immuno-oncology (i-o): seeking to transform the treatment of cancer oncus15ub00535-01 05/15
TRANSCRIPT
Immuno-Oncology (I-O): Seeking to Transform the
Treatment of Cancer
ONCUS15UB00535-01 05/15
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Presentation Overview
• This presentation focuses on developing an understanding of I-O and the critical role of the immune system in cancer
• This presentation provides an overview of I-O pathways and approaches that target the immune system but does not focus on any particular product
• At the end of the program there will be time for questions specific to its content but not specific to any products
I-O, immuno-oncology.
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Presentation Objectives
• Review the current unmet need for improved survival in cancer treatment
• Present an overview of the immune system and its role in cancer
• Describe the regulation of the immune system through immune pathways
• Examine the types of safety considerations associated with different I-O therapy approaches
• Discuss potential clinical response patterns with I-O therapy approaches
• Provide an overview of I-O research in various tumor types
I-O, immuno-oncology.
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Improved Survival Remains a Challenge in Some Advanced Cancers
• 5-year survival remains poor for many patients with advanced metastatic solid tumors1
• In the United States, it is estimated that2:
– A total of 589,430 deaths due to cancer will occur in 2015
Lung
4.0Colorectal
12.9Kidney andRenal Pelvis
12.1
Melanoma
16.1
5-year Survival in Advanced Cancers (%)1
1. Surveillance, Epidemiology and End Results (SEER) Program. Available at: http://seer.cancer.gov. Accessed March 26, 2015.2. Siegel RL et al. CA Cancer J Clin. 2015;65(1):5-29.3. Rosenberg SA. Sci Transl Med. 2012;4(127ps8):1-5.
There is an ongoing need for new treatments and therapeutic modalities for patients with advanced cancers3
Bladder
5.5
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Goal of Current Cancer Research
Years
Su
rviv
al R
ates
*Research Goals1-3:
Long-term survival in most patients
* This is a hypothetical survival curve not based on clinical trials and is to be used for illustration purposes only.1. United States Food and Drug Administration (FDA). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm071590.pdf. Accessed January 16, 2015.2. Goldstein I et al. Trends Mol Med. 2012;18(6):299-303.3. Dickman PW, Adami HO. J Intern Med. 2006;260(2):103-117.
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I-O Is an Evolving Cancer Treatment Modality
• I-O is a fundamentally different approach to fighting cancer that harnesses the body’s own immune system1
Through I-O research, therapies are being investigated in an attempt to utilize the body's own immune system to fight cancer1-3
Chemotherapy/Targeted therapy Radiation
Immuno-OncologySurgery
I-O, immuno-oncology.1. Murphy JF. Oncology. 2010;4:67-80. 2. Kirkwood JM et al. CA Cancer J Clin. 2012;62(5):309-335. 3. Borghaei H et al. Eur J Pharmacol. 2009;625(1-3):41-54.
Case Study of Initial Increase in Tumor Volume
Week 108: Complete remission*
Week 12: Increase in tumor volumeScreening Week 16: Responding
Patient from study CA184-008. *Courtesy of Dr Kaan Harmankaya.
Week 20: Response
This case study represents an example of treatment outcome with ipilimumab, which varies across patients.Harmankaya K et al. Presented at: 33rd ESMO Congress; September 12-16, 2008; Stockholm, Sweden. 7BMS Confidential – Do Not Distribute or Duplicate
The Immune System’s Role in Cancer
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Immune Surveillance: Identification and Elimination of Cancer Cells by the Immune System1-5
Priming APC activation
Antigenrelease
NK cell trafficking& tumor killing
Priming/T-cell activation
Antibodyproduction
Activated T-cellmigration to tumorand tumor killing
Tumor cells
APC, antigen-presenting cell; NK, natural killer.1. Abbas AK et al. Cellular and Molecular Immunology. 7th ed. Philadelphia, PA: Elsevier Saunders;2012.2. Mellman I et al. Nature. 2011;480:480-489.3. Boudreau JE et al. Mol Ther. 2011;19(5):841-853.4. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY:
Garland Science; 2001.5. Pardoll DM. Nat Rev Cancer. 2012;12:252-264.
