Cancer Treatment Reviews 90 (2020) 102088

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevier.com/locate/ctrv

Immunotherapy in cervix cancer T

a b,c a a
Laura Attademo , Valentina Tuninetti , Carmela Pisano , Sabrina Chiara Cecere ,
Marilena Di Napolia, Rosa Tambaroa, Giorgio Valabregab,c, Lucia Musacchiod,
Sergio Venanzio Setolae, Patrizia Piccirilloa, Daniela Califanof, Anna Spinaf, Simona Lositog,
⁎
Stefano Greggih, Sandro Pignataa,
a
Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
b
Candiolo Cancer Institute, FPO-IRCCS Candiolo (TO), Italy
c
Department of Oncology, University of Torino, Italy
d
Department of Maternal and Child Health and Urological Sciences, University “Sapienza”, Policlinico Umberto I, Rome, Italy
e
Radiology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
f
Functional Genomic Unit, Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
g
Surgical Pathology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
h
Gynecologic Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy

A R T I C LE I N FO A B S T R A C T

Keywords: The treatment approach to cervix cancer has remained unchanged for several decades and new therapeutic
Cervix cancer strategies are now required to improve outcomes, as the prognosis is still poor. In the last years, a better un-
Immunotherapy derstanding of HPV tumor–host immune system interactions and the development of new therapeutics targeting
Immune checkpoint inhibitor immune checkpoints generated interest in the use of immunotherapy in cervix cancer. Preliminary phase I–II
HPV
trials demonstrated the efficacy, the duration of responses and the manageable safety of this approach.
Currently, many phase II and III studies are ongoing in both locally advanced and metastatic cervical cancer,
assessing immunotherapy as a single agent or in combination with chemotherapy and radiotherapy. We re-
viewed the published data and the therapeutic implications of the most promising novel immunotherapeutic
agents under investigation in cervix cancer.

Introduction
Incidence and mortality of cervical cancer in developed countries
have both decreased since the introduction of Pap test and screening
campaigns in the 1940s, thanks to an earlier diagnosis [1]. Never-
theless, cervical cancer is still one of the most common malignancies in
the female population worldwide, with higher risk for socioeconomic
disadvantaged groups, and a poor prognosis for advanced disease
[2–4].
Currently, treatment of cervical carcinoma depends on the staging
of the disease. Briefly, according to the International Federation of
Gynecology and Obstetrics (FIGO) staging, treatment of cancers con-
fined to the uterus is based on surgery (from conization to hyster-
ectomy), while concurrent radiotherapy/chemotherapy is considered
the standard of care for locally advanced cancer. Nonetheless, a 20%
recurrence rate is still reported in locally advanced disease treated by
chemo-radiation [5].
A platinum–paclitaxel combination chemotherapy, with the pos-
sible addition of bevacizumab, is considered the treatment of choice for
metastatic disease, but it has only a palliation intent. With this ap-
proach, a 16.8-month median survival is obtained [6–9]. So, new
strategies are needed for both locally advanced and metastatic cervical
cancer.
Human papillomaviruses (HPVs) have been recognized since the
1980 s the main causative agents of the disease and of its precursor
lesions, although concurrent factors may change the risk of progression
[10–16]. Recently, it has been observed that patients with increased
high-risk HPVs viral load tend to be resistant to therapy and to induce a

⁎
Corresponding author at: Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Via Semmola 80131, Naples, Italy.
E-mail addresses: l.attademo@istitutotumori.na.it (L. Attademo), valentina.tuninetti@ircc.it (V. Tuninetti), c.pisano@istitutotumori.na.it (C. Pisano),
s.cecere@istitutotmori.na.it (S.C. Cecere), m.dinapoli@istitutotumori.na.it (M. Di Napoli), r.tambaro@istitutotumori.na.it (R. Tambaro),
giorgio.valabrega@ircc.it (G. Valabrega), lucia.musacchio@uniroma1.it (L. Musacchio), s.setola@istitutotumori.na.it (S.V. Setola),
p.piccirillo@istitutotumori.na.it (P. Piccirillo), d.califano@istitutotumori.na.it (D. Califano), a.spina@istitutotumori.na.it (A. Spina),
s.losito@istitutotumori.na.it (S. Losito), s.greggi@istitutotumori.na.it (S. Greggi), s.pignata@istitutotumori.na.it (S. Pignata).

