Reversing Immune Dysfunction in Cancer
Download
1 / 46

Tyler J. Curiel, MD, MPH [email protected] Professor of Medicine UT Health Science Center - PowerPoint PPT Presentation


  • 103 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Tyler J. Curiel, MD, MPH [email protected] Professor of Medicine UT Health Science Center' - kaloni


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

Reversing Immune Dysfunction in Cancer

Tyler J. Curiel, MD, MPH

[email protected]

Professor of Medicine

UT Health Science Center

San Antonio, TX


Outline
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
Louis Pasteur 1822-1895

Germ theory of immunity 1878

First demonstration of acquired immunity with chicken cholera 1880


Immune surveillance and tumors
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 1957;18:769

Tumors express antigens

Nature 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
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
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



Tumors reprogram dendritic cells to defeat host immunity not the tumor
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
Tumor plasmacytoid DC not the tumorgenerate IL-10+ T cells

Zou, Curiel,

et al., Nature Medicine

2001; 7(12):1339-1346 .


Tumor myeloid dc induce il 10 t cells through b7 h1 signals
Tumor myeloid DC induce IL-10 not the tumor+ 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
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
The big problem significant problem.

  • Anti-tumor immunity is autoimmunity.

  • To generate significant anti-tumor immunity requires breaking self tolerance.


Self-reactive significant problem.

Blood, LN, BM, spleen

Peripheral tolerance

Thymus

Negative selection

Central tolerance

CD4+CD25+

Treg

Naïve thymocytes

Normal repertoire


Regulatory t cells tregs are cd4 cd25 hi t cells

Treg depletion improves endogenous immunity significant problem.

Shimizu, J., et al. J Immunol163, 5211-8 (1999)

Regulatory T cells (Tregs) are CD4+CD25hi T cells

Treg depletion improves

actively-induced immunity

Steitz, J., et al. Cancer Res61, 8643-6 (2001)

Sutmuller, et al. J Exp Med194, 823-32 (2001)


In tumors, many pathways generate Tregs significant problem.

T. J. Curiel 2007 J Clin Invest 117(5):1167-1174


Six fundamental hallmarks of cancer hanahan and weinberg 2000 cell 100 57 70
Six fundamental hallmarks of cancer significant problem.Hanahan and Weinberg 2000. Cell 100:57-70

Self-sufficiency

in growth

signals

Evading

apoptosis

Insensitivity

to anti-growth signals

Sustained

angiogenesis

Limitless

replicative

potential

Tissue invasion

and metastasis


The seventh fundamental hallmark of cancer significant problem.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

Insensitivity

to anti-growth signals

Evading

apoptosis

Sustained

angiogenesis

Tissue invasion

and metastasis

Limitless

replicative

potential


FOXP3 significant problem.+ Tregs in tumors

Curiel, Zou, et al.Nature Medicine10, 942-949 (2004)


40% significant problem.

17%

Treg

-

+

-

+

6

40

8

24

IFN-g

Counts

24

17

Annexin-V-APC

IL-2

Tumor Tregs allow tumor growth despite otherwise sufficient numbers of functional anti-tumor effectors cells

Curiel, Zou, et al.Nature Medicine10, 942-949 (2004)

IL-2


40% significant problem.

17%

Treg

-

+

-

+

6

40

8

24

IFN-g

Counts

24

17

Annexin-V-APC

IL-2

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


Elevated tumor CD4 significant problem.+CD25+ T cells predict

poor survival in ovarian cancer

Curiel, Zou , et al.Nature Medicine10, 942-949 (2004)

1.0

Low Treg

66.4 mos

High Treg

12.8 mos

P<0.0001

0.8

0.6

Survival

low Treg

0.4

medium Treg

0.2

high Treg

0.0

0

20

40

60

80

100

Months


CD4 significant problem.+CD25+

CTCL cell

CD4+CD25+

Treg


Denileukin diftitox depletes significant problem.Tregs in cancer patients


Denileukin diftitox increases blood significant problem.IFN-γ-producing T cells in cancer patients


Patient 4
Patient 4 significant problem.

