This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives: 1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment 2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment 3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy

1. Immunotherapy Shaping the Future of
Cancer Management Landscape:
Opportunities & Challenges
Emad Shash, MBBCh, MSc, MD
Medical Oncology Department
National Cancer Institute, Cairo University

2. Learning Objectives
• Explain:
• The mechanisms of action behind immune response to cancer
• The role of immunotherapy in cancer treatment
• Distinguish new and emerging immunotherapy classes and individual
agents:
• Efficacy
• Safety
• Potential patient responses to therapy in cancer treatment
• Strategies to counsel and assist patients to overcome barriers to therapy,
including
• Treatment side effects to improve adherence to therapy

3. Principles of Cancer
Immunotherapy

4. Immune System Function and Immune Response
Immune surveillance
• Involves both innate and adaptive immune mechanisms
• Non self-associated antigens can be identified by the immune system and destroyed
Innate Immunity Adaptive Immunity
Identify and destroy foreign or abnormal cells in the body
Janeway CA Jr, et al. Immunobiology: the immune system in health and disease. 2001.
Nonspecific
First line of defense
WBCs (natural killer
cells, neutrophils)
Activation of adaptive
response
Specific
Adapts specifically to
diverse stimuli
B-cell antibody
production
T-cell stimulation
Memory functions
Dendritic cell Mast cell
Macrophage
Natural
killer cell
Natural
killer T cell
B cell
T cell
CD4+
T cell
CD8+
T cell
Antibodies
λδ T cell
Complement
protein
Neutrophil
Eosinophil
Basophil
Granulocytes

6. T-Cell Response: First Signal
CD8+ T-cell
T-cell receptor
CD4+ T-cell
Antigen-
presenting cell
Foreign Cell
antigen
Foreign Cell
Class I MHC
Foreign Cell
antigen
T-cell receptor
Class II MHC
Adapted from: Snyder A, et al. Curr Opin Genet Dev. 2015;30:7-16.

7. Immunology: Overview
Foreign
Cells
Cytokines
Activated T-cell
T-cell
clonal expansion
Resting T-cell
LYMPH
NODE
Foreign Cells antigen
Dendritic cell
2
3
1

8. Cytokine-Driven Differentiation of CD4+ T-Cells
Bailey SR, et al. Front Immunol. 2014;5:276.

9. Adaptive Immune System: T-Cells
• 4 main types of T-cells
• Helper T-cells (CD4+)
• Cytotoxic T-cells (CD8+)
• Suppressor T-cells (CD4+ Foxp3+
CD25+ Tregs)
• Memory T-cells (CD4+ or CD8+
CCR7+ CD45RO)
B-cell T-cell
CD4+
T-cell
CD8+
T-cell
Antibodies

10. T-Cell Response: Accelerate or Brake?
CD28
OX40
GITR
CD137
CD27
HVEM
CTLA-4
PD-1
TIM-3
BTLA
VISTA
LAG-3
Activating Signals Inhibitory Signals
T-Cell Stimulation T-Cell Inhibition
T cell
Mellman I, et al. Nature. 2011;480:480-489.

11. T Cell tolerance

12. Tumour
Lymph node
Blood vessel
Key steps for an effective antitumor T cell
response
Chen & Mellman. 2013
Cancer antigen
presentation
(dendritic cells/APCs)
2
Priming and activation
(APCs and T cells)
3
Infiltration of T cells
into tumours
(CTLs, endothelial cells)
5
Recognition of cancer
cells by T cells
(CTLs, cancer cells)
6
Killing of cancer cells
(immune and cancer cells)
7
Trafficking of T cells
to tumours (CTLs)
4
Release of cancer
cell antigens
(cancer cell death)
1