https://doi.org/10.1016/j.ctrv.2020.102088
Received 16 April 2020; Received in revised form 29 July 2020; Accepted 31 July 2020
0305-7372/ © 2020 Published by Elsevier Ltd.
L. Attademo, et al.
decreased surveillance in the immune microenvironment [17]. In fact,
high-risk HPVs integrate into the DNA of the host disrupting the se-
quence of genome products involved in the regulation of HPV replica-
tion. Such a modification enhances the accumulation of genetic changes
leading to immune escape, which may result in a resistance to the
therapy and to the progression of the malignancy [18].
In the last years, a better understanding of HPV tumor–host immune
system interactions, mainly related to cell-mediated immunity directed
to elimination of viral-infected cells, and the development of new
therapeutics targeting immune checkpoints generated interest in the
use of immunotherapy in advanced cervical cancer [19,20]. This ap-
proach is promising and may represent an effective novelty in an area
where therapy has remained unchanged for several decades.
This review reports available evidence on the use of immunotherapy
for cervical cancer, presenting the rationale of this approach and fo-
cusing on clinical data, both from published and ongoing trials.
Methods
For this review of the literature, a non-systematic search was per-
formed in PubMed using the following keywords to retrieve preclinical
data: ‘immune environment’,’ tumor -infiltrating lymphocytes/macro-
phages’, ‘PD-1/PD-L1 expression’, ‘tumor -infiltrating CD4/CD8′. A
search in PubMed with the keywords ‘ipilimumab’, ‘avelumab’, ‘pem-
brolizumab’, ‘atezolizumab’, ‘nivolumab’, ‘durvalumab’, and ‘cemi-
plimab’ was performed to retrieve published clinical trials. Articles in
English or with English abstracts were retrieved. All clinical trials were
read and reviewed, while preclinical evidence was chosen based on the
Authors’ evaluation of relevance. The search concluded in February
2020, and included all articles present in PubMed, without temporal
limits. ClinicalTrial.gov was searched in February 2020 for ongoing
trials that used ipilimumab, avelumab, pembrolizumab, atezolizumab,
nivolumab, durvalumab, cemiplimab and AGEN2034.
Rationale for the immunotherapy of cervical cancer
Based on the HPV-DNA classification 15 HPV subtypes are classified
as high-risk (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and
82) [21]. High-risk HPV subtypes develop distinct strategies for epi-
thelial persistence, permitting malignant progression, related to dif-
ferent virus protein functions, as well as patterns of viral gene expres-
sion, with genotype-specific associations. In the high-risk HPVs,
changes in E6 and E7 expression are thought to account for the de-
velopment of pre-neoplastic and neoplastic lesions [17,22]. In advanced
lesions, HPV is integrated into the host genome; this leads to the in-
activation of E2, an early protein that regulates expression of E6 and E7.
E6 and E7 are the major transforming proteins of HPV, and their dys-
regulated expression allows, over the decades required to develop
malignancy, the accumulation of a variety of genetic changes that fa-
cilitate tumor cell survival and immune escape [23]. In addition, it
appears that cellular environment and the site of infection affect viral
pathogenicity by modulating viral gene expression [24].
The majority of immune-competent individuals infected with HPV,
independently from the mechanisms adopted by the virus to avoid
detection by the host immune system, are eventually able to clear in-
fections. Therefore, although persistent infection is the greatest risk
factor for the development of HPV-related cancers, progression to
cancer requires more than just HPV infection and persistence [25].
The knowledge of the association of HPV infection, im-
munosuppression, and increased risk of cervical cancer lead to the
hypothesis that the use of drugs targeting the immune system may have
an important role in this disease [26].
Distinct alterations in infiltrating lymphocyte subsets have been
found in cervical cancer, and the CD4+/CD8+ cell ratio has been as-
sociated with clinicopathological and prognostic parameters, con-
firming the major role of immunity [27].
2
Cancer Treatment Reviews 90 (2020) 102088
The role of the tumor immune environment in cervical HPV-asso-
ciated lesions has been widely investigated, and checkpoints have been
identified as possible targets for cervical cancer treatment [26,28–35].
Increased CTLA-4 expression and reduced CD28 expression (this
latter one is a protein expressed on T cells that provide co-stimulatory
signals required for T-cell activation and survival) were found in per-
ipheral blood mononuclear cells from patients with advanced cervical
cancer, suggesting a shift of the immune response toward tolerance
[32].
In addition, the proportion of PD-1 expressing CD8+ T cells was
found to be higher in the tumor tissue of HPV-associated cancers than in
the peripheral blood, confirming the hypothesis that the tumor en-
vironment induces PD-1 expression in infiltrating T cells [30].
Clinical evidence for immunotherapy in cervical cancer
The development of immunotherapy and checkpoint inhibition in
cervical cancer is still in the early phase, although promising results
have been published, encouraging further research [36–39].
The human antibody against CTLA-4, ipilimumab (Bristol-Myers
Squibb, Princeton, NJ, USA), the humanized antibody against PD-1
pembrolizumab (Merck & Co. Inc., Whitehouse Station, NJ, USA) as
well the human anti-PD-1 nivolumab (Bristol-Myers Squibb) are ap-
proved for use in several cancers and are the most investigated drugs in
cervical cancer. Multiple clinical trials have been planned and con-
ducted to incorporate these therapeutic agents into treatment regimens
against HPV-associated cancers, and some studies provided results that
prompted approval of the tested products as monotherapy for cervical
cancer.
Published clinical trials
Published clinical trials in cervical cancer are summarized in
Table 1. The safety and antitumor activity of ipilimumab in recurrent or
metastatic cervical cancer were investigated in a phase II multicenter
trial [36]. Eligible patients had measurable disease and a confirmed
progression after prior platinum chemotherapy. A total of 42 patients
were enrolled, of which 29 with squamous cell cervical cancer, and 13
with adenocarcinoma. Positivity for HPV was confirmed in cancer tis-
sues available from 40 patients. Best response (according to the Re-
sponse Evaluation Criteria in Solid Tumours [RECIST] version 1.1) was
partial response in one patient and stable disease in ten subjects out of
34 evaluable ones. A median progression-free survival (PFS) of
2.5 months (95% CI: 2.1–3.2 months) and an overall survival (OS) of
8.5 months (95% CI: 3.6–not reached) were obtained. Treatment was
tolerable, with grade 3 diarrhea in four patients (three had colitis) and
modifications on the immune pathway (an increase of inducible T-cell
co-stimulator, human leukocyte antigen-antigen D related [HLA-DR],
and PD-1) that returned to baseline during maintenance [36].
KEYNOTE-028 and KEYNOTE-158 trials evaluated pembrolizumab
at the dose of 10 mg/kg and 200 mg every 3 weeks, respectively, in
recurrent, metastatic cervical cancer, demonstrating an antitumor ac-
tivity [37,38].
KEYNOTE-028 was a multicenter phase Ib single-arm trial in-
vestigating the safety and efficacy of pembrolizumab in 20 different PD-
L1-positive advanced solid tumors and one cohort included patients
with advanced cervical carcinoma with the squamous histotype [37].
Patients with locally advanced or metastatic, PD-L1-positive cervical
cancer, who progressed after a prior therapy, were candidate to receive
pembrolizumab 10 mg/kg every 2 weeks, for up to 24 months. The
primary endpoint was overall response rate (ORR), and secondary
endpoints included safety, tolerability, PFS, OS, and duration of re-
sponse (DOR). Of 46 screened patients, 24 were enrolled (median age:
42 years). All patients discontinued treatment during the study, four
(17%) because of adverse event (AEs), one (4%) because of his/her
physician’s decision, and 19 (79%) because of progression. ORR was
L. Attademo, et al. Cancer Treatment Reviews 90 (2020) 102088

