Pt w Progression
Pre-Tx Post-Tx
Pre-Tx Post-Tx
Pt w Response
Pt w Progression Ki-67+ Proliferating Cells
Where in the body is anti-CTLA4 working?
[18F]FDG PET
CD8CD8
CD8
CD8
CD8
CD8CD8CD8 CD8
CD8CD8
CD8
Where does lymphocyte replication happen?
Whole Body Imaging with PET Probes: [18F]FDG and [18F]FLT
Shields et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nature Med 1998
[18F]FDG:- Positron emitting glucose analog- Images glucose metabolism
[18F]FLT:- Positron emitting thymidine nucleoside analog- Images cell replication
Tse, … Phelps, Glaspy et al. The application of positron emission tomographic imaging with fluorodeoxyglucose to the evaluation of breast disease. Ann Surg 1992
[18F]FDG and [18F]FLT PET in a Patient with Response to Tremelimumab
Post-treatment
Pre-treatment
[18F]FDG [18F]FLT
[18F]FDG:- Positron emitting glucose analog- Images glucose metabolism
[18F]FLT:- Positron emitting thymidine nucleoside analog- Images cell replication
[18F]FLT PET Tracer Uptake in the Spleen Before and After Tremelimumab
Post
-trea
tmen
tPr
e-tr
eatm
ent GA24 GA33
BeforeTreme
AfterTreme
[18F]FLT SUVmean
Pre Post
SU
V
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
P = 0.018
Molecular imaging with the PET probe [18F]FLT (radiolabeled thymidine) allows mapping and non-invasive imaging of cell proliferation in spleen after CTLA4 blockade in patients with metastatic melanoma.
Ribas… Czernin. JNM 2010
Where in the body is anti-CTLA4 working?
CD8CD8
CD8
CD8
CD8
CD8CD8CD8 CD8
CD8CD8
CD8
Where does lymphocyte replication happen? In lymphoid organs
Conclusions• The main goal of tumor immunotherapy is to bring
activated T cells into tumors:– Vaccination with DC can occasionally achieve durable immune
responses to cancer– CTLA4 blockade induces reproducible but low frequency durable
tumor responses to cancer
• T cell infiltration is necessary but not sufficient to result intumor responses
• FOXP3 and IDO expression in tumors does not seem to be associated with resistance to CTLA4 blockade
• T cell replication upon CTLA4 blockade happens in lymphoid organs and not in tumors