13. Multiple Mechanisms of Immune Escape
Elimination
(cancer immunosurveillance)
Equilibrium
(cancer persistence/dormancy)
Escape
(cancer progression)
Chronic inflammation
Genetic instability and
immunoselection (ie, editing)
VEGF
CD8+
T-cell
CD8+
T-cell CD8+
T-cell
NKT
cell NK
CD4+
T-cell
CD4+
T-cell
CD8+
T cell
γδ
T cell
MΦ
CD4+
T-cell
CD8+
T-cell
NK MΦ
CD8+
T-cell
M2
MΦ
PD-L1
IL-12
CTLA-4
IFN-γ
 TGF-β
 IDO
 IL-10
 Galectin-1
CTLA-4
TregMDSC
Vesely MD, et al. Annu Rev Immunol. 2011;29:235-271.

14. Applying the Principles in
Cancer Therapy

15. Classificationofimmunotherapy
Active
Passive
Specific
Non Specific
Specific
Non Specific
• Cancer-derived vaccines
• Dendritic cell vaccines
• Cytokines:
• Interferon α, IL-2, TNF α
• Immune checkpoint inhibitors:
• Adjuvants:
• CpG, Imiquimod,sLAG-3
• Monoclonal antibodies
• Engineered antibodies/TCR
• MCSP-BiTE, ImmTAC
• Adoptive cell transfer
• TIL, engineered T cells
• Activated NK cells
• Activated non-specific T cells
• aCTLA-4, aPD-1, aPD-L1

16. History of Immunotherapy
Elert E. Nature. 2013;504:S2-S3.
1796: First use of
immunotherapy,
Jenner smallpox
vaccine
1976: BCG vaccine
for bladder cancer
1863: Connection
between
immunotherapy and
cancer recognized
1985: Interferon
first approved for
hairy cell
leukemia
1992: IL-2
approved for RCC
1997: First mAb for
cancer approved,
rituximab
2008: First cancer
vaccine approved for
RCC
2010: Sipuleucel-T
approved for
prostate cancer
2011: CTLA-4
inhibitor approved
for melanoma
2014-2015: PD-1 inhibitors
approved for melanoma,
squamous NSCLC
2015: First oncolytic
virus approved for
melanoma
2016: PD-1 inhibitor
approved for cHL
PD-L1 inhibitor
approved for UC

17. Enhancing the immune system
1- Stimulating effector cells (vaccination, adoptive cellular therapy and
oncolytic virus)
2- Counteracting suppressor and inhibitory effects (chemotherapy,
immune checkpoint inhibitors and antibodies against T-regulatory cells
(CD25 cells)
Farkona et al. BMC Medicine (2016) 14:73

18. Types of Cancer Immunotherapy
Vaccines
Oncolytic
Virus Therapy
Adoptive Cell
Therapy
Immune
Checkpoint
Inhibitors

19. Vaccines

20. Patient’s white blood cells
harvested
Short-term culture with protein
“cassette”
Shipping
Cells infused back into
patient (IV)
GM-CSF
(immune
cell
activator)
Prostatic acid
phosphatase
(expressed in > 95% of
PCa)
Active Cellular Immunotherapy (Sipuleucel-T)
Activation and
proliferation of T
cells targeting PCa

21. IMPACT: Phase III Trial of Sipuleucel-T in mCRPC
• Primary endpoint: OS
Kantoff P, et al. ASCO GU 2010
Sipuleucel-T q2w x
3
(n = 341)
Placebo q2w x 3
(n = 171)
Patients with
asymptomatic or
minimally
symptomatic
mCRPC
(N = 512)
Treat at physician
discretion and/or
salvage protocol
Treat at physician
discretion
*Stratified by primary Gleason score, number of bone metastases, and bisphosphonate use.
Randomized 2:1*
P
R
O
G
R
ES
S
I
O
N

