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