Rheumatology, Immunology, and

Immuno-Oncology Intersect:

Navigating the Complexities of Immune

Checkpoint Inhibition, Autoimmunity,

and Immune-Related Adverse EventsHow Can Rheumatologists Help Minimize the Risks and

Maximize the Benefits of Cancer Immunotherapies?

Maria E. Suarez-Almazor, MD, PhD

Barnts Family Distinguished Professor

Section of Rheumatology and Clinical Immunology

Dept. of General Internal Medicine

University of Texas MD Anderson Cancer Center

Houston, Texas

Disclosures

Maria E. Suarez-Almazor, MD, PhD, has a financial interest/relationship or

affiliation in the form of:

Consultant and/or Advisor for:

AbbVie Inc.

Grant/Research Support from:

Pfizer Inc.

Maria E. Suarez-Almazor, MD, PhD, does intend to include either non-FDA-

approved or investigational use for the following products/devices: cancer

immunotherapies, combinations, and agents for management of irAEs.

William Bradley Coley(1862-1936)

American bone surgeon, cancer researcher, and

pioneer of cancer immunotherapy

Key Milestones in the Evolution of

Cancer Immunotherapy

Allison & Honjo

Nobel Prize

First report of the

successful treatment

with CAR-T cells

targeting CD19 in

refractory ALL

Anti-PD-1 (nivolumab,

pembrolizumab)

FDA approved for

metastatic melanoma

Sipuleucel-T

FDA approved

as autologous

cellular

immunotherapy

in prostate

cancer

Description

of immune

infiltrates in

tumors by

Virchow

Efficacy of

bacillus Calmette-

Guerin (BCG)

immunotherapy in

melanoma

Autologous TIL

used to treat

melanoma

patients

Anti–PD-1

(nivolumab)

FDA

approved for

lung cancer

Anti–CTLA-4

(ipilimumab)

FDA approved for

metastatic melanoma

The new concept

of cancer

“immunoediting”

IL-2

approved

for cancer

therapy

Adoptive cell

transfer for

cancer

Frist study

with IFNα in

melanoma

Hypothesis of cancer

“immunosurveillance”

by Thomas and

Burnet

Frist

demonstration

of a “cancer

vaccine” by Coley

Approvals of

checkpoint

inhibitors and

combinations has

continued across

many different

tumor types

2016 2017 2018 2019Late 1800 1957 1974 1985 1988 1992 2001 2010 2011 2014 2015 2016 2017 2018 2019

CAR-T

Current Pan-Tumor Immunotherapy Landscape:

Continuously Expanding1

1. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Accessed August 5, 2019.

Emergence and

expansion of the

immune

checkpoint

inhibitor

class of agents

→ new 5th

treatment pillar

in oncology

Surgery,

radiotherapy,

chemotherapy,

and targeted

therapy

represent

the previous

4 treatment

pillars of

oncology

Immunotherapy Has Become the New

5th Treatment Pillar in Oncology

Harnessing the Immune System in the

Treatment of Cancer

Cytotoxic T cell

Cancer cell

Antitumor Responses Can Be Induced Through

Blockade of Immune Checkpoints1

1. Ribas A, Wolchock JD. Science. 2018;359:1350-1355.

Immune checkpoint inhibitors modulate T lymphocyte responses against cancer by blocking negative regulation of immune responses

▪ CTLA-4 is a negative regulator of costimulation that

is required for initial activation of an antitumor T cell

in a lymph node upon recognition of a tumor antigen

▪ Activated T cells recognizes cognate antigens presented by

cancer cells → TCR triggered → negative regulatory receptor

PD-1 expressed → IFN-γ produced → reactive expression of

PD-L1 → antitumor T cell responses turned off

Activation of CTLA-4 can be blocked

with anti–CTLA-4 antibody therapies

This negative interaction can be blocked by

anti–PD-1 or anti–PD-L1 antibody therapies

T-Cell Targets for Immunoregulatory

Antibody Therapy1

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

Turning

up the

activating

Blocking

the

inhibiting

Activating

receptors

Inhibitory

receptors

Immune Checkpoint Inhibitors

Combinations

• Nivolumab + ipilimumab

(melanoma, MSI-H or dMMR

CRC, and RCC)

