Immunotherapy Shaping the Future of

Cancer Management Landscape:

Opportunities & Challenges
Emad Shash, MBBCh, MSc, MD
Medical Oncology Department
National Cancer Institute, Cairo University
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
Principles of Cancer
Immunotherapy
Immune System Function and Immune Response
Identify and destroy foreign or abnormal cells in the body
Innate Immunity Adaptive Immunity
Nonspecific Specific
Dendritic cell Mast cell
First line of defense Adapts specifically to
B cell
Macrophage
λδ T cell
diverse stimuli
WBCs (natural killer T cell
cells, neutrophils) B-cell antibody
Natural
Basophil
production
Activation of adaptive killer cell

response Complement
protein Antibodies
T-cell stimulation
Eosinophil Natural CD4+ CD8+
killer T cell T cell T cell Memory functions
Granulocytes
Neutrophil

Immune surveillance
• Involves both innate and adaptive immune mechanisms
• Non self-associated antigens can be identified by the immune system and destroyed

Janeway CA Jr, et al. Immunobiology: the immune system in health and disease. 2001.
T-Cell Response: First Signal
T-cell receptor
Class I MHC

Antigen-
CD8+ T-cell presenting cell
Foreign Cell Class II MHC
antigen
T-cell receptor

Foreign Cell
Foreign Cell
antigen

CD4+ T-cell

Adapted from: Snyder A, et al. Curr Opin Genet Dev. 2015;30:7-16.

Immunology: Overview
3

Cytokines
Resting T-cell
Activated T-cell
Foreign
Cells

2 LYMPH
T-cell NODE
clonal expansion
Foreign Cells antigen

Dendritic cell
Cytokine-Driven Differentiation of CD4+ T-Cells

Bailey SR, et al. Front Immunol. 2014;5:276.

Adaptive Immune System: T-Cells
• 4 main types of T-cells
• Helper T-cells (CD4+) B-cell T-cell

• Cytotoxic T-cells (CD8+)

Antibodies CD4+ CD8+
• Suppressor T-cells (CD4+ Foxp3+ T-cell T-cell

CD25+ Tregs)

• Memory T-cells (CD4+ or CD8+

CCR7+ CD45RO)
T-Cell Response: Accelerate or Brake?
Activating Signals Inhibitory Signals
CD28
OX40 CTLA-4
T cell
GITR PD-1
CD137 TIM-3

CD27 BTLA

HVEM VISTA

LAG-3

T-Cell Stimulation T-Cell Inhibition

Mellman I, et al. Nature. 2011;480:480-489.

T Cell tolerance
Key steps for an effective antitumor T cell
response
4 Trafficking of T cells
to tumours (CTLs)

5 Infiltration of T cells
3 Priming and activation into tumours
(APCs and T cells) (CTLs, endothelial cells)
Blood vessel

Lymph node

2 Cancer antigen 6 Recognition of cancer

presentation cells by T cells
(dendritic cells/APCs) (CTLs, cancer cells)
Tumour

7 Killing of cancer cells

1 Release of cancer
cell antigens (immune and cancer cells)
(cancer cell death)

Chen & Mellman. 2013

Multiple Mechanisms of Immune Escape
Elimination Equilibrium Escape
(cancer immunosurveillance) (cancer persistence/dormancy) (cancer progression)

CD8+ NK MΦ
CD8+ T-cell
CD8+ T-cell IL-12
T-cell NKT CD8+  TGF-β
NK T-cell CTLA-4
cell
CD4+  IDO
IFN-γ PD-L1
T-cell  IL-10
CD4+
T-cell  Galectin-1
CD4+
T-cell

MΦ γδ CD8+
T cell T cell
Genetic instability and
immunoselection (ie, editing)
CD8+
VEGF T-cell
M2
MΦ CTLA-4
MDSC Treg

Chronic inflammation

Vesely MD, et al. Annu Rev Immunol. 2011;29:235-271.

