Transcript Slide 1

Reversing Immune
Dysfunction in Cancer
Tyler J. Curiel, MD, MPH
[email protected]
Professor of Medicine
UT Health Science Center
San Antonio, TX
Outline
• Introduction to tumor immunity
• Limitations of the prevailing cancer drug
development approach
• Failures of the prevailing tumor
immunotherapy strategies
• The new immunotherapy paradigm and its
translational predictions and approaches
Louis Pasteur 1822-1895
Germ theory of
immunity 1878
First demonstration of
acquired immunity with
chicken cholera 1880
Immune surveillance and tumors
Increased cancer in
immunosuppressed hosts
Spontaneous cancer
remissions, especially in
renal cell carcinoma and
melanoma
Demonstration of tumorspecific immunity
J Nat CA Inst 1957;18:769
Tumors express antigens
Nature 304, 165-7 (1983)
The overarching questions
Is there definitive proof of naturallyoccurring immunity against cancers?
●
Could immune therapy for cancer
(of any kind) ever work?
●
●
For which cancers? At what stages?
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What approaches will work?
Tumor Immune Surveillance Exists
.
Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD IFN-γ and lymphocytes
prevent primary tumour development and shape tumour immunogenicity. Nature. 2001 410(6832):1107-11
Punch Line:
T cells, IFN-γ and
adaptive (antigen
specific) immunity are
key elements in
defense against tumors
Current tumor immunotherapy paradigms build on
infectious disease principles that may not apply to cancer
T. Curiel J Clin Invest, 117(5):1167-1174 2007
One answer: give more T cells
Rosenberg, S.A., Spiess, P. &
Lafreniere, R. A new approach
to the adoptive
immunotherapy of cancer
with tumor-infiltrating
lymphocytes. Science 233,
1318-21 (1986).
LAK cells. Rosenberg, S.A. et
al. N Engl J Med 316, 889-897
(1987)
Morgan, R.A., et al. Cancer
regression in patients after
transfer of genetically
engineered lymphocytes.
Science (2006).
Nature Medicine 1996 2(1):52-58
F. Hsu, et al.
B-cell lymphoma, autologous
antigen-pulsed dendritic cells
Nature Medicine 1998 4(3):328
F. Nestle, et al.
Melanoma, peptide- or tumor
lysate-pulsed dendritic cells
Intrinsic tumor strategies
• Hide the tumor
–
–
–
–
–
Reduce class I
Reduce TAA
Defective Ag processing
Reduce co-signaling
Grow in privileged sites
• Prevent active immunity
– Prevent cell ingress
– Promote cell egress
– Kill immune cells
- Alter cell differentiation
• Miscellaneous
– Resist apoptosis
DC subsets
Tumors reprogram dendritic cells to
defeat host immunity, not the tumor
Zou, Curiel, et al., Nature Medicine
2001; 7(12):1339-1346
Tumor plasmacytoid DC
generate IL-10+ T cells
[3H]thymidine incorporation (cpm x 103)
Control
+ tumor PDC
generated T cells
*
+ tumor PDC
generated T cells
+ anti-IL-10R
**
0
Zou, Curiel,
et al.,
Nature
Medicine
2001;
7(12):13391346 .
10
20
30
40
50
60
Tumor myeloid DC induce IL-10+ T
cells through B7-H1 signals
Curiel, Zou,
et al., Nature
Medicine
2003;
9(5):562-567
VEGF and IL-10 from the tumor induce B7-H1 expression
Immune recognition of tumor antigens
as self is a significant problem.
Infection: rapidly
dividing cells of
external origin.
Cancer: rapidly
dividing cells of
internal origin. The
tumor is a part of the
host (self).
The big problem
• Anti-tumor immunity is autoimmunity.
• To generate significant anti-tumor
immunity requires breaking self
tolerance.
Thymus
Negative selection
Central tolerance
Blood, LN, BM, spleen