• Pembrolizumab +

chemotherapy (NSCLC)

• Atezolizumab + bevacizumab

+ chemotherapy (NSCLC)

• Atezolizumab +

chemotherapy (TNBC and

SCLC)

Approved agents

• Ipilimumab (CTLA-4)

• Nivolumab (PD-1)

• Pembrolizumab (PD-1)

• Cemiplimab-rwlc (PD-1)

• Atezolizumab (PD-L1)

• Avelumab (PD-L1)

• Durvalumab (PD-L1)

Cancer Types Treated With Immune

Checkpoint Inhibitors

• Non–small cell lung

• Small cell lung

• Renal cell (kidney)

• Urothelial (bladder)

• Hepatocellular (liver)

• Gastric

• Squamous cell carcinoma of

head and neck

• MSI-H or dMMR colorectal

and other solid tumors

• Cervical

• Melanoma

• Merkel cell

• Cutaneous squamous cell

• Triple-negative breast cancer

• Hodgkin lymphoma

• Primary mediastinal large

B-cell lymphoma

More to come!

Reasons for Increased Use of Cancer

Immunotherapy: Durability1

1. Wolchok JD et al. N Engl J Med. 2017;377:1345-1356.

Long-term

survival

Time, mo

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 483024 362721 42 4533 39

No. at Risk

0Ipilimumab 100113128135148163181203227253285315 20 2107 68

0177186192198200209221226247265292314 27Nivolumab + ipilimumab 3180 131

Nivolumab 0156171175181191201213230244265292316 28 0163 120

Nivolumab + ipilimumab

Nivolumab

Ipilimumab

58%

52%

34%

45%

59%

64%

Ove

rall

Su

rviv

al,

%

Reasons for Increased Use of Cancer

Immunotherapies: Broad Activity

90

5550

4540

2520 20 18 15 15

10

0

20

40

60

80

100

Re

sp

on

se

Ra

te (

Ap

pro

xim

ate

), %

❖ Checkpoint inhibitors have revolutionized

the treatment of cancer, but can also cause

a spectrum of unique adverse events of

autoimmune or autoinflammatory nature

often referred to as:

Immune-related adverse events (irAEs)

or

Immune-mediated adverse reactions (IMARs)

Checkpoints and Autoimmunity1-5

1. Klocke K. PNAS. 2016;E2383-2392. 2. Wing K et al. Science. 2008;322:271. 3. Francisco LM. Immunol Rev 2010;236:219-242.

4. Kong EK et al. Arth Rheum. 2005;52:1058-1062. 5. Kuoi N et al. Immunotherapy. 2018;10:149-160.

• MOA

─ Loss of direct inhibition of

pathogenic T cells

─ Loss of Treg development

and function

• Animal models support

centrality of checkpoints in

immunopathogenesis of

autoimmunity

─ CTLA-4 knockout (KO)–

fulminate disease

─ CTLA-4 KO in foxp3 Tregs

similar phenotype

─ PD-1 KO–systemic lupus

erythematosus in genetically

limited model (C57BL/6)

─ PD-1 and PD-L1 KO

accelerate T1D (NOD)

─ PD-1 KO and anti–PD-1

accelerate experimental

autoimmune

encephalomyelitis

Evidence for Checkpoints in the Pathogenesis of

Human Autoimmunity

• Lessons from primary immunodeficiency disorders (PIDs)

• Lessons from human autoimmunity

– Rheumatoid arthritis (RA)

– Giant cell arteritis (GCA)

