reversing immune dysfunction in cancer: novel treatment paradigms
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Tyler J. Curiel, MD, [email protected]
Professor of MedicineUT Health Science Center
San Antonio, TX
Reversing Immune Dysfunction in Cancer
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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
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Louis Pasteur 1822-1895Louis Pasteur 1822-1895
Germ theory of immunity 1878
First demonstration of acquired immunity with
chicken cholera 1880
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Immune surveillance and tumors
Increased cancer in immunosuppressed hosts
Spontaneous cancer remissions, especially in renal cell carcinoma and melanoma
Demonstration of tumor-specific immunityJ Nat CA Inst 1957;18:769
Tumors express antigensNature 304, 165-7 (1983)
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● Is there definitive proof of naturally-occurring immunity against cancers?
● Could immune therapy for cancer (of any kind) ever work?
The overarching questions
● For which cancers? At what stages?
● What approaches will work?
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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
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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
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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).
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Nature Medicine 1996 2(1):52-58 F. Hsu, et al.
B-cell lymphoma, autologous antigen-pulsed dendritic cells
Nature Medicine 1998 4(3):328F. Nestle, et al.Melanoma, peptide- or tumor lysate-
pulsed dendritic cells
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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
• Miscellaneous– Resist apoptosis
- Alter cell differentiation
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DC subsets
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Tumors reprogram dendritic cells to defeat host immunity, not the tumor
Zou, Curiel, et al., Nature Medicine2001; 7(12):1339-1346
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Tumor plasmacytoid DCgenerate IL-10+ T cells
Zou, Curiel, et al.,
Nature Medicine
2001; 7(12):1339-
1346 .
[3H]thymidine incorporation (cpm x 103)
0
10 20 30 40 50 60
Control
+ tumor PDC generated T cells
+ tumor PDC generated T cells + anti-IL-10R
*
**
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Tumor myeloid DC induce IL-10+ T cells through B7-H1 signals
Curiel, Zou, et al., Nature
Medicine2003;
9(5):562-567
VEGF and IL-10 from the tumor induce B7-H1 expression
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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).
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The big problem
• Anti-tumor immunity is autoimmunity.
• To generate significant anti-tumor immunity requires breaking self tolerance.
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ThymusNegative selectionCentral tolerance
Self-reactive
Normal repertoire
Blood, LN, BM, spleenPeripheral tolerance
CD4+CD25+
Treg
Naïve thymocytes
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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)
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In tumors, many pathways generate TregsT. J. Curiel 2007 J Clin Invest 117(5):1167-1174
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Evading apoptosis
Self-sufficiencyin growth
signals
Insensitivity to anti-growth signals
Tissue invasionand metastasis
Limitless replicativepotential
Sustained angiogenesis
Six fundamental hallmarks of cancer Hanahan and Weinberg 2000. Cell 100:57-70
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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-sufficiencyin growth
signals
Insensitivity to anti-growth
signals
Tissue invasionand metastasis
Limitless replicativepotential
Sustained angiogenesis
Evading apoptosis
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FOXP3+ Tregs in tumors
Curiel, Zou, et al. Nature Medicine 10, 942-949 (2004)
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Tumor Tregs allow tumor growth despite otherwise sufficient numbers of functional anti-tumor effectors cells
IL-2
IFN
- 6 40
24
8 24
17
Treg
40% 17%C
ou
nts
Annexin-V-APC
- + - +
IL-2
Curiel, Zou, et al. Nature Medicine 10, 942-949 (2004)
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Tumor Tregs allow tumor growth despite otherwise sufficient numbers of functional anti-tumor effector cells
IL-2
IFN
- 6 40
24
8 24
17
Treg
40% 17%C
ou
nts
Annexin-V-APC
- + - +
IL-2
Curiel, Zou, et al. 2004Nature Medicine 10, 942-949
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Months
0 20 40 60 80 1000.0
0.2
0.4
0.6
0.8
1.0
low Treg
medium Treg
high Treg
Sur
viva
l
Elevated tumor CD4+CD25+ T cells predict poor survival in ovarian cancer
Low Treg66.4 mos
High Treg12.8 mosP<0.0001
Curiel, Zou , et al. Nature Medicine 10, 942-949 (2004)
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CD4+CD25+
CTCL cellCD4+CD25+
Treg
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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
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Denileukin diftitox depletesTregs in cancer patients
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Denileukin diftitox increases blood IFN-γ-producing T cells in cancer patients
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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.