17% (95% CI: 5–37%); four patients (17%) had partial response, and

IIA with-positive para-aortic lymph nodes only

Locally advanced cervical cancer stage IB2/

and stage IIB/IIIB/IVA with positive lymph

three patients (13%) had stable disease. Median DOR was 5.4 months
(range: 4.1–7.5 months). Treatment-related AEs were experienced by

HPV: human papilloma virus; PD-L1: programmed death ligand 1; DOR: duration of response, G3: grade 3; G4: grade 4; PR: partial response; CR: complete response; CC: cervical cancer; VC: vaginal cancer.
Lipase increase (G3), dermatitis (G3)
18 patients (75%) and five patients experienced grade 3 treatment-re-
lated AEs [37].
The phase II KEYNOTE-158 trial showed an antitumor activity of
pembrolizumab in previously treated advanced cervical cancer and
supported the accelerated approval of pembrolizumab in this setting by
Mayadev et al. [41]

the FDA. Indeed, pembrolizumab was approved for patients with re-
current or metastatic cervical cancer with disease progression on or
Ipilimumab

50 (26–61)

after chemotherapy whose tumors express PD-L1 (Combined Positive

Score [CPS] ≥ 1) as determined by an FDA-approved test in June 2018.
nodes
29

−
−
−
−
The trial was a basket study enrolling multiple cancer types, with
I

one cohort including 98 patients with advanced cervical cancer 94% of

(G3-4), hepatocellular injury (G3-

vulvar or vaginal cancers, HPV+

which were squamous cell carcinoma, 5% adenocarcinoma and 1%

Recurrent or metastatic cervical,

Diarrhea (G3-G4), Pneumonitis

adenosquamous, with progressive disease or intolerance to one or more
lines of prior therapy [38]. Prior treatment for recurrent or metastatic
21.9 (15.1–not reached)

disease had been used in 77/98 subjects and 64 (65%) of the patients
CheckMate 358 [39]

Not reached (range:

23.3–29.5 months)

had already received at least two previous lines of treatment. Pem-

24 (19 CC, 5 VC)

brolizumab 200 mg every 3 weeks was administered for up to

5.1 (1.9–9.1)
51 (28–75)
Nivolumab

24 months. The primary endpoint was ORR, assessed as RECIST version

1.1, and secondary endpoints included safety. Median age of patients
26.3

was 46.0 years (range: 24–75 years). Tumor positivity for PDL-1 was
I/II

CR

4)

assessed in 82 (83.7%) patients. ORR was 12.2% (95% CI: 6.5–20.4%)

Not reached (range: ≥3.7 to ≥ 18.6 months)

hepatitis (G4), severe skin reaction (G4), and

in the whole cohort and 14.6% (95% CI: 7.8%–24.2%) in PD-L1-posi-

tive patients, compared to 0.0% in PD-L1-negative patients; three
intolerance to one or more line of prior
Advanced cervical cancer with PD or

Increased alanine transaminase (G4),

complete and nine partial responses were obtained, all in patients with
PD-L1-positive tumors. Activity of pembrolizumab was found to be
KEYNOTE-158 (Cohort E) [38]

durable: median DOR was not reached (range: ≥3.7

to ≥ 18.6 months), with response in seven patients
adrenal insufficiency (G4)

lasting ≥ 12 months at time of analysis. Median PFS was 2.1 months

(95% CI, 2.0–2.2 and 2.1–2.3) in both the entire population and the PD-
Pembrolizumab

