Immunotherapy of lung cancer copy

Immunotherapy in lung cancer
Dr Ambika Gupta

Will be covering :
• Principles of cancer immunotherapy

Principles of cancer immunotherapy
• The fields of immunology and oncology have been
linked since the late 19th century, when the surgeon
William Coley reported that an injection of killed
bacteria into sites of sarcoma could lead to tumor
shrinkage.
• Since that time, exponential advances in the
understanding of the intersection between immune
surveillance and tumor growth and development
have led to broad therapeutic advances that are
now being studied in all cancer types.

TUMOR IMMUNOLOGY
• An efficient and specific cytotoxic immune
response against a tumor requires a complex,
rapidly evolving interaction between various
immune cell types in the adaptive and innate
immune system.
– CD8+ lymphocytes and Th1/Th2 subclasses of CD4+ T
lymphocytes, traditionally referred to as cytotoxic T cells
and helper T cells.
– CD8+ and CD4+ lymphocytes initiate the distinction
between self and non-self-antigens, through recognition
at the "immune synapse."

Immune synapse
• The most widely studied phenomenon in
immunologic surveillance is the ability of T
lymphocytes to distinguish self- versus non-self-
antigens, which are presented by antigen-
presenting cells (APCs) such as dendritic cells.
• Overall, the cytotoxic activity of a CD8+ T cell is
regulated by the presence and spatial orientation of
a set of stimulatory and inhibitory receptors whose
expression is regulated by a myriad of cytokines.
Together, this configuration is often referred to as
the "immune synapse"

• For efficient activation of a naïve CD8+ T cell, its TCR
must bind to a peptide presented by the MHC in the
presence of a second set of costimulatory signals.
• This interaction leads to CD3 intracellular signaling
that causes secretion of pro-inflammatory cytokines
such as IL-12 and IFN gamma.
• In the absence of a costimulatory signal, a state of
peripheral tolerance to the antigen ("anergy")
develops.
• The most important costimulatory signal in naïve T
cells is CD28, which binds to B7-1 and B7-2
(CD80/86) on the APC.

• This costimulatory process is tightly regulated by
both "agonist" molecules (eg, GITR, OX40, ICOS)
and inhibitory signals on both the APC and T cells,
often collectively referred to as "immune
checkpoint" molecules.
• Examples of co-inhibitory or "immune checkpoint"
molecules include cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4), programmed cell
death-1 (PD-1), TIM3, and LAG3.
• Chronic recognition of an antigen (such as that
present in a malignant clone or in a chronic viral
infection) may lead to feedback inhibition of
effector T cell function, resulting in a phenotype
termed "exhaustion"

Tumor evasion of immune
surveillance
• The prevailing theory of the immune system's
influence on neoplastic progression is termed
"cancer immunoediting" which proceeds in three
phases:
• Elimination phase
• Equilibrium phase
• Escape phase
• The elimination phase consists of innate and
adaptive immune responses to specific tumor-
associated antigens and is characterized by T, B, and
NK cell effector function, which is mediated by
cytokines such as IFN alpha, IFN gamma, and IL-12.

• The equilibrium phase is a balance between
immune-mediated destruction by the adaptive
immune system (eg, activated CD4+ and CD8+ T
cells) and persistence of rare malignant clones.
• Immunologic escape describes the phase where
malignant clones have acquired the ability to evade
the adaptive immune system.
• There are several posited mechanisms for escape
from immune surveillance

• 1)Loss or alteration of specific antigens or antigenic
machinery .Tumors can lose major MHC class 1
expression or the intracellular machinery required
to transport tumor antigens to the tumor surface
for T cell recognition.
• 2) Tumors can promote an immune-tolerant
microenvironment by manipulation of cytokines
(increased secretion of IL-6, IL-10, and TGF-beta;
consumption of IL-2) that encourage infiltration of
Treg cells, myeloid derived suppressor cells
(MDSCs), and other cell types that inhibit cytotoxic
T cell function.

• These cells can then actively suppress proliferation
of CD4+ and CD8+ T lymphocytes that would
otherwise recognize tumor antigens.
• 3)Tumors can upregulate the expression of immune
checkpoint molecules such as PD-1 and PD ligand 1
(PD-L1) that promote peripheral T cell exhaustion

Immunotherapy of lung cancer copy

Checkpoint inhibitors
PD-1 and PD ligand 1/2
•Programmed cell death 1 (PD-1) is a transmembrane protein
expressed on T cells, B cells, and NK cells.
•It is an inhibitory molecule that binds to the PD-1 ligand (PD-
L1; also known as B7-H1) and PD-L2 (B7-H2).

