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The Science Behind Immuno-Oncology ©2015 Bristol-Myers Squibb Company. ONCNL15NP04407-10 07/15 1 Immuno-Oncology: Overview Immune-Tumor Interactions 2 Key Points/Learning Objectives • The immune system is complex, made up of multiple mechanisms that act to defend and protect the human body1,2 – Both innate and adaptive mechanisms are involved1,3-5 • • The immune system can destroy tumor cells via several mechanisms, including T-cell−dependent targeting6 Cancer can evolve to evade immune-mediated clearance through a variety of mechanisms6,7 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 2. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 3. Padmanabhan RR, et al. J Leuk Biol. 1988;43:509-519. 4. Kim R, et al. Immunology. 2007;121:1-14. 5. Vivier E, et al. Science. 2011;331:44-49. 6. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335. 7. Drake CG, et al. Adv Immunol. 2006;90:51-81. 3 Adaptive and Innate Immune Responses1-4 • The adaptive response, capable of responding to new antigens (for example, T-cell or B-cell activation via antigen presentation) • The innate response, involving proteins and cells (for example, natural killer cells) that are considered to be a first line of immune defense 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 2. Padmanabhan RR, et al. J Leuk Biol. 1988;43:509-519. 3. Kim R, et al. Immunology. 2007;121:1-14. 4. Vivier E, et al. Science. 2011;331:44-49. 4 T Cells and the Anti-tumor Response • • • Tumors can trigger a tumor-specific T-cell response1-4 Multiple natural feedback mechanisms affect immune responses by activating or inhibiting T-cell function and proliferation5 Tumors may evade the immune system, in part by exploiting T-cell activation or inhibition pathways1,2,6 – Many immune mechanisms in the anti-tumor response are under clinical investigation in the treatment of cancer1,2 1. 2. 3. 4. 5. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. Mellman I, et al. Nature. 2011;480:480-489. Heemskerk B, et al. EMBO J. 2013;32(2):194-203. Boudreau JE, et al. 2011. Mol Ther. 2011;19(5):841-853. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 6. Dunn GP, et al. Nat Immunol. 2002;3(11):991-998. 55 T Cells and the Anti-tumor Response Tumor Antigen Release Tumor Antigen Presentation to T Cells T-Cell Activation & Expansion T-Cell Recognition of Tumor Antigen T-Cell Recognition and Killing 6 Tumor Antigen Release Tumor Antigen Presentation to T Cells T-Cell Activation & Expansion Tumor Antigen Release The beginning of the anti-tumor response: antigen-presenting cell (APC) captures the released tumor-associated antigens T-Cell Recognition of Tumor Antigen T-Cell Recognition and Killing 7 Tumor Antigen Release • Tumor-associated antigens (TAAs) can trigger a tumor-specific T-cell response1-4 • The initial stages of the anti-tumor immune response involve the capture of TAAs by APCs2,4 • After antigen capture, APCs become activated and can interact with T cells2,4 1. 2. 3. 4. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. Mellman I, et al. Nature. 2011;480:480-489. Heemskerk B, et al. EMBO J. 2013;32(2):194-203. Boudreau JE, et al. 2011. Mol Ther. 2011;19(5):841-853. 8 Tumor Antigen Presentation to T Cells Tumor Antigen Release T-Cell Activation & Expansion Tumor Antigen Presentation to T Cells T-Cell Recognition of Tumor Antigen The APC presents tumor antigens T-Cell Recognition and Killing 9 T-Cell Activation in Response to Tumor Antigen Presentation • APCs present the tumor-associated antigen to T cells1 • Following antigen presentation, a second (co-stimulatory) signal is transmitted from the APC to the T cell1 • Co-stimulation results in T-cell activation and proliferation to initiate an anti-tumor immune response1 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 10 T-Cell Activation in Response to Tumor Antigen Presentation • Several T-cell activation pathways are involved in the immune response, including1-5: – CD28/CD80 or CD866,7 – CD40/CD40L7,8 – OX40/OX40L7,9 – CD137/CD137L7,10 1. Korman AJ, et al. Adv Immunol. 2006;90: 297-339. 2. Gruber S, et al. Anticancer Res. 2008;28: 779-784. 3. Batrla R, et al. Cancer Res. 2002;62:2052-2057. 4. Baruah P, et al. Immunobiology. 2012;217(7):669-675. 