L1-positive population, respectively. Median OS was 9.4 months (95%

46 (24–75)

CI, 7.7–13.1) in the total population and 11 months (95% CI, 9.1–14.1)
therapy

in the PD-L1-positive patients. Safety was considered manageable by

12.2

researchers: treatment-related AEs occurred in 65.3% of patients, and

2.1

9.4

CR
98
II

the most common ones were hypothyroidism (10.2%), decreased ap-

Maculopapular rash (G3), colitis (G3),

petite (9.2%), and fatigue (9.2%). Treatment-related grade 3–4 AEs

histotype) after failure prior systemic
Advanced cervical cancer (squamous

5.4 months (range: 4.1–7.5 months)

occurred in 12.2% of patients, but only four patients (4.1%) dis-

continued the treatment due to adverse events Grade 4 events included
Guillain Barrè syndrome (G3)

increased alanine transaminase, hepatitis, severe skin reaction, and

adrenal insufficiency [38].
KEYNOTE-028 [37]

Safety and efficacy of nivolumab monotherapy in recurrent or me-

therapy, PD-L1+

tastatic cervical carcinoma were evaluated in CheckMate 358

Pembrolizumab

(ClinicalTrials.gov identifier: NCT02488759), a phase I/II basket trial

42 (26–62)

11 (4–15)

[39]. Patients known to have HPV-negative tumors were ineligible, but

2 (2–3)

subjects with unknown state were included. The primary endpoint was
* Response Evaluation Criteria in Solid Tumours, version 1.1
PR
Ib

24

17

ORR, while DOR, PFS and OS were secondary end points, and safety
and patient-reported outcomes were exploratory endpoints. Patients
Metastatic or recurrent cervical cancer
(HPV + ) with progression after prior

received nivolumab 240 mg every 2 weeks for up to 24 months. A total

of 19 patients with cervical squamous cell carcinoma were enrolled,
with median age 51 years (range: 28–75). Prior systemic therapy for
Diarrhea (G3), colitis (G3)

metastatic disease had been used in 78.9% of cases and 21% were
platinum chemotherapy

8.5 (3.6–not reached)

chemo-naïve for metastatic disease. 63% of the patients were positive

Lheureux et al. [36]

for PD-L1 expression. ORR was 26.3% (95% CI: 9.1–51.2) despite the
PD-L1 expression. At a median follow-up of 19.2 months, five responses
2.5 (2.1–3.2)
Ipilimumab

49 (23–78)

were obtained, and median DOR was not reached (range: 23.3–29.5
censored observation). Median OS was 21.9 months (95%
8.8
PR
42

CI:15.1 months to not reached). Any-grade treatment-related AEs were

Published clinical trials.

–
I

reported in 12 of 19 patients (63.2%) with one patient (5.3%) dis-

Main G3–4 toxicities
OS (95% CI); months
Patients enrolled (n)
Median age (range);

continuing treatment after grade 3 pneumonitis. Patient-reported out-

PFS months (95%

comes associated with health status and health-related quality of life

Best response*

(QoL) were generally stabilized [39].

years

ORR (%)