Applying the Principles in
Cancer Therapy
Classification of immunotherapy
• Cancer-derived vaccines
Specific

Active
• Dendritic cell vaccines

Non Specific • Cytokines:

• Interferon α, IL-2, TNF α
• Immune checkpoint inhibitors:
• aCTLA-4, aPD-1, aPD-L1
• Adjuvants:
• CpG, Imiquimod, sLAG-3
• Monoclonal antibodies
Specific
• Engineered antibodies/TCR
• MCSP-BiTE, ImmTAC
• Adoptive cell transfer
Passive
• TIL, engineered T cells

Non Specific • Activated NK cells

• Activated non-specific T cells
 2015: First oncolytic
virus approved for

History of Immunotherapy 1997: First mAb for

melanoma

2011: CTLA-4
cancer approved, inhibitor approved
rituximab for melanoma
1976: BCG vaccine
for bladder cancer 2008: First cancer
vaccine approved for
RCC

1863: Connection 1992: IL-2

1796: First use of 2014-2015: PD-1 inhibitors
between approved for RCC
immunotherapy, approved for melanoma,
Jenner smallpox immunotherapy and squamous NSCLC
vaccine cancer recognized
1985: Interferon 2010: Sipuleucel-T
first approved for approved for 2016: PD-1 inhibitor
hairy cell prostate cancer approved for cHL
leukemia PD-L1 inhibitor
approved for UC

Elert E. Nature. 2013;504:S2-S3.

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

Types of Cancer Immunotherapy

Vaccines

Immune
Oncolytic
Checkpoint
Virus Therapy
Inhibitors

Adoptive Cell
Therapy
Vaccines
Active Cellular Immunotherapy (Sipuleucel-T)

Patient’s white blood cells

harvested

Short-term culture with protein

“cassette”
GM-CSF
(immune
Prostatic acid cell
phosphatase activator)
(expressed in > 95% of
PCa)
Shipping

Cells infused back into

Activation and
patient (IV)
proliferation of T
cells targeting PCa
 IMPACT: Phase III Trial of Sipuleucel-T in mCRPC

• Primary endpoint: OS

Randomized 2:1*
P
Sipuleucel-T q2w x R Treat at physician
Patients with 3 O discretion
asymptomatic or (n = 341) G
minimally R
symptomatic ES
mCRPC S Treat at physician
Placebo q2w x 3
(N = 512) I discretion and/or
(n = 171)
O salvage protocol
N

*Stratified by primary Gleason score, number of bone metastases, and bisphosphonate use.

Kantoff P, et al. ASCO GU 2010

IMPACT: OS With Sipuleucel-T vs Placebo

100
Median OS, Mos 36-Mo OS, %

80 Sipuleucel-T 25.8 31.7

Probability of Survival (%)

Placebo 21.7 23.0

60
HR: 0.78 (95% CI: 0.61-0.98; P = .03)
Sipuleucel-T
40

20 Placebo

0
0 12 24 36 48 60 72
Mos Since Randomization
Pts at Risk, n Sipuleucel-T was approved by the FDA on
Sipuleucel-T 341 274 129 49 14 1 April 30, 2010, for the treatment of
Placebo 171 123 55 19 4 1 metastatic prostate cancer.

Kantoff P, et al. N Engl J Med. 2010.

 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

Farkona et al. BMC Medicine (2016) 14:73
CAR T-Cell
Adoptive Cell Therapy
Clinical Application of CAR T-Cells: An Overview

2. CD3/CD28 selection and

6. Infusion activation with ClinExVivo
1. Apheresis MPC
Individual with
relapsed/refractory B-
cell ALL

3. Gene transfer using

5. Wash and viral vector
formulate with 4. Expansion on Wave
CytoMate Bioreactor

Davila ML, et al. Int J Hematol. 2014;99:361-371.

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
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

 Immune checkpoints inhibitors

CTLA-4 blockade (e.g. PD- (L)1 blockade (e.g. Nivolumab,

Ipilimumab) pembrolizumab, Atezolizumab)

Ledford, Nature 508, 24-26, 2014

 Down-regulation of antigen
presentation leading to impaired
recognition by T cells1

TCR

MHC I
Reduced expression of
B7.1 ligands for co-stimulatory
molecules such as B7.1 and
inducible co-stimulator ligand
(ICOSL) on APCs leading to
defective immune functions2
CCL21
Tumour cell or APC
TGF-β
PD-L1
IDO
PD-1
VEGF IL-10
Creation of an immunosuppressive
Expression of inhibitory receptors,
microenvironment leading to recruitment
e.g. PD-L1 and PD-L2, leading to
of, or promotion of, suppressive immune
T-cell inhibition3
cell differentiation or expansion2