22. IMPACT: OS With Sipuleucel-T vs Placebo
Kantoff P, et al. N Engl J Med. 2010.
Sipuleucel-T
Placebo
Median OS, Mos
25.8
21.7
36-Mo OS, %
31.7
23.0
Sipuleucel-T was approved by the FDA on
April 30, 2010, for the treatment of
metastatic prostate cancer.
HR: 0.78 (95% CI: 0.61-0.98; P = .03)
100
80
60
40
20
0
0 12 24 36 48 60 72
Mos Since Randomization
ProbabilityofSurvival(%)
Sipuleucel-T
Placebo
Pts at Risk, n
Sipuleucel-T
Placebo
341
171
274
123
129
55
49
19
14
4
1
1

23. Oncolytic viruses
• Native or engineered viruses that target, infest and kill cancer cells
• Tumor debulking due to tumor infection and induction of immune
response
• Viral genome can be modified to increase cytotoxicity and attenuate
pathogenicity
Farkona et al. BMC Medicine (2016) 14:73

24. Farkona et al. BMC Medicine (2016) 14:73

29. CAR T-Cell
Adoptive Cell Therapy

30. Clinical Application of CAR T-Cells: An Overview
Davila ML, et al. Int J Hematol. 2014;99:361-371.
1. Apheresis
2. CD3/CD28 selection and
activation with ClinExVivo
MPC
3. Gene transfer using
viral vector
4. Expansion on Wave
Bioreactor
5. Wash and
formulate with
CytoMate
6. Infusion
Individual with
relapsed/refractory B-
cell ALL

31. Advantages of CAR T-Cell Therapy
• HLA-independent antigen recognition, therefore universal application
• Active in both CD4+ and CD8+ T-cells
• Target antigens include proteins, carbohydrates, and glycolipids
• Rapid generation of tumor specific T-cells
• Minimal risk of autoimmunity or GVHD
• A living drug, single infusion

32. Adoptive cell therapy
• Chimeric antigen receptors (CARs) consist of an Ig variable domain
fused to a TCR constant domain
• Omits the need of antigen expressing mechanism to be functional (i.e
MHC) and allows recognition of any expressed antigen by the variable
domain
Farkona et al. BMC Medicine (2016) 14:73

33. Immune checkpoints inhibitors
CTLA-4 blockade (e.g.
Ipilimumab)
Ledford, Nature 508, 24-26, 2014
PD- (L)1 blockade (e.g. Nivolumab,
pembrolizumab, Atezolizumab)

34. Down-regulation of antigen
presentation leading to impaired
recognition by T cells1
Reduced expression of
ligands for co-stimulatory
molecules such as B7.1 and
inducible co-stimulator ligand
(ICOSL) on APCs leading to
defective immune functions2
Creation of an immunosuppressive
microenvironment leading to recruitment
of, or promotion of, suppressive immune
cell differentiation or expansion2
Expression of inhibitory receptors,
e.g. PD-L1 and PD-L2, leading to
T-cell inhibition3
TGF-β
VEGF IL-10
CCL21
IDO
B7.1
PD-L1
PD-1
MHC I
TCR
Tumour cell or APC
1. Topfer, et al. 2011
2. Nurieva, et al. 2013
3. Mellman, et al. 2011

35. Immune checkpoint inhibitors
• Everyone is talking about it today with too many data that can’t be
summarized in one presentation and across different tumor types.
• CTLA-4 blockage leads to non-specific T-cell response could account for
the significant immune-related toxicities observed in patients (eg.
Ipilumumab)
• Removal of the blockage of specific T-cells by Anti PD1 (eg. Nivolumab
and Pembrolizumab) or anti PDL1 (Atezolizomab and Daratumumab)
reflects their lower toxicity profile when compared to anti CTLA-4

36. Management of Immune
Related Adverse Events

37. Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.
Kinetics of Appearance of irAEs With
Ipilimumab Rash, pruritus
Liver toxicity
Diarrhea, colitis
Hypophysitis
ToxicityGrade
Wks
140 2 4 6 8 10 12
Combined analysis of 325 participants with 10 mg/kg IV q3w x 4