An interim analysis of this trial regarding the combination of ni-

CI)
Setting
Table 1

Phase
Drug

DOR

volumab and ipilimumab in two different settings (nivolumab 3 mg/kg

every 2 weeks + ipilimumab 1 mg/kg every 6 weeks (Combo A arm) or

3
L. Attademo, et al.
nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for four
doses followed by nivolumab 240 mg every 2 weeks (Combo B arm) in
patients with recurrent or metastatic cervical carcinoma with or
without prior systemic therapies, was presented at the European Society
for Medical Oncology (ESMO) 2019 conference [40]. In this analysis,
median follow-up was 10.7 months for Combo A (n = 45) and
13.9 months for Combo B (n = 46). A higher ORR was found in Combo
B vs Combo A regardless the previous therapy (46% vs 32% and 36% vs
23% without and with prior systemic therapy, respectively). Overall,
the trial suggests a benefit from two regimens in patients with recurrent
or metastatic cervical cancer regardless of PD-L1 status.
A phase I trial (NCT01711515) investigated whether the treatment
with ipilimumab after chemoradiotherapy was tolerable and effective
for lymph node-positive locally advanced cervical cancer. The 21 pa-
tients who received ipilimumab completed at least two cycles of
treatments (18 [86%] of them completed 4 cycles and 3 [14%] com-
pleted 2 cycles) and the maximum tolerated dose was 10 mg/kg. The
good outcome in term of toxicity, with two patients (9.5%) showing
toxic effects (lipase increase and dermatitis) suggests the possible ap-
plication of such therapy after chemoradiotherapy [41].
AGEN2034 is a fully human immunoglobulin (IgG)-4 monoclonal
antibody targeting PD-1. In a Phase I/II trial, AGEN 2034, safety and
activity were assessed with escalating dose of the drug in advanced
solid malignancies and in a Phase II expansion cohort in subjects with
relapsed/refractory cervical cancer. In total, 30 cancer patients were
enrolled at dose cohorts of 1, 3, and 10 mg/kg. 21 of 30 patients had
treatment-related AEs (TRAEs). Three partial responses (two con-
firmed) were noted in patients with cervical, ovarian and breast cancers
in the 1 and 3 mg/kg cohorts [42].
Ongoing trials
Main ongoing trials with checkpoint inhibitors for the treatment of
cervical cancer, as of February 2020, are reported in Tables 2 and 3.
These studies are evaluating ipilimumab, atezolizumab, pem-
brolizumab, avelumab, nivolumab, durvalumab, cemiplimab, dos-
tarlimab and AGEN2034, alone or in combination with radiotherapy or
chemotherapy. Out of 31 trials, locally advanced tumors are included in
13 studies, while metastatic, persistent and recurrent tumors are stu-
died in 21 trials.
Locally advanced cervical cancer
New treatment strategies are needed for advanced cervical cancer as
patients receiving currently available therapy have a poor prognosis;
locally advanced cervical cancer has a high recurrence rate. Some phase
I/II studies are investigating checkpoint inhibitors in combination with
chemo-radiotherapy. Preclinical and preliminary clinical observations
provide a strong rationale for testing radiotherapy and cisplatin in
combination with immune checkpoint inhibitors. Several effects of
radiotherapy may have a role in this synergism. Radiotherapy modifies
the tumor cell phenotype and the tumor microenvironment, with local
and systemic immunomodulating effects, which may maximize anti-
tumor responses in combination with immunotherapy [43,44]. Ther-
apeutic radiation doses, as well as some cytotoxic agents, induce im-
munogenic cell death and the release of tumor antigens that can
effectively prime antigen-presenting cells [45]. Radiotherapy and che-
motherapy have been found to decrease immunosuppression in the
tumor microenvironment by inducing the release of cytokines and
promoting T-cell chemotaxis [46]. In addition, radiotherapy may in-
crease the tumor-infiltrating lymphocytes number and broaden their T-
cell receptor repertoire of cytotoxic effectors cells [47,48]. Finally,
radiotherapy increases the expression of PD-L1 on tumor cells [49]. The
phenomenon of immunogenic cell death induced by some chemother-
apeutics, is the scientific basis for the combined approach of che-
motherapy with immunotherapy. Preclinical and clinical studies
4
Cancer Treatment Reviews 90 (2020) 102088
showed that cytotoxic agents have immunomodulatory effects, with the
potential of modifying the tumor microenvironment and activating
multiple pathways related to innate and adaptive immune response
[50]. Macrophages maturation and differentiation, Natural killer cell
proliferation, increased levels of Toll-like receptor 4 and enhanced ex-
pression of major histocompatibility complex I (MHC-I) on tumor sur-
face are immune stimulatory signals observed during chemotherapy
[50].
A phase I clinical trial assessing the optimal sequencing of atezoli-
zumab and standard chemoradiotherapy in patients with locally ad-
vanced cervical cancer that has spread to the lymph nodes is currently
not recruiting and on interim monitoring (NCT03738228) [51]. Ate-
zolizumab was given 21 days before the start of chemoradiotherapy,
then on day 0 and 21 in one arm, and on day 0, 21 and 42 in the second
arm. The primary outcome was the different activation of the immune
system measured as clonal expansion of T-cell receptor beta in per-
ipheral blood on day 21. Secondary outcomes were toxicity, T-cell re-
ceptor clonality, diversity, and frequency in peripheral blood and tissue
PD-L1 expression level in tissues.
A phase II trial with nivolumab (NCT03527264) and one with
pembrolizumab (NCT02635360) are enrolling patients undergoing
radiotherapy with concurrent cisplatin. BrUOG 355 (NCT03527264)
has three different arms, all using radiotherapy and cisplatin, but each
arm evaluating the addition of nivolumab at different time points. In
cohort 1, nivolumab is administered during chemo-radiation with ex-
tended field; in cohort 2, as maintenance after chemo-radiation; and in
cohort 3, nivolumab is used both during chemo-radiation and as
maintenance. The primary endpoints are acute treatment-related toxi-
cities and PFS.
NCT02635360 is assessing safety and effectiveness of 200 mg in-
travenous pembrolizumab every 21 days for 3 months, during or after
concurrent chemotherapy and radiotherapy in locally advanced cer-
vical cancer. Primary outcome measures are change in immunologic
markers and the identification of the DLTs.
The MITO CERV-3 (NCT04238988) is a single-arm multicenter
phase II trial evaluating pembrolizumab in combination with carbo-
platin/paclitaxel chemotherapy in locally advanced cervical cancer.
Patients receive 3 cycles of neoadjuvant carboplatin-paclitaxel (carbo-
platin with target AUC = 5 + paclitaxel 175 mg/
m2) + pembrolizumab (200 mg intravenous [IV]) every 21 days. After
3 cycles of neo-adjuvant platinum-based chemotherapy, patients who
do not progress undergo radical surgery. After surgery, patients pre-
senting with high-risk factors will receive 3 cycles of adjuvant carbo-
platin-paclitaxel chemotherapy + pembrolizumab in combination, and
maintenance with pembrolizumab 200 mg every 3 weeks until pro-
gression or unacceptable toxicity or patient consent withdrawal for up
to 35 cycles. The primary endpoint is 2-year PFS.
ATEZOLACC (NCT03612791) is a phase II trial assessing the benefit
of atezolizumab, administered concomitantly with chemoradiotherapy,
and continued as adjuvant therapy, in comparison with the standard
chemoradiotherapy, in locally advanced cervical cancer.
Atezolizumab is administered at 1200 mg every 3 weeks, starting
1 week before chemoradiotherapy and continued as an adjuvant for a
maximum of 20 cycles. The primary outcome is PFS.
ATOMICC, a randomized, open label phase II trial, is designed to
test the use of the checkpoint inhibitor dostarlimab as consolidation
treatment following concurrent chemoradiation therapy in locally ad-
vanced cervical cancer, compared to no other further treatment.
Dostarlimab 500 mg is given every 3 weeks for four doses and then at
1000 mg every 6 weeks up to 24 months and the primary outcome
measure will be PFS.
Some checkpoint inhibitors are under evaluation in phase III trials.
KEYNOTE-A18/ENGOT-cx11 (NCT04221945), a randomized, double-
blind, placebo-controlled study, is designed to evaluate the efficacy and
safety of pembrolizumab with concurrent chemoradiotherapy followed
by pembrolizumab in locally advanced cervical cancer. The efficacy
 L. Attademo, et al.