– Antineutrophil cytoplasmic antibody-associated vasculitis

(AAV), inflammatory bowel disease (IBD) and others

CHAI and LATAIE: New Genetic Diseases of

CTLA-4 Checkpoint Insufficiency1

1. Lo B et al. Blood. 2016;128:1037-1042.

• Two new PIDs

have been

described involving

deficiency states of

the CTLA-4

checkpoint

• Lead to widespread

end-organ

inflammation,

autoantibody

formation, and

impaired humoral

immunity

• Mimic irAEs in

many ways

Checkpoints and Autoimmunity: Humans

1. Moret F et al. Arth Care Res. 2014;16497.

Kuol N et al. Immunotherapy. 2018;10:149-160. → Excellent review of PD-1 in autoimmunity

• In RA plasma-soluble PD-1 correlates with tender joint count (TJC)

• Soluble PD-1 is induced by IFNG, TNF, and IL-17

• Soluble PD-1 in synovial fluid is correlated with TNF

• Blockade of PD-1 leads to enhanced proliferation of Tm cells1

• Evidence of defective CHECKPOINTS in RA and GCA

• irAEs can affect any organ system and may be mild to life-threatening

• Many irAEs mirror rheumatic diseases

Immune-Related Adverse Events1

1. Calabrese LH et al. Nat Rev Rheumatol. 2018;14:569-579.

General Features of Checkpoint Inhibitor

Therapy-Associated irAEs1-3

1. Martins F et al. Lancet. 2019;20:e54. 2. Michot JM et al. Eur J Cancer. 2016;54:139-148. 3. Puzanov I et al. J ImmunoTherapy Cancer. 2017;5:595.

• Grade 3 up to 43% anti–CTLA-4 and <20% anti–PD-1/PD-L1

• May occur singly or in combination (50%)

• Fatal 0.6%

• Incidence of irAEs for anti–CTLA-4 and anti–PD-1 is dose dependent

• Some irAEs are drug and or tumor-lineage dependent

Kinetics of Appearance of irAEs1

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

1. Calabrese LH et al. Nat Rev Rheumatol. 2018;14:569-579.

Atypical Autoimmune Adverse Effects With

Checkpoint Inhibitors1

1. Friedman CF, Snyder A. Ann Oncol. 2017;28:206-207.

Systematic Review: Rheumatic and

Musculoskeletal irAEs

1. Cappelli LC et al. Arthritis Care Res (Hoboken). 2017;69:1751-1763.

• Inclusion: PD-1, PD-L1, and/or CTLA-4 inhibitor; musculoskeletal or

rheumatic irAE mentioned; original data

• Trial data from 33 trials:

– Arthralgia 1% to 43% (n = 24), myalgia 2% to 20% (n = 12)

– Arthritis reported in only 5 of 33 trials, 1% to 7%

– Xerophthalmia, xerostomia 3% to 24% (n = 4)

– Isolated reports of vasculitis, sarcoid, and others

Inflammatory Arthritis (IA)

1. Kostine M et al. Ann Rheum Dis. 2018;77:393-398. 2. Lidar M et al. Autoimmun Rev. 2018;17:284-289. 3. Le Burel S et al. Ann Rheum Dis. 2017;76:2061-2064.

4. Cappelli L et al Rheumatology. 2018.

• Incidence difficult to assess; 1.1%-3.8%

• Single-center registries

– N = 504; rheumatic irAEs (RirAEs) = 11; 3.8% RA like, all

seronegative, 100% PD-11

– N = 400; IA = 11 (2.8%); 1/3 positive family history, mixed

anticitrullinated protein/peptide antibody (ACPA); glucocorticoid (GC)

>20 mg in most with methotrexate added2

• Multicenter (REISAMIC)

– N = 908; RirAEs = 21; 1.1% IA, median time to onset 57 days,

immune checkpoint inhibitor withdrawn in 12/40; 83% Rx, GC 17%

DMARDS, favorable outcomes in most3

• Shared epitope > healthy controls but largely seronegative4

• MAY BE CHRONIC in 15%-35%?????????????

Polymyalgia Rheumatica (PMR)1

1. Belkhir R et al. Ann Rheum Dis. 2017;76:1747-1750. 2. Calabrese C et al. 2017 American College of Rheumatology Annual Meeting. Abstract 352.

