rheumatology, immunology, and immuno-oncology intersect
TRANSCRIPT
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
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