Peripheral tolerance
CD4+CD25+
Treg
Naïve thymocytes
Self-reactive
Normal
repertoire
Regulatory T cells (Tregs) are CD4+CD25hi T cells
Treg depletion improves
endogenous immunity
Shimizu, J., et al. J Immunol 163, 5211-8
(1999)
Treg depletion improves
actively-induced immunity
Steitz, J., et al. Cancer Res 61, 8643-6 (2001)
Sutmuller, et al. J Exp Med 194, 823-32 (2001)
In tumors, many pathways generate Tregs
T. J. Curiel 2007 J Clin Invest 117(5):1167-1174
Six fundamental hallmarks of cancer
Hanahan and Weinberg 2000. Cell 100:57-70
Evading
apoptosis
Sustained
angiogenesis
Limitless
replicative
potential
Self-sufficiency
in growth
signals
Insensitivity
to anti-growth signals
Tissue invasion
and metastasis
The seventh fundamental hallmark of cancer
Dunn, G.P., Old, L.J., and Schreiber, R.D. 2004. Annu Rev Immunol 22:329-360.
Zitvogel, L., Tesniere, A., and Kroemer, G. 2006. Nat Rev Immunol 6:715-727.
T. J. Curiel. 2007 J Clin Invest, 117(5):1167-1174.
Lack of
immune
rejection
Self-sufficiency
in growth
signals
Evading
apoptosis
Insensitivity
to anti-growth
signals
Sustained
angiogenesis
Tissue invasion
and metastasis
Limitless
replicative
potential
FOXP3+ Tregs in tumors
Curiel, Zou, et al. Nature Medicine 10, 942-949 (2004)
Tumor Tregs allow tumor
growth despite
otherwise sufficient
numbers of functional
anti-tumor effectors cells
Curiel, Zou, et al. Nature Medicine 10, 942-949 (2004)
6
-
+
40
24
8
24
Counts
IFN-g
Treg
+
40%
17%
IL-2
17
IL-2
Annexin-V-APC
Curiel, Zou, et al. 2004
Nature Medicine 10, 942-949
Tumor Tregs allow
tumor growth despite
otherwise sufficient
numbers of functional
anti-tumor effector cells
6
-
+
40
24
8
24
Counts
IFN-g
Treg
+
40%
17%
IL-2
17
IL-2
Annexin-V-APC
Elevated tumor CD4+CD25+ T cells predict
poor survival in ovarian cancer
Curiel, Zou , et
al. Nature Medicine 10, 942-949 (2004)
Survival
1.0
Low Treg
66.4 mos
0.8
0.6
High Treg
12.8 mos
P<0.0001
low Treg
0.4
medium Treg
0.2
high Treg
0.0
0
20
40
60
Months
80
100
CD4+CD25+
CTCL cell
CD4+CD25+
Treg
Patient
DT
μg/kg
Age in
years
Gender
Tumor
type
Prior
treatments
1
9
59
F
ovarian
S, C
2
9
41
F
breast
HT, C
3
9
50
M
lung
C, RT
4
12
53
F
ovarian
C, RT, S
5
12
31
F
ovarian
C, S
6
12
36
F
ovarian
C, S
7
12
72
M
pancreatic
C, HT, S
Denileukin diftitox depletes
Tregs in cancer patients
Denileukin diftitox increases blood
IFN-γ-producing T cells in cancer patients
Patient 4
• Stage IV (metastatic) ovarian cancer.
• First recipient of the dose-escalated 12
µg/kg, with significant immune response.
• Because she had measurable disease,
she received six additional denileukin
diftitox doses to test clinical efficacy.
Denileukin diftitox reduces metastatic tumor
in treatment-refractory ovarian cancer
4
months
Corroborating trials
• Ovarian: Barnett, B., Kryczek, I., Cheng, P., Zou,
W. & Curiel, T.J. Am J Reprod Immunol 54:369377; 2005
• Renal cell: Dannull, J., et al. The Journal of
Clinical Investigation 115:3623-3633; 2005
• Melanoma: Mahnke, K., et al. Int J Cancer 120:
2723-33; 2007
• Melanoma: Rasku, M. A, et al. J. Translational
Med, 6:12;2008
Even when the system works,
tumors can develop:
“The Three Es of Cancer Immunoediting”
R. Schreiber Annu Rev Immunol 33:329 2004
Fig: L. Zitvogel et al., Nature Reviews Immunology 6, 715-727 (October 2006)
Salvaging DT failure in ovarian cancer
DT treatmentfailed
failure
treatment
1500
DT
DT + IFN-
1035
1000
595
500
985
536
333 383
186 152
150
4
IF
N+