• PD-L1 is expressed on the surface of multiple tissue
types, including many tumor cells, as well as
hematopoietic cells
• PD-L2 is more restricted to hematopoietic cells.
• The PD-1:PD-L1/2 interaction:
– directly inhibits apoptosis of the tumor cell
– promotes peripheral T effector cell exhaustion and
– promotes conversion of T effector cells to Treg cells
• Additional cells such as NK cells, monocytes, and
dendritic cells also express PD-1 and/or PD-L1.

• Based upon prolonged overall survival in
phase III trials and durable responses in phase
II studies, antibodies inhibiting PD-1
(pembrolizumab, nivolumab) and PD-L1
(atezolizumab, avelumab, durvalumab) have
been approved for a number of clinical
indications and are being evaluated in
multiple other malignancies

Lung malignancy
• Lung cancer is the most common cancer worldwide
and is still responsible for the most cancer deaths
according to the World Health Organization, more
than double the next two highest cancers of liver
and lower gastrointestinal tract.

Overview of the initial treatment of
advanced non-small cell lung cancer
• Treatment of patients with lung cancer depends upon
the cell type (non-small cell versus small cell), tumor
stage, molecular characteristics, and an assessment of
the patient's overall medical condition.
• Rapid advances in understanding the molecular
pathogenesis of NSCLC have demonstrated that NSCLC
is a heterogeneous group of diseases.
• Although the initial treatment of localized disease is the
same, the molecular characterization of tumor tissue in
patients with NSCLC serves as a guide to treatment
both in those who present with metastatic disease and
in those who relapse after primary therapy.

• Currently defined NSCLC subsets for which specific
targeted therapies have been standard therapy
include those with mutations in the epidermal
growth factor receptor (EGFR) as well as B-Raf
proto-oncogene (BRAF), those with the echinoderm
microtubule-associated protein-like 4 (EML4)-
anaplastic lymphoma kinase (ALK) fusion oncogene,
and c-ROS oncogene 1 (ROS1) fusions.
• Other driver mutations have also been identified
and specific treatments are being developed.

EGFR mutation
• Mutations in the epidermal growth factor receptor
(EGFR) tyrosine kinase are observed in approximately
15 percent of NSCLC adenocarcinomas in the United
States and occur more frequently in nonsmokers.
• In Asian populations, the incidence of EGFR mutations
is substantially higher, up to 62 percent
• In advanced NSCLC, the presence of an EGFR mutation
confers a more favorable prognosis and strongly
predicts for sensitivity to EGFR tyrosine kinase
inhibitors (TKIs) such as erlotinib, gefitinib, afatinib,
and osimertinib, and therefore, targeted therapy
should be used ahead of chemotherapy and
immunotherapy in EGFR-positive NSCLC.

ALK rearrangements
• Rearrangements involving the anaplastic lymphoma
kinase (ALK) tyrosine kinase are present in
approximately 4 percent of NSCLC adenocarcinomas
in the United States and occur more frequently in
nonsmokers and younger patients
• In advanced-stage NSCLC, the presence of
an ALK gene rearrangement (ALK-positive NSCLC)
strongly predicts for sensitivity to ALK TKIs
(eg, crizotinib, ceritinib, alectinib), and treatment
with these agents significantly prolongs
progression-free survival (PFS)

ROS1 rearrangements
• The ROS1 tyrosine kinase is highly sensitive to
the tropomyosin receptor kinase (TRK)/ROS1
inhibitor entrectinib as well as crizotinib, due
to a high degree of homology between
the ALK and ROS tyrosine kinase domains.

BRAF mutation
• Activating BRAF mutations have been observed in 1
to 3 percent of NSCLCs and are usually associated
with a history of smoking.
• For patients with NSCLC with BRAF V600E
mutations who have progressed on chemotherapy,
the combination of dabrafenib plus trametinib is
approved by the FDA.
• BRAF inhibition with single oral small-molecule TKIs
(eg, vemurafenib, dabrafenib) initially appeared to
be an effective strategy in the treatment of
progressive BRAF V600-mutant NSCLC.