Retrospective multicenter collection of patients with rheumatoid

arthritis or PMR occurring after checkpoint inhibitor treatment through:

• Club Rhumatismes et Inflammation (CRI), a French network of almost

2400 physicians

• 10 patients developed RA or PMR, 1-9 months after PD-1/PD-L1, 6 with

RA and no previous history

• All 6 were + ACPA/rheumatoid factor (3 with + baseline asymptomatic

ACPA)

• 3 more patients described similarly with ACPA + RA-like disease2

Polymyalgia Rheumatic-Like Syndrome From Checkpoint Inhibitor

Therapy: Case Series and Systematic Review of the Literature1

1. Calabrese C et al. 2018 American College of Rheumatology Annual Meeting. Abstract 352.

• The largest series of patients with PMR-like syndrome from checkpoint

inhibitor therapy

• Objective: To determine if cases meet the 2012 European League Against

Rheumatism/American College of Rheumatology provisional criteria for

PMR

– Case series: 20 reported cases from Cleveland Clinic Foundation,

Johns Hopkins University, and University Hospital of Bordeaux

– Systematic review: 29 additional cases

• Out of 49 patients, 37 (75%) provided adequate information to apply criteria;

of these, 28 cases fulfilled the criteria

• The main reason for failure to meet criteria was presence of other joint

involvement

• Other atypical features: Requirement for higher doses of prednisone, and

normal inflammatory markers

• Conclusion: 25% of reported cases of checkpoint inhibitor-related PMR

were based on incomplete reporting data

Rheumatic irAEs: Myositis

1. Liewluck T et al. J Immunother. 2018;41:208-211. 2. Chen J-H et al. Medicine (Baltimore). 2017;96:e9262. 3. Johnson D et al. N Engl J Med. 2016;375:1749-1755.

4. Cappelli LC et al. Ann Rheum Dis. 2017;76:43-50.

• Rare event with estimates of 0.76%-1.2% of exposures to PD-L1 based

therapy1 and also reported with combined checkpoint inhibitor treatment

• Only 1/2 of reports with tissue diagnosis

• Clinically variable: Asymptomatic to fulminate; onset after median of 2

cycles of a checkpoint inhibitor, progression to max weakness 9-30 days

• Pathology: Necrotizing myopathy, polymyositis, and dermatomyositis

• Distinctive features: Frequently associated with bulbar features, ptosis,

axon loss peripheral nervous system, concomitant myasthenia gravis2,

and myocarditis3

• Scattered case reports with minority displaying autoantibodies4

Connective Tissue Disease (CTD) irAEs

1. Le Burel S et al. Ann Rheum Dis. 2018;77:468-470. 2. Daxini A et al. Clin Rheumatol. June 19, 2018. [Epub ahead of print]

3. Chen J-H et al. Medicine (Baltimore). 2017;96:e9262.

• Vasculitis, Sjögren's syndrome, primary Sjögren's syndrome, systemic

lupus erythematosus, and mixed CTD

• Frequency: REISAMIC (French Network)

• Of 447 patients treated with checkpoint inhibitors, CTD occurred in 0.7%

(n = 4): Sjögren's syndrome = 2; myosotis = 1; and Cryo vasculitis = 11

• CTD: 0.7%1 (sicca like, vasculitis2, myositis3, systemic lupus

erythematosus)

Diagnostic and Treatment Approach

• Work-up

- Diagnosis of exclusion

- Not all musculoskeletal symptoms are inflammatory or RirAEs

- Aggressive diagnostic approach with high suspicion of irAEs is

important → referral

• Key treatments

– Steroids

– infliximab

– symptomatic care

Treatment of irAEs

Guidelines

SITC

ASCO

NCCN• Complex

• Generally follows

– Grade 1: Observation

– Grade 2: Diagnostic mode

➢ Symptomatic therapy

➢ Low-dose glucocorticoid

• Grade 3: Withhold immunotherapy

– Start IV glucocorticoids

– If unable to taper GC to <10-

20mg QD, consider DMARDs

(either csDMARDs or bDMARDs)

