Here is a list of KO mice lacking various components of the immune system and the conclusion from this study was that if you knocking out the important components of the immune system, you get increased of spontaneous tumors, especially T cells, IFN-gamma and components of the adaptive immunity. Therefore, T cells, INF-gamma and adaptive immunity are key elements in immunological surveillance and in defense against tumors. This demonstrates that a number of immune effector cells and pathways are important for suppression of tumor development, mainly IFN-g and adoptive immunity.
In 2000, Hannahan and Weinberg defined six fundamental hallmarks of cancer. They described the characteristics of tumor very well, however, a consideration of the host responses to the tumor was not included.
It has recently been appreciated that lack of immune rejection is the seventh fundamental hallmark of cancer. And this has been supported by several investigators.
7/31/02 TAH/BSO,8/02-1/03 carbo/taxol x 6, 2/03 ex lap ,xrt to pelvis, 4/03-9/03 doxil, pet/ct, 11/03 l groin lymphocele, FNA r +, 3/04 CA-125, with PET/ct
The “three Es hypothesis” was proposed by Schreiber and colleagues. The idea is that immunosurveillance is one phase of a more comprehensive process-immunoediting-which can be broken up into three component phases: elimination, equilibrium and escape. In the elimination phase, immune system recognizes and eliminates tumor cells very efficiently and prevent solid tumor from forming. This process of selection gives rise to a cancer cell that can eventually form a tumor that stay in an equilibrium with immunoselection. In this phase, there is no net growth of tumor. Cells are still being eliminated and replaced in the tumor. This can continue for years. Then, some tumors escape. This last phase occurs when a tumor mutates sufficiently to evade elimination by the immune system and grows out. This results cancer.
* p<0.05 ** p<0.01 *** p<0.001 Fig4 not finished
Reversing immune dysfunction in cancer: novel treatment paradigms
Tyler J. Curiel, MD, MPH firstname.lastname@example.org Professor of Medicine UT Health Science Center San Antonio, TX Reversing Immune Dysfunction in Cancer
Outline <ul><li>Introduction to tumor immunity </li></ul><ul><li>Limitations of the prevailing cancer drug development approach </li></ul><ul><li>Failures of the prevailing tumor immunotherapy strategies </li></ul><ul><li>The new immunotherapy paradigm and its translational predictions and approaches </li></ul>
Louis Pasteur 1822-1895 <ul><li>Germ theory of immunity 1878 </li></ul>First demonstration of acquired immunity with chicken cholera 1880
Immune surveillance and tumors <ul><li>Increased cancer in immunosuppressed hosts </li></ul><ul><li>Spontaneous cancer remissions, especially in renal cell carcinoma and melanoma </li></ul><ul><li>Demonstration of tumor-specific immunity </li></ul><ul><li>J Nat CA Inst 1957;18:769 </li></ul><ul><li>Tumors express antigens </li></ul><ul><li>Nature 304, 165-7 (1983) </li></ul>
● 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 <ul><li>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). </li></ul><ul><li>LAK cells . Rosenberg, S.A. et al. N Engl J Med 316, 889-897 (1987) </li></ul><ul><li>Morgan, R.A. , et al. Cancer regression in patients after transfer of genetically engineered lymphocytes . Science (2006). </li></ul>
<ul><li>Nature Medicine 1996 2(1):52-58 F. Hsu, et al. </li></ul><ul><li>B-cell lymphoma, autologous antigen-pulsed dendritic cells </li></ul><ul><li>Nature Medicine 1998 4(3):328 </li></ul><ul><li>F. Nestle, et al. </li></ul><ul><li>Melanoma, peptide- or tumor lysate-pulsed dendritic cells </li></ul>
Intrinsic tumor strategies <ul><li>Hide the tumor </li></ul><ul><ul><li>Reduce class I </li></ul></ul><ul><ul><li>Reduce TAA </li></ul></ul><ul><ul><li>Defective Ag processing </li></ul></ul><ul><ul><li>Reduce co-signaling </li></ul></ul><ul><ul><li>Grow in privileged sites </li></ul></ul><ul><li>Prevent active immunity </li></ul><ul><ul><li>Prevent cell ingress </li></ul></ul><ul><ul><li>Promote cell egress </li></ul></ul><ul><ul><li>Kill immune cells </li></ul></ul><ul><li>Miscellaneous </li></ul><ul><ul><li>Resist apoptosis </li></ul></ul>- Alter cell differentiation
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 Zou, Curiel, et al., Nature Medicine 2001; 7(12):1339-1346 .