Table 2
Ongoing trials in locally advanced cervical cancer.
Phase Description Drug Primary endpoint Status Trial Identifier

I Chemoradiation Therapy and Ipilimumab in Treating Patients with Stages IB2/IIA With Positive Para-Aortic Lymph Nodes Ipilimumab MTD, LTD, AE Active, not recruiting NCT01711515
Only and Stage IIB/IIIB/IVA With Positive Lymph Nodes Cervical Cancer
I Atezolizumab Before and/or With Chemoradiotherapy in Immune System Activation in Patients With Node Positive Stage Atezolizumab TCRB clonal expansion in Suspended (Scheduled Interim NCT03738228
IB2, II, IIIB, or IVA Cervical Cancer peripheral blood Monitoring)
I/II A Multi-Center, Open-label Phase Ib-II Trial of the Combination of GX-188E Vaccination and Pembrolizumab in Patients Pembrolizumab DLT/ORR Recruiting NCT03444376
with Advanced, Non-Resectable HPV-Positive Cervical Cancer
I/II A Phase-I Study of Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Nivolumab DLT Recruiting NCT03298893
Cancers Followed by Adjuvant Nivolumab for up to 6 Months. NiCOL
II Trial Assessing the Inhibitor of Programmed Cell Death Ligand (PD-L1) Immune Checkpoint Atezolizumab (ATEZOLACC) Atezolizumab PFS Recruiting NCT03612791
II Study Evaluating the Interest to Combine UCPVax a CD4 TH1-inducer Cancer Vaccine and Atezolizumab for the Treatment Atezolizumab ORR Active, not recruiting NCT03946358
of Human PapillomaVirus Positive Cacncers
II Carboplatin-Paclitaxel-Pembrolizumab in Neoadjuvant Treatment of Locally Advanced Cervical cancer (MITO CERV 3) Pembrolizumab PFS Active, not recruiting NCT04238988

5
II Trial Assessing the Inhibitor of Programmed Cell Death Ligand 1 (PD-L1) Immune Checkpoint Atezolizumab Atezolizumab PFS Recruiting NCT03612791
II A Randomized Study of Chemoradiation and Pembrolizumab for Locally Advanced Cancer Pembrolizumab DLT Recruiting NCT02635360
II The LATENT Trial: Lytic Activation To Enhance Neoantigen-directed Therapy A Study to Evaluate the Feasibility and Avelumab ORR Recruiting NCT03357757
Efficacy of the Combined Use of Avelumab With Valproic Acid for the Treatment of Virus-associated Cancer
II BrUOG 355: A Pilot Feasibility Study Incorporating Nivolumab to Tailored Radiation Therapy With Concomitant Cisplatin in Nivolumab PFS, AE Recruiting NCT03527264
the Treatment of Patients With Cervical Cancer
II A Randomized, Open Label, Phase II Trial of Anti-PD1, TSR-042, as Maintenance Therapy for Patients With High-risk Locally Dostarlimab PFS Recruiting NCT03833479
Advanced Cervical Cancer After Chemo-radiation (ATOMICC)
III A Phase III, Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab in Durvalumab PFS Recruiting NCT03830866
Combination With and Following Chemoradiotherapy Compared to Chemoradiotherapy Alone for Treatment in Women
With Locally Advanced Cervical Cancer
III A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or Without Pembrolizumab for the Treatment of Pembrolizumab PFS, OS Not yet recruiting NCT04221945
High-risk, Locally Advanced Cervical Cancer (KEYNOTE-A18 / ENGOT-cx11)

LA: locally advanced; MTD: maximum tolerated dose; DLT: dose-limiting toxicities; AE: adverse events; M: metastatic; R: recurrent; HPV: human papilloma virus; ORR: overall response rate; PFS: progression-free survival;
OS: overall survival; TCRB: T-cell receptor beta, BOR: best overall response.
Cancer Treatment Reviews 90 (2020) 102088
 L. Attademo, et al.

