tyler j. curiel, md, mph curielt@uthscsa professor of medicine ut health science center
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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 - PowerPoint PPT PresentationTRANSCRIPT
Tyler J. Curiel, MD, [email protected]
Professor of MedicineUT Health Science Center
San Antonio, TX
Reversing Immune Dysfunction in Cancer
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 1822-1895Louis 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 tumor-specific immunityJ Nat CA Inst 1957;18:769
Tumors express antigensNature 304, 165-7 (1983)
● 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?
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):328F. 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
• Miscellaneous– Resist apoptosis
- Alter cell differentiation
DC subsets
Tumors reprogram dendritic cells to defeat host immunity, not the tumor
Zou, Curiel, et al., Nature Medicine2001; 7(12):1339-1346
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
*
**
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
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.
ThymusNegative selectionCentral tolerance
Self-reactive
Normal repertoire
Blood, LN, BM, spleenPeripheral tolerance
CD4+CD25+
Treg
Naïve thymocytes
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 TregsT. J. Curiel 2007 J Clin Invest 117(5):1167-1174
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
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
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
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)
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
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)
CD4+CD25+
CTCL cellCD4+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 depletesTregs 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 54:369-377; 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
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
Patient SAOC03
S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation
Interferon-α improves Treg depletion and DT efficacy in ovarian cancer
Patient SAOC03
S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation
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
Special cases
• Sex
• Age
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
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
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
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
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
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.
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)
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