DT IFN 1
+ -
DT IFN 2
+ -
DT IFN 3
+ -
IF
N- 4

5
3
DT
DT
+
DT
2
DT
DT
1
0
DT
Patient SAOC03
blood CA-125 U/mL
S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation
cycle number
Interferon-α improves Treg depletion
and DT efficacy in ovarian cancer
DT treatmentfailed
failure
treatment
1500
DT
DT + IFN-
1035
1000
595
500
985
536
333 383
186 152
150
4
IF
N+

DT IFN 1
+ -
DT IFN 2
+ -
DT IFN 3
+ -
IF
N- 4

5
DT
DT
+
DT
3
DT
2
DT
1
0
DT
Patient SAOC03
blood CA-125 U/mL
S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation
cycle number
How IFN-α boosts
Treg depletion effects
• Directly activates CD8+ T cells
• Boosts T cell-activating capacity of
dendritic cells
• Increases T cell trafficking into tumor
• Does NOT appear to affect Treg function
or regeneration after depletion
Special cases
• Sex
• Age
Females respond better to anti-B7-H1 blockade in B16 melanoma
1400
WT + isotype
WT + isotype
WT + B7-H1
1000
80
WT + B7-H1
800
68.0%
600
400
90.8%
Suppression (%)
1200
60
WT + B7-H1
p=0.017
40
20
200
0
0
0
2
4
6
8
10
12
14
16
1:1
Mouse 1
0.25%
0.36%
0.38%
0.55%
CD8
Mouse 2
0.24%
0.35%
0.42%
0.52%
WT + isotype
Mouse 3
0.27%
0.29%
0.46%
0.56%
WT
+ isotype
WT
+ isotype
WT
+ αB7-H1
WT
+ αB7-H1
WT + isotype
Total number of tumorspecific CD8+ cells (105)
c
1:0.5
Eff:Treg ratio
Days post B16 challenge
Pentamerr
Tumor volume (mm3)
WT + isotype
WT + isotype
WT + B7-H1
b
a
WT + B7-H1
WT + B7-H1
p=0.009
6
p=0.028
4
2
0
p=0.013
Sex differences in female Tregs
• B7-H1-dependent reduction in Treg function
• B7-H1 effects are estrogen-dependent
• Functional differences are due to defective
mTOR/PTEN signaling
• Treg function is rescued with dendritic cell B7H1 signals, estrogen withdrawal or rapamycin
Treg depletion does not work in
aged female mice with B16
PBS
800
Young PBS
young
tumor volume (mm3)
700
DT
Young DT
600
PBS
500
Aged PBS
400
DT
aged
Aged DT
300
200
100
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15
day after challenge
Aged female mice have more
CD11b+Gr-1+ myeloid suppressors that
are more suppressive than young
p=0.01
100
suppression by CD11b+Gr-1+
from spleen at 1:1 ratio (%)
CD11b+Gr-1+ cells in spleen
(%)
6
4
2
0
no tumor
PBS
young
DT
no tumor
PBS
aged
DT
1:1 ratio of MDSC from Spleen
80
60
40
p=0.10
20
p=0.02
p=0.01
0
no tumor
PBS
young
DT
no tumor
PBS
aged
DT
Depleting Gr-1+ cells improves tumor
immunity and slows B16 in aged females
p=0.019
900
800
tumor volume (mm3)
700
600
500
400
300
control mAb
Young
PBS
young
anti-Gr1
Young
anti-Gr-1
controlPBS
mAb
Aged
aged
anti-Gr1
Aged
antiGr-1
200
100
Percent IFNγ+ of CD8+ T
cells in spleen
B
4
p=0.21
3
2
1
0
no tumor
0
control mAb
-Gr-1 mAb control mAb
-Gr-1 mAb
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
day after challenge
young
aged
Summary and conclusions
• Cancers are immunogenic and thus
should be amenable to effective immune
therapies in the new paradigm.
• Immune therapies are adjuncts in multimodal treatment approaches.
• Immune therapy is not appropriate for all
patients.
Ways forward
• Identify patients with relatively intact
immune systems for trials
• Test available agents: DT, anti-CTLA-4
• Test reversing immune dysfunction with
immunization or immune boost (e.g., antiCTLA-4 or DT plus a vaccine)
Final Thoughts
• We need a better understanding of
immune dysfunction in cancer.
• We need a better understanding of the
immune effects of current agents.
• Willingness of investigators to try immune
therapies will help, but they have to be
convinced.
Acknowledgements
• Curiel lab members
• National Cancer Institute
• Hayes, Voelcker, Rippel Foundations and
Trusts, Eisai
• UTHSCSA endowments
• Cancer Therapy & Research Center