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B Cell–Mediated Cytotoxicity
B cells1
Immune cells that bind free-floating antigens in the blood or lymph through B-cell receptors
Once activated, B cells differentiate to become plasma cells, which can secrete large quantities of antibodies against a specific antigen1
Natural Killer cells1,2
Cytotoxic lymphocytes that attack infected or malignant cells based on recognition of antibodies on a cell surface
Mature B cell
NK cells
Activated B cells
Apoptotic tumor cell
Tumor cells
Tumor-associated antigens
NK, natural killer.1. Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY:
Garland Science; 2001.2. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
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T Cell–Mediated Cytotoxicity
Antigen-presenting cells1,2
Take up antigens from infected or malignant cells and process them into shorter peptide segments
T cells1,2
APCs present antigens to naïve T cells, which can recognize tumor-associated antigens
Together with a second, positive co-stimulation signal, T cells become activated…
…and play a major role in killing infected or malignant cells when activated
Activated T cells
Apoptotictumor cell
Inactive T cell
APC
Tumor cells
Tumor-associated antigens
APC, antigen-presenting cell.1. Mellman I et al. Nature. 2011;480(7378):480-489.2. Boudreau JE et al. Mol Ther. 2011;19(5):841-853.
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Immune Evasion in the Tumor Microenvironment
• The tumor microenvironment, a network of cells and structures that surround a tumor, creates conditions that may foster tumor growth and immune evasion1,2
• Immune cell activity is regulated by multiple activation and inhibition pathways that modulate the duration and level of the immune response2
• Tumors may target these pathways to alter the immune system’s response to cancer cells, resulting in tumor evasion of the immune system3
Tumor cells
Active T cell
Inactive T cell
Tumor-associated antigens
APC
APC, antigen-presenting cell.1. Gajewski TF et al. Nat Immunol. 2013;14(10):1014-1022.2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.3. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
Immune-Based Therapeutic Approaches
Immunotherapies Encompass a WideVariety of Classes
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• Interleukins• Interferons
• Cell-based• Single antigen/
peptide-based
Immune effector cell modulators
• Checkpoint inhibitors
• Co-stimulatory agonists
Active(Designed to act on the immune system itself)
Immunotherapy1,2
• Tumor-directed mAbs
• Cell therapies
Passive(Designed to act on the tumor)
Therapeutic cancer vaccinesCytokines I-O
therapiesAntitumor
mAbs Adoptive
I-O, immuno-oncology; mAb, monoclonal antibody.1. Finn OJ. Ann Oncol. 2012;23(suppl 8 ):viii6-viii9. 2. Mellman I et al. Nature. 2011;480:480-489.
Passive Immunotherapy
• Passive immunotherapies act on the tumor, in some cases, using immune-based mechanisms to fight cancer, but they do not require the patient’s own immune system to initiate a response1-3
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In vitro modification and expansion
Tumor-directed mAbs2-3
TAA-reactive monoclonal antibodies are isolated and
injected into a patient
Cell therapies4
Autologous immune cells are removed from the cancer-
bearing patient, then activated and expanded in culture away from the immunosuppressive
tumor environmentNK cell
Tumor cell death
ActivatedT cell
mAbs, monoclonal antibodies; NK, natural killer; TAA, tumor-associated antigen.1. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9. 2. Rescigno M et al. Biochim Biophys Acta. 2007;1776:108-123.3. Mellman I et al. Nature. 2011;480:480-489.4. Rosenberg SA. Sci Transl Med. 2012;4(127ps8):1-5.