5. Wang Q, et al. Croat Med J. 2088;49:192-200. 6. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 7. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 8. Howland KC, et al. J Immunol. 2000;164(9):4465-4470. 9. Redmond WL, et al. Crit Rev Immunol. 2009;29(3): 187-201. 10. Palazon A, et al. Cancer Res. 2011;71:801-811. 11 T-Cell Activation & Expansion Tumor Antigen Release Tumor Antigen Presentation to T Cells T-Cell Activation & Expansion T-Cell Recognition of Tumor Antigen T-cell co-stimulation and activation generate an effector anti-tumor T-cell response T-Cell Recognition and Killing 12 Inhibition of T-Cell Activation and Expansion • A number of negative feedback mechanisms provide a natural counterbalance to immune activation pathways, including1-5: – LAG-31,6 – CTLA-41,7 – B7-H31,8 1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 2. Hemon P, et al. J Immunol. 2011,186:5173-5183. 3. Weiner Z, et al. J Investig Dermatol. 2007;127:906-914. 4. Shah KV, et al. J Invest Dermatol. 2008;128(12):2870-2879. 5. Zang X, et al. PNAS. 2007;104(49):19458-19463. 6. Workman CJ, et al. J Immunol. 2004;172(9):5450-5455. 7. Hastings WD, et al. Eur J Immunol. 2009;39(9):2942-2501. 8. Leitner J. Eur J Immunol. 2009;39(7):1754-1764. 13 T-Cell Recognition of Tumor Antigen Tumor Antigen Release Tumor Antigen Presentation to T Cells T-Cell Activation & Expansion T-Cell Recognition of Tumor Antigen Activated T cells migrate to the tumor and recognize expressed tumor antigen T-Cell Recognition and Killing 14 T-Cell−Mediated Killing of Tumor Cells • T-cell co-stimulation and activation can generate a cytotoxic (“killer”) T-cell response1 – These tumor-specific cytotoxic T cells specifically recognize and bind to antigens on tumor cells1 – Cytotoxic T cells then can attack the tumor and may induce apoptosis of the tumor cell1 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 15 Inhibition of T-Cell Killing • • A number of negative feedback mechanisms are involved in the immune response These inhibitory pathways provide a natural counterbalance to T-cell activity, and include1: – LAG31,2 – PD1/PD-L1 or PD-L21 1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 2. Workman CJ, et al. J Immunol. 2004;172(9):5450-5455. 16 Tumor Evasion of the Immune System • While the immune system can destroy tumor cells,1,2 tumors can evolve to evade immune-mediated clearance3,4 • Cancer cell growth may be associated with an imbalance in the natural feedback mechanisms (eg, immune checkpoints) that modulate the immune response2,5 • Understanding how immune pathways can be modulated to overcome tumor evasion of the immune system is an active focus of clinical research2,5 1. 2. 3. 4. 5. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335. Drake CG, et al. Adv Immunol. 2006;90:51-81. Mellman I, et al. Nature. 2011;480:480-489. 17 Tumor Evasion Mechanisms: T-Cell Activation & Proliferation • Tumors may evade the immune system in part by exploiting immune activation pathways1-3 • The presence of tumors has been associated with modulation of activation and inhibitory pathways: – – – – 1. 2. 3. 4. 5. 6. 7. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. Dunn GP, et al. Nat Immunol. 2002;3(11):991-998. Mellman I, et al. Nature. 2011;480:480-489. Baruah P, et al. Immunobiology. 2012;217(7):669-675. Hemon P, et al. J Immunol. 2011,186:5173-5183. Zang X, et al. PNAS. 2007;104(49):19458-19463. Leitner J. Eur J Immunol. 2009;39(7):1754-1764. OX40 (activation)4 CTLA-4 (inhibitory)1 LAG-3 (inhibitory)2,5 B7-H3 (inhibitory)2,6,7 18 Tumor Evasion Mechanisms: T-Cell Activation & Proliferation, cont’d. The presence of tumors has been associated with: • Decreased T-cell expression of OX40, which may inhibit the ability to mount an effective anti-tumor response1 • T-cell expression of CTLA-4, which inhibits the anti-tumor response by restricting T-cell activation and proliferation2 • Increased T-cell expression of the immune checkpoint LAG-3, increasing the inhibition of T-cell activation and function2,3 • Tumor cell expression of B7-H3, which may impair T-cell−mediated immune responses, however, the precise role of B7-H3 in cancer has not been fully elucidated2,5,6 1. 2. 3. 4. 5. 6. Baruah P, et al. Immunobiology. 2012;217(7):669-67 Pardoll DM. Nat Rev Cancer. 