• Patients with EGFR-, ALK-, ROS1-, or BRAF-
positive tumors should be treated with the
appropriate front-line targeted therapy.
• However, those with other driver mutations,
like those lacking driver mutations, are
generally treated initially with immunotherapy
and/or chemotherapy.

Management of advanced non-small cell
lung cancer lacking a driver mutation:
Immunotherapy
• More than 80 percent of lung cancers are classified
as non-small cell lung cancer (NSCLC).
• Although targeted therapies have redefined
treatment options for patients with molecularly
defined NSCLC (eg,EGFR-mutant,ALK-rearranged
NSCLC), these therapies are ineffective in those
whose tumors lack such genetic alterations, who
comprise the majority of NSCLC patients.

• However, immunotherapy has become
integrated into the treatment of such patients,
which has led to improvements in survival and
quality of life.

FACTORS IN CHOOSING INITIAL
THERAPY
• Immune checkpoint inhibitors targeting either
programmed cell death protein 1 (PD-1) or
programmed cell death ligand 1 (PD-L1) have
become routinely part of the clinical approach for
management of NSCLC.
• Factors that affect choice of treatment in NSCLC
that lacks a driver mutation include the level of PD-
L1 expression, the extent of disease, and histology.

• Specifically, patients with PD-L1 expression ≥50
percent are typically offered monotherapy with the
anti-PD-1 antibody pembrolizumab, although some
with rapidly progressing or very extensive disease
may be treated with a platinum doublet and
chemotherapy.
• For patients with PD-L1 expression <50 percent, the
combination of a platinum-doublet chemotherapy
and pembrolizumab is standard.
• Although immunotherapy is entering treatment
paradigms for those with driver mutations, we
typically do not integrate it into treatment
strategies until progression has occurred on
available next-generation targeted agents.

• Particular caution should be taken when using
PD-1 or PD-L1 blockade prior to or concurrent
with osimertinib in patients with epidermal
growth factor receptor (EGFR) mutations
because increased risk of pulmonary toxicity
has been reported when these medications
are used together

PD-L1-low (<50 percent expression) or
unknown
• Preferred option: Immunotherapy plus
chemotherapy
• Pembrolizumab has received US Food and Drug
Administration (FDA) approval for the frontline
treatment of metastatic nonsquamous NSCLC in
combination with pemetrexed and carboplatin,
irrespective of programmed cell death ligand 1 (PD-
L1) expression.
• This combination is our preferred treatment option
for those with PD-L1 expression <50 percent or
unknown advanced adenocarcinomas.

Nonsquamous
• Pembrolizumab-based treatment
• Atezolizumab-based treatment

Pembrolizumab-based treatment
• The frontline addition of pembrolizumab (200 mg
intravenous [IV] every three weeks) to platinum-
doublet chemotherapy (platinum agent
and pemetrexed) has improved outcomes relative
to chemotherapy alone in two randomized trials
enrolling patients with advanced, nonsquamous
NSCLC.
• KEYNOTE-189 trial
• KEYNOTE-021 trial

• KEYNOTE-189 trial, 616 patients with advanced, PD-
L1-unselected, nonsquamous NSCLC were
randomized in a 2:1 ratio to chemotherapy
(cisplatin or carboplatin with pemetrexed) with or
without pembrolizumab
• Those receiving chemotherapy alone could receive
pembrolizumab upon progression
• At a median follow-up of 10.5 months, the addition
of pembrolizumab to chemotherapy improved 12-
month overall survival (OS) rates relative to
chemotherapy alone (69 versus 49 percent)

• Twelve-month OS improvements were observed in
all PD-L1 categories, with the greatest numerical
differences observed in PD-L1-expressing tumors:
•<1 percent – 62 versus 52 percent
•1 to 49 percent – 72 versus 51 percent
•≥50 percent – 73 versus 48 percent
• Median progression-free survival (PFS), the other
primary endpoint, was also improved with the
addition of pembrolizumab

• These results confirmed findings of the earlier
phase II KEYNOTE-021 trial, in which 123 patients
were randomized in a 1:1 ratio to chemotherapy
with or without pembrolizumab.
• Results from this study led to initial accelerated
approval of combination therapy
with carboplatin, pemetrexed, and pembrolizumab
for patients with advanced, untreated,
nonsquamous NSCLC without activating epidermal
growth factor receptor (EGFR) or anaplastic
lymphoma kinase (ALK) alterations.