Active Immunotherapy
• Active immunotherapies act directly on the body’s own immune system to elicit an immune response to fight cancer1-2
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Therapeuticcancer vaccines2-4
Therapeutic cancer vaccines may prime the immune system to attack existing cancer cells in the body by introducing immune
cells to one or more tumor-associated antigens
Cytokines5
Cytokines are small proteins that boost the effector
functions of immune cells, thereby strengthening the
antitumor response
Antigenrelease
NK cell
ActivatedT cell
ActivatedB cell
Tumor cell death
NK, natural killer.1. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9.2. Rescigno M et al. Biochim Biophys Acta. 2007;1776:108-123.3. Lizee G et al. Annu Rev Med. 2013;64:71-90.4. Mellman I et al. Nature. 2011;480:480-489.5. List T, Neri D. Clin Pharmacol. 2013;5(suppl):29-45.
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Immuno-Oncology:Mediators of Immune Cell Activation
Active T cell
Tumor cells
NK cell
APCImmuno-Oncology
Mediators of immune cell activation are monoclonal antibodies that have been engineered to either agonize or antagonize specific immune pathways thought to be manipulated by cancer cells to impede the antitumor response. They can also target proteins to both activate and engage natural killer cells. In doing so, they may be able to strengthen the antitumor response1-2
APC, antigen-presenting cell; NK, natural killer.1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.2. Hsi ED et al. Clin Cancer Res. 2008;14:2775-2784.
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Immuno-Oncology:Immune System Activating Pathways
• Activating pathways enable cytotoxic activity by binding to receptors or ligands on APCs; they can also be expressed or preferentially upregulated by tumor cells1-4
• Several activating receptors are thought to be involved in regulating NK Cell activity, including CD137 and SLAMF71,2
• T-cell activity may be regulated by pathways, including CD40, CD137, CD28, and OX403,4
Natural Killer Cell T Cell
CD137
SLAMF7
CD40L
CD28
OX40
CD137
APC, antigen-presenting cell; NK, natural killer.1. Long EO et al. Annu Rev Immunol. 2013;13:227–258. 2. Benson DM Jr et al. J Clin Oncol. 2012;30:2013-2015.3. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 4. Kirkwood JM, et al. CA Cancer J Clin. 2012;62(5):309-335.
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Immuno-Oncology:Immune System Inhibitory Pathways
Natural Killer Cell T Cell
LAG-3
PD-1
CTLA-4
• Tumors may enhance inhibitory pathways to block NK cell and T-cell activation1-3
• Several inhibitory receptors are thought to be involved in regulating NK cell activity, including inhibitory KIRs2,3
• T-cell activity may be negatively regulated by pathways including LAG-3, CTLA-4, B7-H3, and PD-12
KIR
B7-H3receptor*
*Defined receptors are not yet known and precise mechanism of T-cell inhibition by B7-H3 is currently unknown.KIR, killer-cell immunoglobulin-like receptor; NK, natural killer.1. Long EO et al. Annu Rev Immunol. 2013;31:227-258.2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.3. Kirkwood JM et al. CA Cancer J Clin. 2012;62(5):309-335.
Potential Clinical Implications and Response Patterns Associated With T-Cell Modulating I-O Therapy
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Response to I-O Therapy Is a Multistep Process That May Impact Response Kinetics
The response to I‐O therapies that modulate T-cell activity may be characterized as a multistep process1
Days to Weeks
Immune cell activation and proliferation2
Start
Initial I-O therapy administration2
Several Months
Effect on survival2
Weeks to Months
Effect on tumor2
I-O, immuno-oncology.1. Hoos A, Britten CM. OncoImmunology. 2012;1:334-339.2. Hoos A et al. J Natl Cancer Inst. 2010;102:1388-1397.
Potential Patterns of Response to I-O Therapy
Therapies that affect the immune system may not induce a measurable impact on tumor growth immediately after administration. Potential effects may be seen weeks to months after initial administration. The potential patterns of response to I-O therapies that modulate T-cell activity are1,2:
Immediate response3
Lack of tumor shrinkage but a slowing of tumor progression3
Early but clinically insignificant progression3
Tumor regression after early radiographical progression that may be caused by T cells infiltrating the tumor site or appearance of new lesions upon imaging3,4
There is also the potential that patients may not respond to therapy.
