Immuno-Oncology (I-O):
Seeking to Transform the
Treatment of Cancer
ONCUS15UB00535-01 05/15
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.
2
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.
3
Improved Survival Remains a Challenge
in Some Advanced Cancers
5-year Survival in Advanced Cancers (%)1
• 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
4.0
Colorectal
Kidney and
Renal Pelvis
12.9 12.1
Melanoma
Bladder
16.1
5.5
There is an ongoing need for new treatments and therapeutic
modalities for patients with advanced cancers3
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.
4
Goal of Current Cancer Research
Research Goals1-3:
Survival Rates*
Long-term survival in most patients
Years
* 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.
5
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
Chemotherapy/
Targeted therapy
Surgery
Radiation
Immuno-Oncology
Through I-O research, therapies are being investigated in an attempt to utilize the
body's own immune system to fight cancer1-3
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.
6
Case Study of Initial Increase in
Tumor Volume
Screening
Week 12: Increase in tumor volume
Week 20: Response
Week 16: Responding
Week 108: Complete remission*
Patient from study CA184-008. *Courtesy of Dr Kaan Harmankaya.
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.
BMS Confidential – Do Not Distribute or Duplicate
7
The Immune System’s Role in Cancer
Immune Surveillance: Identification and Elimination of
Cancer Cells by the Immune System1-5
Priming/
T-cell activation
Antibody
production
Priming APC
activation
NK cell trafficking
& tumor killing
Antigen
release
Activated T-cell
migration to tumor
and 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.
9
B Cell–Mediated Cytotoxicity
B cells1
Activated
B cells
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
Mature
B cell
Natural Killer cells1,2
Tumorassociated
antigens
Tumor cells
Cytotoxic lymphocytes that
attack infected or malignant
cells based on recognition of
antibodies on a cell surface
NK cells
Apoptotic
tumor cell
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
T cells1,2
Antigen-presenting cells1,2
Inactive
T cell
Take up antigens from infected
or malignant cells and process
them into shorter peptide
segments
Activated
T cells
APC
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…
Tumorassociated
antigens
Tumor
cells
Apoptotic
tumor cell
…and play a major role in
killing infected or malignant
cells when activated
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
APC
Active T cell
Tumorassociated
antigens
Tumor cells
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.
Inactive T cell
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Immune-Based Therapeutic Approaches
Immunotherapies Encompass a Wide
Variety of Classes
Immunotherapy1,2
Passive
(Designed to act on the tumor)
Antitumor
mAbs
• Tumor-directed
mAbs
Adoptive
• Cell therapies
Active
(Designed to act on the immune system itself)
Cytokines
• Interleukins
• Interferons
Therapeutic
cancer vaccines
I-O
therapies
• Cell-based
• Single antigen/
peptide-based
Immune effector
cell modulators
• Checkpoint
inhibitors
• Co-stimulatory
agonists
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.
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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
Cell therapies4
NK cell
Activated
T cell
In vitro
modification and
expansion
Tumor-directed mAbs2-3
TAA-reactive monoclonal
antibodies are isolated and
injected into a patient
Autologous immune cells are
removed from the cancerbearing patient, then
activated and expanded in
culture away from the
immunosuppressive tumor
environment
Tumor cell death
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.
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Active Immunotherapy
• Active immunotherapies act directly on the body’s own immune system to elicit an
immune response to fight cancer1-2
Activated
B cell
Therapeutic
cancer vaccines2-4
Activated
T cell
Therapeutic cancer vaccines
may prime the immune system
to attack existing cancer cells in
the body by introducing immune
cells to one or more tumorassociated antigens
Cytokines5
NK cell
Cytokines are small proteins
that boost the effector
functions of immune cells,
thereby strengthening the
antitumor response
Antigen
release
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
Immuno-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
Active T cell
NK cell
Tumor cells
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
Natural Killer Cell
T Cell
CD40L
CD137
CD137
SLAMF7
CD28
OX40
• 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
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
KIR
CTLA-4
B7-H3
receptor*
PD-1
• 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
*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.
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Potential Clinical Implications and Response Patterns
Associated With T-Cell Modulating I-O Therapy
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
Start
Days to Weeks
Weeks to Months
Several Months
Initial I-O therapy
administration2
Immune cell activation
and proliferation2
Effect on tumor2
Effect on survival2
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.
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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.
22
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
1,2
upon imaging.
I-O therapy
Tumor cells
T cells
infiltrating the
tumor site
Appearance of new
lesions upon imaging
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.
23
Differentiating Disease Progression From
Non-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:
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 response
Appear 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.
23
Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions related to T-cell modulation may affect
certain organ systems1
1.
2.
3.
4.
5.
Nervous system2
Eyes1,3
Skin1,2,4
Respiratory system1,2
Liver2,4
Endocrine system2,4
Gastrointestinal tract1-4
Hematopoietic cells5
Amos SM et al. Blood. 2011;118(3):499-509.
Chow LQ. Am Soc Clin Oncol Educ Book. 2013:280-285.
Robinson MR et al. J Immunother. 2004;27(6):478-479.
Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377.
Lin TS et al. J Clin Oncol. 2010;28(29):4500-4506.
25
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
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
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.
26
The Potential of I-O
The Potential Applicability for I-O
Bladder 1-3
Breast 4-7,11
Colorectal 1,4,6,8-10
Esophageal 1,4,11
Gastric 10,11
Tumor-mediated
inhibition of the
immune system has
been observed in
multiple tumor types
Head and Neck 12,13
Hepatocellular 14,15
Leukemia 16
Lung 6,10,11,17-19
Lymphoma 6
Melanoma 4,6,10,15,20,21
Myeloma 22-25
Ovarian1,4,6,10,11,15,20,21,26
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.
Pancreatic 5,10
Prostate 4,27
Renal Cell Carcinoma1,4,6,15,28
27
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
Natural Killer Cell3-5
T Cell3-5
Inhibitory
receptors
Inhibitory
receptors
Activating
receptors
Activating
receptors
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.
28
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 antitumor immune response, I-O therapy combination and sequencing strategies
can help to empower the immune system in the fight against cancer
AR, adverse reaction; I-O, immuno-oncology.
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Q&A