Reversing immune dysfunction in cancer: novel treatment paradigmsPresentation Transcript
Tyler J. Curiel, MD, MPH email@example.com Professor of Medicine UT Health Science Center San Antonio, TX Reversing Immune Dysfunction in Cancer
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 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
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).
Regulatory T cells (Tregs) are CD4 + CD25 hi 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 Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasis Limitless replicative potential Sustained angiogenesis
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. Evading apoptosis Lack of immune rejection Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasis Limitless replicative potential Sustained angiogenesis
FOXP3 + Tregs in tumors Curiel, Zou , et al. Nature Medicine 10 , 942-949 (2004)
Months 0 20 40 60 80 100 0.0 0.2 0.4 0.6 0.8 1.0 low Treg medium Treg high Treg Survival Elevated tumor CD4 + CD25 + T cells predict poor survival in ovarian cancer Low Treg 66.4 mos High Treg 12.8 mos P<0.0001 Curiel, Zou , et al. Nature Medicine 10 , 942-949 (2004)
CD4 + CD25 + CTCL cell CD4 + CD25 + Treg
Patient DT μ g/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
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
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 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
68.0% 90.8% Suppression (%) Eff:Treg ratio b p =0.017 1:1 1:0.5 60 40 20 0 80 Total number of tumor-specific CD8 + cells (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 + isotype WT + α B7-H1 WT + α B7-H1 c Pentamerr 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 a Tumor volume (mm 3 ) Days post B16 challenge WT + isotype WT + B7-H1 WT + isotype 0 2 6 4 8 10 12 14 16 800 600 400 200 0 1200 1400 1000 WT + B7-H1 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 tumor volume (mm 3 ) 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 CD11b + Gr-1 + cells in spleen (%) 6 4 2 0 PBS DT PBS DT no 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 suppression by CD11b + Gr-1 + from spleen at 1:1 ratio (%) PBS DT PBS DT no tumor no tumor young aged
Depleting Gr-1 + cells improves tumor immunity and slows B16 in aged females B Percent IFN γ + of CD8 + T cells in spleen 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 tumor volume (mm 3 ) day after challenge anti-Gr1 control mAb anti-Gr1 young aged control mAb
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.
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)
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.
Curiel lab members
National Cancer Institute
Hayes, Voelcker, Rippel Foundations and Trusts, Eisai