1. Topfer, et al. 2011

2. Nurieva, et al. 2013
3. Mellman, et al. 2011
 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
Management of Immune
Related Adverse Events
Kinetics of Appearance of irAEs With
Ipilimumab Rash, pruritus
Liver toxicity
Diarrhea, colitis
Hypophysitis

Toxicity Grade

0 2 4 6 8 10 12 14
Wks

Combined analysis of 325 participants with 10 mg/kg IV q3w x 4

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Immune-Related AEs With Immunotherapy
Eye Endocrine
Skin  Uveitis  Hypothyroidism
 Dermatitis exfoliative  Iritis  Hyperthyroidism
 Erythema multiforme  Adrenal
 Stevens-Johnson syndrome insufficiency
 Toxic epidermal necrolysis  Hypophysitis
 Vitiligo
 Alopecia
Pulmonary
 Pneumonitis
Hepatic  Interstitial lung
 Hepatitis, disease
autoimmune  Acute interstitial
pneumonitis
Gastrointestinal
 Colitis Neurologic
 Enterocolitis  Autoimmune neuropathy
 Necrotizing colitis  Demyelinating
 GI perforation Polyneuropathy
 Guillain-Barre
Renal  Myasthenia gravis–like
 Nephritis, If not vigilant, may syndrome
autoimmune result in more serious
 Renal failure immune-related AEs
Immune-Mediated Colitis: Symptom
Surveillance
• Monitor for signs and
symptoms Clinical Pearl: colitis can
occur without diarrhea;
• Median time to onset important to take all GI-
from first dose ~ 10 wks related symptoms
from first dose seriously and evaluate!
• Ask pts to report any
bowel habit changes
promptly
• Rule out other causes of
diarrhea

Nivolumab [package insert]. 2014.

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  Colonoscopy and steroids

above baseline (persistent)  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
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.
Immune-Mediated Hepatitis: Symptom
Management
• Rule out other causes of LFT • Mycophenolate may be useful
abnormalities • LFT abnormalities appear to be
• Increase LFT monitoring dose dependent
• Corticosteroid treatment with
grade ≥ 2 LFTs (prolonged taper
may be required)

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 > 10.0 x ULN
ULN
ALT/AST > ULN to 2.5 x ULN > 2.5 to 5.0 x ULN > 5.0 to 20.0 x > 20.0 x ULN
ULN
Albumin < LLN to 3 g/dL < 3 to 2 g/dL < 2 g/dL --
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.
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
Immune-Mediated Endocrinopathies
• Can be serious or fatal if not Hypothalamus
managed correctly
Pituitary gland
• Hypophysitis, thyroid disease, and
primary adrenal insufficiency have
Thyroid gland
all been reported
• Mechanism of injury not fully T4 >> T3 T3/TR
understood 02.03 rT3,T2
T4→T3 inactive
• Monitor pt for pituitary, thyroid, or
01
adrenal disease T4 T3
liver
• Check TFTs at baseline and prior to T4/T3-sulfate
each dose SULTs T4/T3-glucuronide
UGTs inactive
• Time to onset may be much later;
median 11 wks Excretion

Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:1361-1375.

Immune-Mediated Endocrinopathies:
Symptom Management
• Hormone replacement,
Does a preexisting thyroid
corticosteroids disorder put pts at higher
• Possibly delay treatment risk of developing
additional
• Co-syntropin stimulation endocrinopathies?
test
Not as far as we know.
• Many endocrinopathies
can be controlled and
treatment continued
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
Immune-Related Pneumonitis: Signs and
Symptoms
• May be detected just on
• Shortness of breath imaging
• Dry cough • Decreasing O2 sat on
• New or increasing oxygen requirements room air

2/21/14:
11/15/2013: 1/21/14: Improved with steroids; taper
Pre-pneumonitis Pneumonitis completed 3/7/14
Other Immune-Related AEs
• Immune-related AEs include
• Ocular manifestations
• Neurologic complications
• Sarcoidosis
• Systemic vasculitis, including renal disease
• Autoimmune pancreatitis
• Hematologic
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
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
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
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
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