38. If not vigilant, may
result in more serious
immune-related AEs
Pulmonary
 Pneumonitis
 Interstitial lung
disease
 Acute interstitial
pneumonitis
Neurologic
 Autoimmune neuropathy
 Demyelinating
Polyneuropathy
 Guillain-Barre
 Myasthenia gravis–like
syndrome
Hepatic
 Hepatitis,
autoimmune
Gastrointestinal
 Colitis
 Enterocolitis
 Necrotizing colitis
 GI perforation
Endocrine
 Hypothyroidism
 Hyperthyroidism
 Adrenal
insufficiency
 Hypophysitis
Eye
 Uveitis
 Iritis
Renal
 Nephritis,
autoimmune
 Renal failure
Skin
 Dermatitis exfoliative
 Erythema multiforme
 Stevens-Johnson syndrome
 Toxic epidermal necrolysis
 Vitiligo
 Alopecia
Immune-Related AEs With Immunotherapy

39. Immune-Mediated Colitis: Symptom
Surveillance
• Monitor for signs and
symptoms
• Median time to onset
from first dose ~ 10 wks
from first dose
• Ask pts to report any
bowel habit changes
promptly
• Rule out other causes of
diarrhea
Nivolumab [package insert]. 2014.
Clinical Pearl: colitis can
occur without diarrhea;
important to take all GI-
related symptoms
seriously and evaluate!

40. Immune-Mediated Colitis: Symptom Management
Grade Management
Mild/grade 1: ≤ 4 stools/day above baseline  Manage symptomatically (bland diet, PPI,
antidiarrheal)
 Consider delaying treatment until symptoms improve
Moderate/grade 2: increase of 4-6 stools/day
above baseline (persistent)
 Colonoscopy and steroids
 Low-dose steroids may be sufficient
 Hold treatment
Severe/grade ≥ 3: ≥ 7 stools/day above baseline  Initiate high-dose steroids
 Discontinue treatment
Prevention  No known methods

41. Immune-Mediated Hepatitis: Symptom
Surveillance
• Monitor LFTs at baseline
and prior to each dose of
treatment
• Pts with abnormal LFTs
should be monitored more
frequently
• Hepatotoxicity appears
worse when ipilimumab
combined other drugs[1-3]
1. Robert C, et al. N Engl J Med. 2011;364:2517-2526.
2. Ribas A, et al. N Engl J Med. 2013;368:1365-1366.
3. Wolchok JD, et al. Ann Oncol. 2013;24:2174-2180.

42. Immune-Mediated Hepatitis: Symptom
Management
• Rule out other causes of LFT
abnormalities
• Increase LFT monitoring
• Corticosteroid treatment with
grade ≥ 2 LFTs (prolonged taper
may be required)
• Mycophenolate may be useful
• LFT abnormalities appear to be
dose dependent
LFT Grade 1 Grade 2 Grade 3 Grade 4
Bilirubin > ULN to 1.5 x ULN > 1.5 to 3.0 x ULN > 3.0 to 10.0 x
ULN
> 10.0 x ULN
ALT/AST > ULN to 2.5 x ULN > 2.5 to 5.0 x ULN > 5.0 to 20.0 x
ULN
> 20.0 x ULN
Albumin < LLN to 3 g/dL < 3 to 2 g/dL < 2 g/dL --

43. Immune-Mediated Dermatitis
• Reported in up to 40% of pts
with anti–CTLA-4 and anti–PD-1
agents
• Occasionally severe rashes
• Onset within a few wks of
starting or several wks/mos into
therapy
• Severity driven by symptoms
• Rule out other etiologies
• Generally not infusion related
Hodi FS, et al. N Engl J Med. 2010;363:711-723.
Image courtesy Matthew M. Burke, MBA, RN, MSN, APRN-BC.