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Denileukin diftitox reduces metastatic tumor in treatment-refractory ovarian cancer
4 months
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Corroborating trials
• Ovarian: Barnett, B., Kryczek, I., Cheng, P., Zou, W. & Curiel, T.J. Am J Reprod Immunol 54:369-377; 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
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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)
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Salvaging DT failure in ovarian cancer
Patient SAOC03
S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation
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Interferon-α improves Treg depletion and DT efficacy in ovarian cancer
Patient SAOC03
S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation
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How IFN-α boostsTreg 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
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Special cases
• Sex
• Age
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WT + isotype
WT + isotype
WT + αB7-H1
WT + αB7-H1
c
Pen
tam
err
CD8
0.25% 0.24% 0.27%
0.36% 0.35% 0.29%
0.38% 0.42% 0.46%
0.56%0.52%0.55%
Mouse 1 Mouse 2 Mouse 3
68.0%
90.8%
a
Tum
or v
olum
e (m
m3)
Days post B16 challenge
WT + isotype
WT + B7-H1
WT + isotype
0 2 64 8 10 12 14 16
800
600
400
200
0
1200
1400
1000
WT + B7-H1
Sup
pres
sion
(%
)
Eff:Treg ratio
b
p=0.017
1:1 1:0.5
60
40
20
0
80
Tot
al n
umbe
r of
tum
or-
spec
ific
CD
8+ c
ells
(10
5 )
p=0.009
p=0.013
p=0.028
6
4
2
0
WT + isotype
WT + B7-H1
WT + isotype
WT + B7-H1
Females respond better to anti-B7-H1 blockade in B16 melanoma
WT + isotype
WT + B7-H1
WT + isotype
WT + B7-H1
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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 B7-H1 signals, estrogen withdrawal or rapamycin
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Treg depletion does not work in aged female mice with B16
tum
or
volu
me
(m
m3)
day after challenge
young
aged
PBS
DT
PBS
DT
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Aged female mice have more CD11b+Gr-1+ myeloid suppressors that
are more suppressive than young
p=0.01
CD
11b+
Gr-
1+ c
ells
in s
plee
n (%
)
6
4
2
0
PBS DT PBS DTno tumor no tumor
young aged
1:1 ratio of MDSC from Spleen
p=0.10
p=0.02
p=0.01
80
60
40
20
0
100
supp
ress
ion
by
CD
11b+
Gr-
1+
from
sp
leen
at
1:
1 r
atio
(%
)
PBS DT PBS DTno tumor no tumor
young aged
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Depleting Gr-1+ cells improves tumor immunity and slows B16 in aged females
tum
or
volu
me
(m
m3)
day after challenge
anti-Gr1
control mAb
anti-Gr1
young
aged
control mAb
B
Per
cent
IFN
γ+ o
f CD
8+ T
ce
lls in
spl
een
0
1
2
3
4
no tumor control mAb -Gr-1 mAb -Gr-1 mAb
young aged
control mAb
p=0.21
p=0.019
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Summary and conclusions
• Cancers are immunogenic and thus should be amenable to effective immune therapies in the new paradigm.
• Immune therapies are adjuncts in multi-modal treatment approaches.
• Immune therapy is not appropriate for all patients.
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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., anti-CTLA-4 or DT plus a vaccine)
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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.
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Acknowledgements• Curiel lab members
• National Cancer Institute
• Hayes, Voelcker, Rippel Foundations and Trusts, Eisai
• UTHSCSA endowments
• Cancer Therapy & Research Center