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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 • 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 tumorspecific immunity J Nat CA Inst 1957;18:769 Tumors express antigens Nature 304, 165-7 (1983) The overarching questions Is there definitive proof of naturallyoccurring immunity against cancers? ● Could immune therapy for cancer (of any kind) ever work? ● ● 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):328 F. 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 - Alter cell differentiation • Miscellaneous – Resist apoptosis DC subsets 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 [3H]thymidine incorporation (cpm x 103) Control + tumor PDC generated T cells * + tumor PDC generated T cells + anti-IL-10R ** 0 Zou, Curiel, et al., Nature Medicine 2001; 7(12):13391346 . 10 20 30 40 50 60 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. 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. Thymus Negative selection Central tolerance Blood, LN, BM, spleen Peripheral tolerance CD4+CD25+ Treg Naïve thymocytes Self-reactive Normal repertoire 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 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 Sustained angiogenesis Limitless replicative potential Self-sufficiency in growth signals Insensitivity to anti-growth signals Tissue invasion and metastasis 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-sufficiency in growth signals Evading apoptosis Insensitivity to anti-growth signals Sustained angiogenesis Tissue invasion and metastasis Limitless replicative potential 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 Curiel, Zou, et al. Nature Medicine 10, 942-949 (2004) 6 - + 40 24 8 24 Counts IFN-g Treg + 40% 17% IL-2 17 IL-2 Annexin-V-APC 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 6 - + 40 24 8 24 Counts IFN-g Treg + 40% 17% IL-2 17 IL-2 Annexin-V-APC Elevated tumor CD4+CD25+ T cells predict poor survival in ovarian cancer Curiel, Zou , et al. Nature Medicine 10, 942-949 (2004) Survival 1.0 Low Treg 66.4 mos 0.8 0.6 High Treg 12.8 mos P<0.0001 low Treg 0.4 medium Treg 0.2 high Treg 0.0 0 20 40 60 Months 80 100 CD4+CD25+ CTCL cell CD4+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 depletes Tregs 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 54:369377; 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 DT treatmentfailed failure treatment 1500 DT DT + IFN- 1035 1000 595 500 985 536 333 383 186 152 150 4 IF N+ DT IFN 1 + - DT IFN 2 + - DT IFN 3 + - IF N- 4 5 3 DT DT + DT 2 DT DT 1 0 DT Patient SAOC03 blood CA-125 U/mL S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation cycle number Interferon-α improves Treg depletion and DT efficacy in ovarian cancer DT treatmentfailed failure treatment 1500 DT DT + IFN- 1035 1000 595 500 985 536 333 383 186 152 150 4 IF N+ DT IFN 1 + - DT IFN 2 + - DT IFN 3 + - IF N- 4 5 DT DT + DT 3 DT 2 DT 1 0 DT Patient SAOC03 blood CA-125 U/mL S. Wall, S. Thibodeaux, T. Curiel, et al., in preparation cycle number 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 Special cases • Sex • Age Females respond better to anti-B7-H1 blockade in B16 melanoma 1400 WT + isotype WT + isotype WT + B7-H1 1000 80 WT + B7-H1 800 68.0% 600 400 90.8% Suppression (%) 1200 60 WT + B7-H1 p=0.017 40 20 200 0 0 0 2 4 6 8 10 12 14 16 1:1 Mouse 1 0.25% 0.36% 0.38% 0.55% CD8 Mouse 2 0.24% 0.35% 0.42% 0.52% WT + isotype Mouse 3 0.27% 0.29% 0.46% 0.56% WT + isotype WT + isotype WT + αB7-H1 WT + αB7-H1 WT + isotype Total number of tumorspecific CD8+ cells (105) c 1:0.5 Eff:Treg ratio Days post B16 challenge Pentamerr Tumor volume (mm3) WT + isotype WT + isotype WT + B7-H1 b a WT + B7-H1 WT + B7-H1 p=0.009 6 p=0.028 4 2 0 p=0.013 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 B7H1 signals, estrogen withdrawal or rapamycin Treg depletion does not work in aged female mice with B16 PBS 800 Young PBS young tumor volume (mm3) 700 DT Young DT 600 PBS 500 Aged PBS 400 DT aged Aged DT 300 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 day after challenge Aged female mice have more CD11b+Gr-1+ myeloid suppressors that are more suppressive than young p=0.01 100 suppression by CD11b+Gr-1+ from spleen at 1:1 ratio (%) CD11b+Gr-1+ cells in spleen (%) 6 4 2 0 no tumor PBS young DT no tumor PBS aged DT 1:1 ratio of MDSC from Spleen 80 60 40 p=0.10 20 p=0.02 p=0.01 0 no tumor PBS young DT no tumor PBS aged DT Depleting Gr-1+ cells improves tumor immunity and slows B16 in aged females p=0.019 900 800 tumor volume (mm3) 700 600 500 400 300 control mAb Young PBS young anti-Gr1 Young anti-Gr-1 controlPBS mAb Aged aged anti-Gr1 Aged antiGr-1 200 100 Percent IFNγ+ of CD8+ T cells in spleen B 4 p=0.21 3 2 1 0 no tumor 0 control mAb -Gr-1 mAb control mAb -Gr-1 mAb 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 day after challenge young aged Summary and conclusions • Cancers are immunogenic and thus should be amenable to effective immune therapies in the new paradigm. • Immune therapies are adjuncts in multimodal 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., antiCTLA-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