2012;11:252-264 Hemon P, et al. J Immunol. 2011,186:5173-5183. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335. Zang X, et al. PNAS. 2007;104(49):19458-19463. Leitner J. Eur J Immunol. 2009;39(7):1754-1764. 19 Tumor Evasion Mechanisms: T-Cell−Mediated Killing • Cancer cell growth may be associated with an imbalance in the natural feedback mechanisms that modulate the immune response1,2 • The expression of several of these molecules is characteristic of what has been termed “exhausted” T cells that exhibit reduced killing activity1 1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264 2. Mellman I, et al. Nature.2011;480:480-489. 20 Tumor Evasion Mechanisms: T-Cell−Mediated Killing, cont’d. The presence of tumors has been associated with: • Tumor expression of PD-1 ligand (PD-L); both PD-L1 and PD-L2 bind to the PD-1 receptor on activated T cells, which inhibits the T cells and T-cell attack1 • Increased T-cell expression of the immune “checkpoint” LAG-3, increasing the inhibitory effect on T-cell activation and function2 1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264 2. Hemon P, et al. J Immunol. 2011,186:5173-5183. 21 Summary • The immune system continuously detects and destroys tumor cells1,2 • One mechanism of immune clearance of tumors involves T-cell− mediated tumor cell killing3-6 • Tumor cells can evade immune clearance through a variety of mechanisms1,2 – Tumors may evade clearance by exploiting immune activation or inhibition pathways7-9 • A number of immune activation and inhibitory mechanisms are under clinical investigation for their role in tumor evasion of the immune system10-18 1. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335. 2. Drake CG, et al. Adv Immunol. 2006;90:51-81. 3. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 4. Padmanabhan RR, et al. J Leuk Biol. 1988;43:509-519. 5. Kim R, et al. Immunology. 2007;121:1-14. 6. Vivier E, et al. Science. 2011;331:44-49. 7. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 8. Dunn GP, et al. Nat Immunol. 2002;3(11):991-998. 9. Mellman I, et al. Nature. 2011;480:480-489. 10. Korman AJ, et al. Adv Immunol. 2006;90: 297-339. 11. Gruber S, et al. Anticancer Res. 2008;28: 779-784. 12. Batrla R, et al. Cancer Res. 2002;62:2052-2057. 13. Baruah P, et al. Immunobiology. 2012;217(7):669-675. 14. Wang Q, et al. Croat Med J. 2088;49:192-200. 15. Hemon P, et al. J Immunol. 2011,186:5173-5183. 16. Weiner Z, et al. J Investig Dermatol. 2007;127:906-914. 17. Shah KV, et al. J Invest Dermatol. 2008;128(12):2870-2879. 18. Zang X, et al. PNAS. 2007;104(49):19458-19463. 22 Appendix 23 Activation Pathways Involved in T-Cell Modulation • CD28 binding to its ligand (CD80 [also known as B7-1] or CD86) enhances T-cell activation via co-stimulation1-2 • CD40 signaling promotes APC activation and enhances the anti-tumor immune response2,3 • OX40 (also known as CD134) promotes anti-tumor immune responses by promoting T-cell proliferation and survival2,4 • CD137 (also known as 4-1BB) promotes the activation and proliferation of T cells2,5 1. 2. 3. 4. 5. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. Howland KC, et al. J Immunol. 2000;164(9):4465-4470. Redmond WL, et al. Crit Rev Immunol. 2009;29(3):187-201. Palazon A, et al. Cancer Res. 2011;71:801-811. 24 Inhibitory Pathways Involved in T-Cell Modulation • LAG-3 (also known as CD223) is an immune “checkpoint” molecule that can inhibit T-cell activity and serves as a modulator of T-cell activation1,2 • CTLA-4 is an immune “checkpoint receptor” that plays a key role in modulating T-cell function. Interaction of CTLA-4 on the T cell with its ligands (CD80 [also known as B7-1] and CD86) on the APC leads to T-cell inhibition1,3 • B7-H3, a member of the B7 family, is thought to be an immune “checkpoint” pathway, and may inhibit the T-cell response beyond CD80/CD86 T-cell response. The precise mechanism of B7 familymediated inhibition of T cells is under investigation1,4 • PD-1 is an immune “checkpoint” receptor that inhibits the T-cell response and plays a key role in modulating T-cell function1 1. 2. 3. 4. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. Workman CJ, et al. J Immunol. 2004;172(9):5450-5455. Hastings WD, et al. Eur J Immunol. 2009;39(9):2942-2501. Leitner J. Eur J Immunol. 2009;39(7):1754-1764. 25