Atezolizumab-based treatment
• is an anti-PD-L1 antibody
• The combination of platinum-based doublet
chemotherapy, bevacizumab, and atezolizumab is a
potential alternative to pembrolizumab and
chemotherapy in patients with nonsquamous
NSCLC, and this regimen now has regulatory
approval for patients without an epidermal growth
factor receptor (EGFR) mutation or anaplastic
lymphoma kinase (ALK) translocation.

• The IMpower 150 trial randomly assigned 1202
patients with PD-L1-unselected, advanced,
nonsquamous NSCLC to first-line chemotherapy
(carboplatin and paclitaxel) combined with
either atezolizumab (ACP), atezolizumab
plus bevacizumab (ABCP), or bevacizumab (BCP)
• Among 692 EGFR/ALK wild-type patients, those
receiving ABCP experienced improved PFS (8.3
versus 6.8 months) and OS (19.2 versus 14.7
months,relative to those receiving BCP.

• The most common grade 3 or 4 treatment-related
adverse events were neutropenia, febrile
neutropenia, and hypertension.
• Rash, stomatitis, febrile neutropenia, and
hemoptysis were higher among those receiving
ABCP than among those in the BCP group by <10
percentage points.
• This regimen has now been FDA approved as a
treatment alternative for driver mutation-negative
patients with advanced, nonsquamous NSCLC.

Squamous
• The addition of frontline pembrolizumab to platinum-
based doublet chemotherapy has also improved
outcomes in squamous cell cancers, without adding
substantial toxicity.
• In the phase III KEYNOTE-407 559 patients with PD-L1-
unselected, treatment-naïve, advanced squamous
NSCLC were randomized in a 1:1 ratio to chemotherapy
(carboplatin with either paclitaxel or nabpaclitaxel)
with either pembrolizumab or placebo. At a median
follow-up of 7.8 months, the addition of
pembrolizumab to chemotherapy improved coprimary
endpoints of OS (15.9 versus 11.3 months and PFS
(median, 6.4 versus 4.8 months)

Alternative: Nivolumab plus
ipilimumab
• Nivolumab plus ipilimumab has demonstrated a
superior survival compared with chemotherapy in
the CheckMate-227 trial, irrespective of PD-L1
expression.
• As such, we consider it a reasonable alternative
to pembrolizumab and chemotherapy for those
with low or unknown PD-L1 expression.

• Less favored options — Although we
prefer pembrolizumab and chemotherapy for
most patients with PD-L1-low tumors (1 to 49
percent), there is also evidence to consider
using pembrolizumab monotherapy as an
alternative in patients with low PD-L1
expression (but not in PD-L1-negative tumors).

• In the ongoing phase III KEYNOTE-042 trial of patients
with treatment-naïve, advanced, EGFR/ALK wild-type
NSCLC and at least 1 percent tumor PD-L1
expression, pembrolizumab monotherapy is being
compared with platinum-doublet chemotherapy,
chosen according to histology.
• At a median follow-up of 12.8 months, results are as
follows. OS, the primary endpoint, was prolonged
among patients receiving pembrolizumab compared
with those receiving chemotherapy as follows,
according to PD-L1 expression:
– ≥50 percent (599 patients), 20 versus 12 months

• Chemotherapy plus pembrolizumab was superior to
chemotherapy in those with intermediate PD-L1
expression in KEYNOTE-189, while pembrolizumab
monotherapy was only equivalent to chemotherapy
in this subgroup in KEYNOTE-042.
• We therefore typically favor the combination of
pembrolizumab and chemotherapy over
pembrolizumab monotherapy for those with PD-L1
expression 1 to 49 percent.
• Still, for patients with intermediate PD-L1
expression who decline chemotherapy,
pembrolizumab monotherapy is an acceptable, but
likely inferior, option compared with
pembrolizumab and chemotherapy.

