Tyler J. Curiel, MD, MPH

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Reversing Immune Dysfunction in Cancer

• Tyler J. Curiel, MD, MPH
• curielt_at_uthscsa.edu
• Professor of Medicine
• UT Health Science Center
• San Antonio, TX

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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 1822-1895

• 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 immunity
• J Nat CA Inst 195718769
• Tumors express antigens
• Nature 304, 165-7 (1983)

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? Is there definitive proof of naturally-occurrin
g 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-? and lymphocytes prevent
primary tumour development and shape tumour
immunogenicity. Nature. 2001 410(6832)1107-11
Punch Line T cells, IFN-? 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)328
• F. 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 Medicine 2001
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 .
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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
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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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Blood, LN, BM, spleen Peripheral tolerance
Thymus Negative selection Central tolerance
CD4CD25 Treg
Naïve thymocytes
Normal repertoire
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Regulatory T cells (Tregs) are CD4CD25hi 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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Six fundamental hallmarks of cancer Hanahan and
Weinberg 2000. Cell 10057-70
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The seventh fundamental hallmark of cancer Dunn,
G.P., Old, L.J., and Schreiber, R.D. 2004. Annu
Rev Immunol 22329-360.Zitvogel, L., Tesniere,
A., and Kroemer, G. 2006. Nat Rev Immunol
6715-727.T. J. Curiel. 2007 J Clin Invest,
117(5)1167-1174.
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
Curiel, Zou, et al. Nature Medicine 10, 942-949
(2004)
IL-2
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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
IL-2
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Elevated tumor CD4CD25 T cells predict poor
survival in ovarian cancer
Curiel, Zou , et al. Nature Medicine 10, 942-949
(2004)
1.0
Low Treg 66.4 mos High Treg 12.8
mos Plt0.0001
0.8
0.6
Survival
low Treg
0.4
medium Treg
0.2
high Treg
0.0
0
20
40
60
80
100
Months
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CD4CD25 CTCL cell
CD4CD25 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-?-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
  54369-377 2005
• Renal cell Dannull, J., et al. The Journal of
  Clinical Investigation 1153623-3633 2005
• Melanoma Mahnke, K., et al. Int J Cancer 120
  2723-33 2007
• Melanoma Rasku, M. A, et al. J. Translational
  Med, 6122008

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Even when the system works,tumors can
developThe Three Es of Cancer
ImmunoeditingR. Schreiber Annu Rev Immunol
33329 2004
Fig L. Zitvogel et al., Nature Reviews
Immunology 6, 715-727 (October 2006)
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Salvaging DT failure in ovarian cancer
S. Wall, S. Thibodeaux, T. Curiel, et al., in
preparation
Patient SAOC03
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Interferon-a improves Treg depletion and DT
efficacy in ovarian cancer
S. Wall, S. Thibodeaux, T. Curiel, et al., in
preparation
Patient SAOC03
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How IFN-a 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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Females respond better to anti-B7-H1 blockade in
B16 melanoma
b
80
p0.017
60
68.0
Suppression ()
40
90.8
20
0
11
10.5
EffTreg ratio
WT isotype
WT isotype
WT ?B7-H1
WT ?B7-H1
p0.009
6
p0.028
4
Total number of tumor-specific CD8 cells (105)
p0.013
2
0
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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
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Aged female mice have more CD11bGr-1 myeloid
suppressors that are more suppressive than young
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Depleting Gr-1 cells improves tumor immunity and
slows B16 in aged females
B
p0.019
4
p0.21
3
Percent IFN? of CD8 T cells in spleen
2
1
0
no tumor
control mAb
?-Gr-1 mAb
?-Gr-1 mAb
control mAb
young
aged
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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