  • 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 significant problem.in treatment-refractory ovarian cancer

4

months


Corroborating trials
Corroborating trials significant problem.

  • Ovarian: Barnett, B., Kryczek, I., Cheng, P., Zou, W. & Curiel, T.J. Am J Reprod Immunol54:369-377; 2005

  • Renal cell: Dannull, J., et al.The Journal of Clinical Investigation115:3623-3633; 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, significant problem.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
Salvaging DT failure in ovarian cancer significant problem.

S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation

Patient SAOC03


Interferon improves treg depletion and dt efficacy in ovarian cancer
Interferon- significant problem.α improves Treg depletion and DT efficacy in ovarian cancer

S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation

Patient SAOC03


How ifn boosts treg depletion effects
How IFN- significant problem.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
Special cases significant problem.

  • Sex

  • Age


Females respond better to anti-B7-H1 blockade in B16 melanoma

a

1400

WT + isotype

b

1200

WT + isotype

1000

WT+ B7-H1

800

WT+ B7-H1

Tumor volume (mm3)

WT + isotype

80

600

WT + isotype

400

p=0.017

200

60

68.0%

WT+ B7-H1

0

0

2

4

6

8

10

12

14

16

Suppression (%)

40

Days post B16 challenge

WT+ B7-H1

90.8%

c

Mouse 1

Mouse 2

Mouse 3

20

WT

+ isotype

0.25%

0.24%

0.27%

0

1:1

1:0.5

WT

+ isotype

Eff:Treg ratio

0.36%

0.35%

0.29%

WT + isotype

WT

+ αB7-H1

0.42%

0.46%

0.38%

WT + isotype

WT+ B7-H1

WT+ B7-H1

WT

+ αB7-H1

0.55%

0.52%

0.56%

p=0.009

6

Pentamerr

p=0.028

CD8

4

Total number of tumor-specific CD8+ cells (105)

p=0.013

2

0


Sex differences in female tregs
Sex differences in female Tregs melanoma

  • 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
Treg depletion does not work in aged female mice with B16 melanoma

tumor volume (mm3)

PBS

young

DT

PBS

aged

DT

day after challenge


Aged female mice have more cd11b gr 1 myeloid suppressors that are more suppressive than young
Aged female mice have more CD11b melanoma+Gr-1+ myeloid suppressors that are more suppressive than young

6

p=0.01

4

CD11b+Gr-1+ cells in spleen (%)

2

0

no tumor

no tumor

PBS

DT

PBS

DT

young

aged

100

1:1 ratio of MDSC from Spleen

80

60

suppression by CD11b+Gr-1+

from spleen at 1:1 ratio (%)

40

p=0.10

20

p=0.02

p=0.01

0

no tumor

no tumor

PBS

DT

PBS

DT

young

aged


Depleting gr 1 cells improves tumor immunity and slows b16 in aged females
Depleting Gr-1 melanoma+ cells improves tumor immunity and slows B16 in aged females

tumor volume (mm3)

B

p=0.019

control mAb

young

4

anti-Gr1

p=0.21

control mAb

aged

anti-Gr1

3

day after challenge

Percent IFNγ+ of CD8+ T cells in spleen

2

1

0

no tumor

control mAb

-Gr-1 mAb

control mAb

-Gr-1 mAb

young

aged


Summary and conclusions
Summary and conclusions melanoma

  • 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
Ways forward melanoma

  • 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
Final Thoughts melanoma

  • 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
Acknowledgements melanoma

  • Curiel lab members

  • National Cancer Institute

  • Hayes, Voelcker, Rippel Foundations and Trusts, Eisai

  • UTHSCSA endowments

  • Cancer Therapy & Research Center


ad