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
Immune recognition of tumor antigens as self is a significant problem. <ul><li>Infection: rapidly dividing cells of external origin. </li></ul>Cancer: rapidly dividing cells of internal origin. The tumor is a part of the host (self).
The big problem <ul><li>Anti-tumor immunity is autoimmunity. </li></ul><ul><li>To generate significant anti-tumor immunity requires breaking self tolerance. </li></ul>
Regulatory T cells (Tregs) are CD4 + CD25 hi T cells <ul><li>Treg depletion improves endogenous immunity </li></ul><ul><li>Shimizu, J., et al. J Immunol 163 , 5211-8 (1999) </li></ul>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)
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
Patient 4 <ul><li>Stage IV (metastatic) ovarian cancer. </li></ul><ul><li>First recipient of the dose-escalated 12 µg/kg, with significant immune response . </li></ul><ul><li>Because she had measurable disease, she received six additional denileukin diftitox doses to test clinical efficacy. </li></ul>
Denileukin diftitox reduces metastatic tumor in treatment-refractory ovarian cancer 4 months
Corroborating trials <ul><li>Ovarian: Barnett, B., Kryczek, I., Cheng, P., Zou, W. & Curiel, T.J. Am J Reprod Immunol 54 :369-377; 2005 </li></ul><ul><li>Renal cell: Dannull, J. , et al. The Journal of Clinical Investigation 115 :3623-3633; 2005 </li></ul><ul><li>Melanoma: Mahnke, K. , et al. Int J Cancer 120: 2723-33; 2007 </li></ul><ul><li>Melanoma: Rasku, M. A, et al. J. Translational Med , 6:12;2008 </li></ul>
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 <ul><li>Directly activates CD8 + T cells </li></ul><ul><li>Boosts T cell-activating capacity of dendritic cells </li></ul><ul><li>Increases T cell trafficking into tumor </li></ul><ul><li>Does NOT appear to affect Treg function or regeneration after depletion </li></ul>
Special cases <ul><li>Sex </li></ul><ul><li>Age </li></ul>
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 <ul><li>B7-H1-dependent reduction in Treg function </li></ul><ul><li>B7-H1 effects are estrogen-dependent </li></ul><ul><li>Functional differences are due to defective mTOR/PTEN signaling </li></ul><ul><li>Treg function is rescued with dendritic cell B7-H1 signals, estrogen withdrawal or rapamycin </li></ul>
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 <ul><li>Cancers are immunogenic and thus should be amenable to effective immune therapies in the new paradigm. </li></ul><ul><li>Immune therapies are adjuncts in multi-modal treatment approaches. </li></ul><ul><li>Immune therapy is not appropriate for all patients. </li></ul>
Ways forward <ul><li>Identify patients with relatively intact immune systems for trials </li></ul><ul><li>Test available agents: DT, anti-CTLA-4 </li></ul><ul><li>Test reversing immune dysfunction with immunization or immune boost ( e.g., anti-CTLA-4 or DT plus a vaccine) </li></ul>
Final Thoughts <ul><li>We need a better understanding of immune dysfunction in cancer. </li></ul><ul><li>We need a better understanding of the immune effects of current agents. </li></ul><ul><li>Willingness of investigators to try immune therapies will help, but they have to be convinced. </li></ul>
Acknowledgements <ul><li>Curiel lab members </li></ul><ul><li>National Cancer Institute </li></ul><ul><li>Hayes, Voelcker, Rippel Foundations and Trusts, Eisai </li></ul><ul><li>UTHSCSA endowments </li></ul><ul><li>Cancer Therapy & Research Center </li></ul>
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