PD-L1-high (≥50 percent expression)
• Randomized trials have demonstrated that a high
level of programmed cell death ligand 1 (PD-L1)
expression predicts response to the checkpoint
inhibitor pembrolizumab. This level of PD-L1
expression may be seen in approximately 30
percent of advanced NSCLCs.
• Preferred in absence of rapidly progressive disease
• Preferred for rapidly progressive disease

Preferred in absence of rapidly
progressive disease
• Pembrolizumab monotherapy
• Alternative: Nivolumab plus ipilimumab
• — Pembrolizumab is approved by the FDA for the
frontline treatment of patients with
advanced EGFR/ALK wild-type NSCLC whose tumors
have ≥50 percent PD-L1 expression.
• In general, for such patients, we recommend
pembrolizumab monotherapy, although exceptions are
made for those with rapidly progressive disease, in
whom we suggest chemotherapy and pembrolizumab.

• Use of pembrolizumab for patients with PD-L1
expression ≥50 percent is supported by the phase
III KEYNOTE-024 trial
• Although randomized trial data have demonstrated
improved outcomes with chemotherapy
plus pembrolizumab versus chemotherapy alone,
no trial has evaluated chemotherapy plus
pembrolizumab versus pembrolizumab alone.
• Therefore, the question remains regarding whether
patients with high PD-L1 expression would benefit
from the addition of chemotherapy to
pembrolizumab.

• In the absence of direct comparative data, we
generally suggest pembrolizumab monotherapy
over pembrolizumab plus chemotherapy for most
patients with PD-L1-high tumors, given better
tolerability, thus allowing for the option of using a
platinum-based doublet in the second-line setting.

Alternative: Nivolumab plus
ipilimumab
• In a randomized trial of patients with
chemotherapy-naïve NSCLC, among 397 patients
with PD-L1 expression ≥50
percent, nivolumab plus ipilimumab showed an OS
advantage over chemotherapy (median, 21 versus
14 months.

Preferred for rapidly progressive
disease
• Pembrolizumab plus chemotherapy — For patients
with rapidly progressive disease, or such a high
tumor burden that early progression might lead to
functional decline precluding chemotherapy in the
second-line setting, we suggest
concurrent pembrolizumab with chemotherapy. The
approach is analogous to those with PD-L1-low
tumors.

• As such, for those with rapidly progressing disease,
in whom an early response may be beneficial, we
suggest chemoimmunotherapy. For others with PD-
L1-high tumors, we prefer pembrolizumab
monotherapy to avoid the toxicities of concurrent
treatment and to reserve chemotherapy for
subsequent-line treatment.
• Atezolizumab in squamous NSCLC —
Although atezolizumab is an acceptable alternative
to pembrolizumab, when either is used in
combination with chemotherapy for those with PD-
L1-unselected or low nonsquamous tumors, we do
not suggest this combination in squamous tumors.

• Durvalumab and tremelimumab have preliminarily
shown efficacy over chemotherapy among those with
high tumor mutational burden (TMB), though we await
further data prior to routine clinical use of this
combination or of TMB as a biomarker.
• MYSTIC was a phase 3 trial that
evaluated durvalumab and durvalumab plus
tremelimumab versus chemotherapy in patients with
NSCLC. In preliminary results of the study, neither
durvalumab nor durvalumab plus tremelimumab
improved outcomes compared with chemotherapy
• For patients with unresectable, stage III NSCLC whose
disease has not progressed following concurrent
platinum-based chemotherapy and radiation therapy,
durvalumab is approved by the FDA.

FOLLOWING PLATINUM-BASED CHEMOTHERAPY
• Although our preferred approach is incorporation of
immunotherapy into the initial treatment strategy
for most patients, many patients will have been
treated with frontline chemotherapy, given previous
treatment paradigms.
• For such patients, we suggest either an anti-
programmed cell death protein 1 (PD-1) or anti-
programmed cell death ligand 1 (PD-L1) antibody in
the second-line setting, rather than single-agent
chemotherapy.

• Nivolumab or atezolizumab are appropriate
options (regardless of tumor PD-L1 expression). If
tumor PD-L1 has been identified on at least 1
percent of tumor cells (using the Dako 22C3 PD-
L1 assay), pembrolizumab is also an option.
• A choice among these agents depends on
provider familiarity and local practice patterns,
given a lack of data directly comparing these
agents.