44. Immune-Mediated Dermatitis: Symptom
Management
Severity Management
Mild/moderate (rash/pruritus)  Topical nonsteroidal cream, antihistamine, oatmeal
baths
 Skin care, moisturize, sunscreen, avoid sun
Persistent (> 1 wk) or interferes with ADLs  Moderate-potency steroid creams or
 Moderate-dose parenteral steroids
Severe  Discontinue treatment
 High-dose steroids
 Avoid rapid steroid taper

45. Immune-Mediated Endocrinopathies
• Can be serious or fatal if not
managed correctly
• Hypophysitis, thyroid disease, and
primary adrenal insufficiency have
all been reported
• Mechanism of injury not fully
understood
• Monitor pt for pituitary, thyroid, or
adrenal disease
• Check TFTs at baseline and prior to
each dose
• Time to onset may be much later;
median 11 wks
Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:1361-1375.
Pituitary gland
Hypothalamus
Thyroid gland
T4 T3
SULTs
UGTs
liver
01
T4→T3
T3/TR
rT3,T2
inactive
T4/T3-sulfate
T4/T3-glucuronide
inactive
Excretion
T4 >> T3
02.03

46. Immune-Mediated Endocrinopathies:
Symptom Management
• Hormone replacement,
corticosteroids
• Possibly delay treatment
• Co-syntropin stimulation
test
• Many endocrinopathies
can be controlled and
treatment continued
Does a preexisting thyroid
disorder put pts at higher
risk of developing
additional
endocrinopathies?
Not as far as we know.

47. Immune-Mediated Pneumonitis
• Fairly uncommon, but potentially serious
• Deaths have been reported
• Need to carefully monitor pts
• Pts at increased risk for pneumonitis
• NSCLC in the setting of chronic lung inflammation
• Heavily pretreated pts
• Combination of CTLA-4 and PD-1 agents
• Prior radiation to lung
• History of COPD

48. Immune-Related Pneumonitis: Signs and
Symptoms
• Shortness of breath
• Dry cough
• New or increasing oxygen requirements
• May be detected just on
imaging
• Decreasing O2 sat on
room air
11/15/2013:
Pre-pneumonitis
1/21/14:
Pneumonitis
2/21/14:
Improved with steroids; taper
completed 3/7/14

49. Other Immune-Related AEs
• Immune-related AEs include
• Ocular manifestations
• Neurologic complications
• Sarcoidosis
• Systemic vasculitis, including renal disease
• Autoimmune pancreatitis
• Hematologic

50. Keys to Optimal Pt Management
• Education of healthcare team, pts, and caregivers
• Rapid and timely intervention
• Corticosteroids for some intolerable grade 2 irAEs and any grade 3/4 irAEs
• SLOW taper of glucocorticoids
• Reinitiation of treatment may be possible
This goal is attainable through communication between all members
of the healthcare team and pts

51. Special Populations
• Pregnancy and lactation
• Antibodies are known to cross placental barrier
• Pregnancy category C; immune checkpoint inhibitors are not recommended
• Advise pts to use highly effective contraception
• Safety of breast-feeding has not been studied

52. Infusion Reactions
• Infusion reactions with checkpoint inhibitors are very rare
• Reported in up to 10% of pts (often much fewer)
• Usually mild: stop the infusion and restart at a lower rate
• No steroids: premedications are not necessary
• As with any infusion, monitor carefully and have emergency medications
available

53. Pt Education on Novel Therapies
• Unique MOA and time to response
• Toxicity profiles differ from standard chemotherapy
• Early recognition of irAEs essential
• irAEs infrequent, treatable, and respond well to steroids
• Whom and when to call for AEs
• These new therapies are helping many people
• Reinforce teaching points at every point of contact
• Notify healthcare team if the pt is admitted to another hospital

54. Take home messages
• Immune system is the key player in defeating cancer
• Immunotherapy is changing the landscape in Cancer Field
• Different Mechanism of action with different toxicity profile
• Physicians, Pharmacists & PATIENTS should be well educated about
Immunotherapy DATA, MOA & TOXICITY