Table 3
Ongoing trials in metastatic/recurrent cervical cancer.
Phase Description Drug Primary Endpoint Status Trial Identifier

I Study of Durvalumab, Tremelimumab and Radiotherapy in Recurrent Gynecologic Cancer Durvalumab MTD Recruiting NCT03277482
I Multi-Center Study of Stereotactic Ablative Radiotherapy (SABR) in Combination With Durvalumab and Tremelimumab in Durvalumab Safety and Recruiting NCT03452332
Patients With Recurrent/Metastatic Advanced Cervical, Vaginal, or Vulvar Cancer tollerability
I Open-label, Dose-Escalation Trial for MSB0011359C (M7824) with consecutive parallel-group expansion in selected solid tumor MSB0011359C (M7824), Safety and Active, not NCT02517398
indications, testing safety and tolerability bintrafusp alfa tollerability recruiting
I/II Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Subjects With Metastatic or Locally AGEN2034 DLT, MTD, BOR Recruiting NCT03104699
Advanced Solid Tumors, With Expansion to Second-Line Cervical Cancer
II A Phase II Evaluation of Nivolumab, a Fully Human Antibody Against PD-1, in the Treatment of Persistent or Recurrent Cervical Nivolumab ORR, AE Active, not NCT02257528
Cancer recruiting
II A Two-arm, Randomized, Non-comparative Trial of AGEN2034 (Anti-PD-1) as a Monotherapy or Combination Therapy With AGEN2034 ORR Recruiting NCT03894215
AGEN1884 (Anti-CTLA4) or With Placebo in Women With
II The LATENT Trial: Lytic Activation To Enhance Neoantigen-directed Therapy A Study to Evaluate the Feasibility and Efficacy of Avelumab ORR Recruiting NCT03357757
the Combined Use of Avelumab With Valproic Acid for the Treatment of Virus-associated Cancer
II Single Arm Study of Combination Pembrolizumab, Chemotherapy and Bevacizumab in Patients With Recurrent, Persistent, or Pembrolizumab ORR Recruiting NCT03367871
Metastatic Cervical Cancer
II Cabozantinib plus Pembrolizumab for Recurrent, Persistent and/or Metastatic Cervical Cancer Pembrolizumab PFS Not yet recruiting NCT04230954
II Investigation of Pembrolizumab in Combination With Radiation and an Immune Modulatory Cocktail in Patients Pembrolizumab ORR Recruiting NCT03192059
With Cervical and Uterine Cancer (PRIMMO Trial)

6
II A Randomized, Intra-patient Crossover, Safety, Biomarker and Anti-Tumor Activity Assessment of the Combination Atezolizumab AE Active, not NCT03073525
of Atezolizumab and Vigil in Patients With Advanced Gynecological Cancers recruiting
II Basket trial Phase II study to evaluate the antitumor activity of RO6874281 in combination with atezolizumab in participants Atezolizumab ORR Recruiting NCT03386721
with advanced and/or metastatic solid tumors
II Atezolizumab and Bevacizumab in Treating Patients With Recurrent, Persistent, or Metastatic Cervical Cancer Atezolizumab ORR Active, not NCT02921269
recruiting
II Prospective Randomized Phase II Trial Comparing Doxorubicin Alone Versus Atezolizumab Alone Versus Doxorubicin Atezolizumab PFS Recruiting NCT03340376
and Atezolizumab in Recurrent Cervical Cancer
II Study of Stereotactic Body Radiation Therapy and Atezolizumab in the Management of Recurrent, Persistent, or Atezolizumab ORR Recruiting NCT03614949
Metastatic Cervical Cancer
II Study of Ipilimumab in Women With Metastatic or Recurrent HPV-Related Cervical Carcinoma of Either Squamous Cell or Ipilimumab ORR, AE Active, not NCT01693783
Adenocarcinoma Histologies recruiting
III Randomized, Double-Blind, Placebo-Controlled Trial of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Chemotherapy Pembrolizumab PFS, OS Recruiting NCT03635567
Plus Placebo for the First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer (KEYNOTE-826)
III An Open-Label, Randomized, Phase 3 Clinical Trial of REGN2810 Versus Investigator's Choice of Chemotherapy in Recurrent or Cemiplimab OS Recruiting NCT03257267
Metastatic Cervical Carcinoma
III A Randomized Trial of Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and Atezolizumab Versus Platinum Atezolizumab, OS Recruiting NCT03556839
Chemotherapy Plus Paclitaxel and Bevacizumab in Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the Cervix
N/A Avelumab With Axitinib in Persistent or Recurrent Cervical Cancer After Platinum-based Chemotherapy - a Proof-of-concept Avelumab ORR Recruiting NCT03826589
Study (ALARICE Study)