TOXICITY OF IMMUNE CHECKPOINT
INHIBITORS

DURATION OF TREATMENT
• In general, we continue treatment with a
programmed cell death protein 1 (PD-1) axis
inhibitor until progression or unacceptable toxicity
occurs, although discontinuation after two years of
treatment may be a reasonable alternative.
• For patients whose initial regimen includes
platinum-based chemotherapy, we continue
chemotherapy typically for four to six cycles.

• This approach is based upon the randomized clinical
trials leading to US Food and Drug Administration
(FDA) approval of PD-1 axis inhibitors in which
respective agents were continued until progression.
• Additional clinical trials evaluating alternatives to
indefinite continuous dosing are needed, based
upon the potential for durable responses to PD-1
axis inhibitors, continuous risk of toxicity, and the
high cost of indefinite therapy.
• However, other preliminary data suggest that
discontinuation of pembrolizumab after two years
may be an appropriate strategy

MANAGING RESISTANCE TO PD-1 AXIS
INHIBITORS
• Data are evolving in regards to management of
resistance to programmed cell death protein 1 (PD-1)
axis inhibitors.
• In general, patients who have progressed on a
checkpoint inhibitor may be offered chemotherapy
upon progression, either with a platinum-based
doublet, if they are chemotherapy naïve, or with single-
agent chemotherapy, if they are not.
• However, if progression occurs several months or years
after the last dose of PD-1 or programmed cell death
ligand 1 (PD-L1) blockade, rechallenge may be
attempted, as some responses have been reported

• Additionally, if progression on a PD-1 axis inhibitor
after initial response is limited to one or two sites
("oligoprogression"), local therapy to the site(s) of
progression (ie, radiation, thermal ablation, or
surgery) with continuation of systemic therapy with
the PD-1 axis inhibitor may represent an alternative
to salvage systemic therapy, recognizing that data
supporting this approach are limited.

SPECIAL CONSIDERATIONS
Limitations in biomarkers
• Although trials have demonstrated that tumor programmed
cell death ligand 1 (PD-L1) expression associates with
increased likelihood of response to checkpoint inhibitors, it
neither guarantees response in those with high tumor PD-L1
expression nor eliminates the possibility of response in those
tumors that lack PD-L1 expression.
• There may be PD-L1 heterogeneity within tumors and
between tumor sites and tumor PD-L1 expression can change
over time in response to therapy.
• Nevertheless, based on the data from KEYNOTE-024 above,
we recommend routine PD-L1 testing in all patients with
newly diagnosed NSCLC to inform use
of pembrolizumab monotherapy in the frontline setting.

Impact of steroids on efficacy of immunotherapy
• Available data, largely from studies of immunotherapy in
melanoma, suggest that corticosteroids for treatment of
immune-related adverse events do not affect efficacy.
• However, some evidence suggests that baseline corticosteroid
use of ≥10 mg prednisone equivalent is associated with
poorer outcomes with immunotherapy.
• It remains unclear if the less favorable outcomes in these
patients are directly related to the immunosuppressive effect
of chronic corticosteroid use versus possibly a reflection of
the unfavorable factors that necessitated use of steroids (eg,
symptomatic brain metastases, weight loss, profound fatigue,
or other factors).
• Although larger confirmatory studies are needed, we advise
that corticosteroids be used sparingly and judiciously at the
time of initiation of immunotherapy unless necessary for
medical treatment (such as brain metastases).

Patterns of response and progression
• The patterns of response to treatment with
immunotherapy agents can differ from those with
molecularly targeted agents or cytotoxic
chemotherapy. For example, patients may have a
transient worsening of radiologic lesions prior to
disease stabilization or regression, though this is an
uncommon presentation, and any evidence of
clinical worsening makes this unlikely to be the
case.

• Additionally, hyperprogressive disease, in which an
acceleration of tumor growth occurs upon initiation of
a given therapy, may occur among patients treated with
immunotherapy, though this concept remains the
subject of some debate even among experts in
immunotherapy.
• If hyperprogressive disease is suspected, for example if
tumor burden doubles or more at the first restaging
scan, prompt recognition and transition to
chemotherapy is warranted.
• In a retrospective study of over 400 previously treated
patients with advanced NSCLC, hyperprogressive
disease, defined as tumor growth rate exceeding 50
percent per month, occurred in 14 percent of those
treated with PD-1/PD-L1 inhibitors and 5 percent of
those treated with single-agent chemotherapy

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