I-O, immuno-oncology.1. Hoos A et al. OncoImmunol. 2012;1:334-339. 2. Aarntzen EHJG et al. Cell Mol Life Sci. 2013;70:2237-2257.3. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420. 4. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
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Non-Conventional Response and I-O Therapy
Apparent progression upon radiographic imaging after initial I-O therapy can actually be a sign of non-conventional response to I-O therapy. This response may occur when T cells infiltrate the tumor site and cause tumors to flare or appearance of new lesions upon imaging.
1,2
T cells infiltrating the
tumor site
Appearance of new lesions upon imaging
I-O therapy
Tumor cells
I-O, immuno-oncology.1. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420. 2. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
Differentiating Disease Progression FromNon-Conventional Response With I-O Therapy
• T-cell infiltration can cause tumors to flare or new lesions may appear upon imaging1
• Considerations that may indicate disease progression vs. non-conventional response include1,2:
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Disease Progression Non-Conventional Response
Performance status Deterioration of performance Remains stable or improves
Systemic symptoms Worsen May or may not improve
Symptoms of tumor enlargement
Present May or may not be present
Tumor burden Baseline New lesions
Increase Appear and increase in size
Increase followed by responseAppear then remain stable and/or subsequently respond
Biopsy may reveal Evidence of tumor growth Evidence of T-cell infiltration
I-O, immuno-oncology.1. Wolchok JD et al. Clin Cancer Res. 2009;15(23):7412-7420. 2. Eisenhauer EA et al. Eur J Cancer. 2009;45(2):228-247.
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Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions related to T-cell modulation may affect certain organ systems1
Nervous system2 Respiratory system1,2Eyes1,3 Skin1,2,4
Liver2,4 Hematopoietic cells5Endocrine system2,4 Gastrointestinal tract1-4
1. Amos SM et al. Blood. 2011;118(3):499-509. 2. Chow LQ. Am Soc Clin Oncol Educ Book. 2013:280-285. 3. Robinson MR et al. J Immunother. 2004;27(6):478-479. 4. Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377. 5. Lin TS et al. J Clin Oncol. 2010;28(29):4500-4506.
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Clinical Implications of Immune-Mediated ARs
Since I-O can increase immune system activity, the potential exists for toxicity against healthy tissues in addition to cancer cells1
• ARs can be serious and potentially fatal2,3
– An AR is any unfavorable medical occurrence temporally associated with the use of a medical treatment2
– Serious ARs are defined as any AR that requires hospitalization, is life-threatening, results in death, or otherwise causes persistent or significant incapacity3
• Remain vigilant throughout and after treatment4
– Educate and encourage patients to monitor for and report symptoms of immune-mediated ARs
AR, adverse reaction; I-O, immuno-oncology.1. Amos SM et al. Blood. 2011;118(3):499-509. 2. NCI. Radiation therapy for cancer. V4.0. US Department of Health and Human Services. 2010.3. FDA. What is a serious adverse event? http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm.
Accessed January 28, 2015. 4. Gelao L et al. Toxins. 2014;6:914-933.