• Grade 4: Consider advanced

immunosuppression

– TNFi, anti-IL-6, antimetabolites,

etc

Initiate referral to:

• Endocrinologist

• Gastroenterologist

• Pulmonologist

• Dermatologist

• Rheumatologist

• Nephrologists

• Neurologist, etc

More than

glucocorticoids

and TNFi

Treatment of irAEs With Glucocorticoids and TNFi

Case

62-year-old male with

stage IV RCC

• Diagnosed via biopsy of

spinal lesion 6/22/18

• Metastases to bone and

brain

• Gamma knife to brain

lesion 7/9/19

Treatment

• Checkpoint inhibitor

combination therapy

(anti–PD-1 + anti–CTLA-4)

started 7/30/18 x 4 cycles

• Admitted 8/5/18 for PE,

pneumonitis, and

diverticulitis

• Admitted again 8/29/18

for diverticulitis

• September: Hyperthyroid,

increased T4, TSH 0.007,

on methimazole

Case (Cont’d)

• History of osteoarthritis; advanced in the right knee and shoulder

(had been recommended to have shoulder replacement in the past)

• Now has spinal fracture from metastasis, with significant pain

• Had stirrings of pain in the fingers and wrists since his first

combination infusion

• First anti–PD-1 monotherapy maintenance: 10/24/18

• Symptoms worsened significantly

– Finger joint, wrist, elbow pain and swelling

– Bilateral shoulder pain

– Significant stiffness

– Felt terrible

Case (Cont’d)

Seen by rheumatologist on 11/3/18

• Tenderness and synovitis involving most proximal interphalangeal

and metacarpophalangeal joints, wrists, and elbows

• Bilateral shoulder pain with abduction

• Lower extremities OK for the most part

• Erythrocyte sedimentation rate 46 mm/Hg

• C-reactive protein 2.4 mg/dL

• Autoimmune serology negative

• Sister has rheumatoid arthritis

Case (Cont’d)

• Started prednisone 15 mg and within 1 day felt significantly better

– “The best I’ve felt in 2 years!”

• No pain

• Minimal stiffness in the hands

• Tapered prednisone to 12.5 mg after 3 weeks, with no worsening of

symptoms

• Transient worsening after checkpoint inhibitor infusion on 11/21/18

• Transient worsening after his 12/20/18 infusion, but continues to do

well, with prednisone taper

Case: Questions for Discussion

• The oncology plan is for him to get anti–PD-1 checkpoint inhibitor

therapy every month for the foreseeable future

Questions

• What is this entity? Atypical polymyalgia rheumatica?

• Next steps if he worsens with subsequent infusions?

• Continued prednisone?

• Further immunosuppression?

Questions Regarding irAEs

• Does the occurrence of an irAE serve as a biomarker of

antitumor response?

irAEs: Predictive of Response Against Cancer?1

1. Kostine M et al. European Congress of Rheumotology 2018. Absract OP88.

• 633 patients with cancer

• 274 (43%) with irAEs

Questions Regarding irAEs (Cont’d)1

1. Abdel-Wahab N et al. Ann Intern Med. 2018;168:121-130.

• What about patients with pre-existing autoimmune diseases—

25 million (US) or more?

• Are they candidates for immune checkpoint inhibitor

therapy for cancer?

• How to evaluate?

• What role can rheumatologists play?

Interdisciplinary Approach

• Major centers need to develop interprofessional groups with

interested and invested consultants in all areas who can share

experiences

• irAE tumor board design

• Triage systems vital for optimal care

• Education is critically needed at the community oncologist,

specialist, generalist, and advanced practitioner level

Audience

Q&A

Visit us at: www.peerview.com/Rheum19

• Download slides and Practice Aids

• Watch for the onDemand version of this symposium

• Join the conversation on Twitter @PeerView

• Request a live meeting at your institution

Thank you.

Please remember to complete and submit

your Post-Test and Evaluation for

CME/MOC/CNE credit.

Missed anything?