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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
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 cellCD8+
T cell
Antibodies
λδ T cell
Complement
protein
Neutrophil
Eosinophil
Basophil
Granulocytes
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.
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
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+)
• 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-cellCD8+
T-cellAntibodies
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.
T Cell tolerance
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)
3Infiltration 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
Multiple Mechanisms of Immune Escape
Elimination(cancer immunosurveillance)
Equilibrium(cancer persistence/dormancy)
Escape(cancer progression)
Chronic inflammation
Genetic instability andimmunoselection (ie, editing)
VEGF
CD8+T-cell
CD8+T-cell CD8+
T-cellNKTcell NK
CD4+T-cell
CD4+T-cell
CD8+T cell
γδT cell
MΦ
CD4+T-cell
CD8+T-cell
NK MΦ
CD8+T-cell
M2MΦ
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.
Applying the Principles in Cancer Therapy
Cla
ssif
icat
ion
of
imm
un
oth
erap
yActive
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
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 cHLPD-L1 inhibitor
approved for UC
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
Oncolytic Virus Therapy
Adoptive Cell Therapy
Immune Checkpoint Inhibitors
Vaccines
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
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*PROGRESSION
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
00 12 24 36 48 60 72
Mos Since Randomization
Pro
bab
ility
of
Surv
ival
(%
)
Sipuleucel-T
Placebo
Pts at Risk, nSipuleucel-TPlacebo
341171
274123
12955
4919
144
11
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-CellAdoptive Cell Therapy
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
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.eMHC) 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.
Ipilimumab)
Ledford, Nature 508, 24-26, 2014
PD- (L)1 blockade (e.g. Nivolumab,
pembrolizumab, Atezolizumab)
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
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
Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.
Kinetics of Appearance of irAEs With Ipilimumab
Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis
To
xic
ity G
rad
e
Wks
140 2 4 6 8 10 12
Combined analysis of 325 participants with 10 mg/kg IV q3w x 4
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
Immune-Mediated Colitis: Symptom Surveillance
• Monitor for signs and symptoms
• Median time to onset from first dose ~ 10 wksfrom 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!
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
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 ipilimumabcombined 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
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 --
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 ManagementSeverity 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 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
Immune-Mediated Endocrinopathies:Symptom Management
• Hormone replacement, corticosteroids
• Possibly delay treatment
• Co-syntropin stimulation test
• Many endocrinopathiescan 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.
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• 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
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