Not all immune-mediated ARs will require permanent cessation of therapy. Providing optimal care for your patients includes following
management algorithms for certain immune-mediated ARs.4
The Potential of I-O
The Potential Applicability for I-O
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Tumor-mediated inhibition of theimmune system hasbeen observed in multiple tumor types
Bladder 1-3
Breast 4-7,11
Colorectal 1,4,6,8-10
Esophageal 1,4,11
Gastric 10,11
Head and Neck 12,13
Hepatocellular 14,15
Lung 6,10,11,17-19
Lymphoma 6
Melanoma 4,6,10,15,20,21
Ovarian1,4,6,10,11,15,20,21,26
Pancreatic 5,10
Prostate 4,27
Leukemia 16
Renal Cell Carcinoma1,4,6,15,28
Myeloma 22-25
I-O, immuno-oncology.1. Sharma P et al. Proc Natl Acad Sci U S A. 2007;104(10):3967-3972. 2. Winerdal ME et al. BJU Int. 2011;108(10):1672-1678. 3. Inman BA et al. Cancer. 2007;109(8):1499-1505. 4. Zhang L et al. N Engl J Med. 2003;348(3):203-213. 5. Liyanage UK et al. J Immunol. 2002;169(5):2756-2761. 6. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 7. Rody A et al. Breast Cancer Res. 2009;11(2):1-13. 8. Pages F et al. N Engl J Med. 2005;353(25):2654-2666. 9. Salama P et al. J Clin Oncol. 2009;27(2):186-192. 10. Kono K et al. Cancer Immunol Immunother. 2006;55(9):1064-1071. 11. Ichihara F et al. Clin Cancer Res. 2003;9(12):4404-4408. 12. Badoual C et al. Clin Cancer Res. 2006;12(2):465-472. 13. Schaefer C et al. Br J Cancer. 2005;92(5):913-920. 14. Gao Q et al. Clin Cancer Res. 2009;15(3):971-979. 15. Mellman I et al. Nature. 2011;480(7378):480-489. 16. Karube K et al. Br J Haematol. 2004;126(1):81-84. 17. Dieu-Nosjean MC et al. J Clin Oncol. 2008;26(27):4410-4417. 18. Hiraoka K et al. Br J Cancer. 2006;94(2):275-280. 19. Woo EY et al. J Immunol. 2002;168(9);4272-4276. 20. Taylor RC et al. J Clin Oncol. 2007;25(7):869-875. 21. Chapon M et al. J Invest Dermatol. 2011;131(6):1300-1307. 22. Carbone E et al. Blood. 2005;105(1):251-258. 23. von Lilienfeld-Toal M et al. Cancer Immunol Immunother. 2010;59(6):829-839. 24. Nielsen H et al. APMIS. 1991 Apr;99(4):340-346. 25. Jurisic V et al. Med Oncol. 2007;24(3):312-317.26. Hamanishi J et al. PNAS. 2007;104(9):3360-3365. 27. Kärjä V et al. Anticancer Res. 2005;25(6C):4435-4438. 28. Thompson RH et al. Clin Cancer Res. 2007;13(6):1757-1761.
I-O Therapies Have the Potential To Be Used As Monotherapy or Part of Combination Regimens
• I-O research and development will continue to inform future strategies, including new targets and rationales for combinations and sequencing1
• By understanding multiple barriers that tumor cells use to evade the anti-tumor immune response, combination and sequencing strategies can help to empower the immune system in the fight against cancer1,2
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I-O, immuno-oncology.1. Drake CG. Ann Oncol. 2012;23(suppl 8):viii41–viii46.2. Ribas A et al. Curr Opin Immunol. 2013:25(2):291–296.3. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.4. Benson DM, Byrd JC. J Clin Oncol. 2012;30:2013-2015.5. Mellman I et al. Nature. 2011;480(7378):480-489.
Natural Killer Cell3-5 T Cell3-5
Inhibitoryreceptors
Inhibitoryreceptors
Activatingreceptors
Activatingreceptors
Summary
• I-O research goals aim to address the unmet need for improved survival
• As response to I-O therapies that modulate T-cell activity is a multistep process, they may not induce a measureable impact on tumor growth immediately after I-O treatment
• I-O therapies that modulate T-cell activity may also target normal tissues and can be associated with immune-mediated ARs; understanding how to recognize and manage immune-mediated ARs is critical
• By understanding multiple barriers that tumor cells use to evade the anti-tumor immune response, I-O therapy combination and sequencing strategies can help to empower the immune system in the fight against cancer
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AR, adverse reaction; I-O, immuno-oncology.
Q & A