LA: locally advanced; MTD: maximum tolerated dose; DLT: dose-limiting toxicities; AE: adverse events; M: metastatic; R: recurrent; HPV: human papilloma virus; ORR: overall response rate; PFS: progression free survival;
OS: overall survival; TCRB: T cell receptor beta, BOR: best overall response.
Cancer Treatment Reviews 90 (2020) 102088
L. Attademo, et al.
endpoints are PFS and OS. Patients in the experimental arm will receive
IV pembrolizumab 200 mg every 3 weeks for five cycles with standard
of care chemo-radiotherapy regimen, followed by IV pembrolizumab
400 mg every 6 weeks, for additional 15 cycles.
CALLA (NCT03830866), a randomized, multicenter, double-blind,
placebo-controlled, phase III study, has the purpose to assess the effi-
cacy and safety of durvalumab in addition to standard of care chemo-
radiotherapy versus chemo-radiotherapy alone, in patients with locally
advanced cervical cancer. Women will be randomized in a 1:1 ratio to
receive either concurrent durvalumab + standard of care or pla-
cebo + standard of care, followed by durvalumab or placebo main-
tenance for 24 months. The primary endpoint is PFS.
The latter three trials (ATOMICC, KEYNOTE-A18/ENGOT-cx11 and
CALLA) enroll patients with squamous cell carcinoma, adenocarci-
noma, or adenosquamous carcinoma of the cervix and positive nodes.
Patients included in the ATOMICC trial must have received chemor-
adiotherapy with at least four doses of weekly cisplatin and have
completed the chemoradiotherapy 12 weeks before the enrollment. On
the other hand, the KEYNOTE-A18/ENGOT-cx11 and CALLA studies
enroll patients that have not received either prior radiation or chemo
systemic therapy for cervical cancer, highlighting the aim of defining
the efficacy of immunotherapy as support to standard first-line care.
Metastatic and recurrent cervical cancer
Recurrent or metastatic cervical cancers have an estimated OS ap-
proximately of 1 year, with only one-third of responding patients.
Recent evidence supports a potential benefit of immunotherapy for
cervical cancer, either as monotherapy or in combination with che-
motherapy or radiation.
Several trials are ongoing to evaluate the benefit of immunotherapy
also in this setting. Here, we report the current studies according to the
trial phase.
The tolerability of durvalumab is under investigation in two Phase I
trials. NCT03277482 is the first study in which the combination of
durvalumab, tremelimumab and abdominal or pelvic radiation is used
in humans. This Phase I trial will evaluate if the combination with
radiotherapy will improve the response to immunotherapy.
NCT03452332 is assessing stereotactic body radiation therapy (SBRT)
in combination with durvalumab and tremelimumab in recurrent and
metastatic gynecological cancers, including cervical cancer. Patients
will receive IV tremelimumab followed by IV durvalumab on day 1 of
each cycle. Participants will also undergo stereotactic body radiation
therapy on days 8, 10, and 12 of cycle 1. Treatment with tremelimumab
is repeated every 4 weeks for up to four cycles, and treatment with
durvalumab every 4 weeks for up to eight cycles in the absence of
disease progression or unacceptable toxicity. Both studies are now re-
cruiting.
Another immunotherapy option involves the double targeting of
TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII antibody
[52]. The use of a bifunctional antibody targeting both PD-L1 and TGF-
β aims to an efficient checkpoint inhibition and a simultaneous reg-
ulation of the immunosuppressive role of the tumor microenvironment.
The microenvironment surrounding the tumor is in fact populated by
different entities such as cytokines and growth factors that participate
to tumor progression. TGF-β is one of the players involved in cell
proliferation, angiogenesis and motility and may also suppress the host
antitumor immune response. The M7824 antibody (bintrafusp alfa) is
and IgG1 targeting PD-L1 fused with two TGF-β receptor II molecules
designed to ‘trap’ TGF-β in the tumor microenvironment, thus owing
double immunosuppressive action. Preliminary results from a phase I
study (NCT02517398) involving the use of bintrafusp alfa in patients
with metastatic or locally advanced solid tumors, for which no standard
effective therapy exists or standard therapy has failed, reported a good
safety profile and indication for efficacy as showed by one ongoing
confirmed complete response in a patient with cervical cancer [53].
7
Cancer Treatment Reviews 90 (2020) 102088
AGEN2034, an anti-PD-1 monoclonal antibody, is under study in a
Phase I/II clinical trial (NCT03104699). Patients with recurrent, un-
resectable or metastatic cervical cancer that has progressed after a
platinum-based treatment regimen, will receive AGEN2034 3 mg/kg
every 2 weeks for a maximum of 2 years or until confirmed progression
or unacceptable toxicity. As monotherapy, nivolumab is investigated in
persistent, recurrent or metastatic cervical cancer in study
NCT02257528. This phase II clinical trial is enrolling patients to receive
IV nivolumab over approximately 60 min every 2 weeks for a maximum
of 46 doses over 92 weeks in the absence of disease progression or
unacceptable toxicity. ORR and incidence of AEs are the primary end-
points.
AGEN2034 in combination with AGEN1885 (an anti-CTLA4) vs
AGEN2034/placebo is studied in a randomized, blinded, phase II,
clinical trial (NCT03894215), in recurrent, persistent or metastatic
cervical cancer patients who have progressed following first-line
therapy. The endpoint is ORR. Preliminary results presented at
European Society for Medical Oncology (ESMO) 2018 conference
showed a well toleration of the combined dose of AGEN1884 (1 mg/kg
every 6 weeks) + AGEN2034 (3 mg/kg every2 weeks) [54].
The phase II LATEN study (NCT03357757) is evaluating the feasi-
bility and the efficacy of avelumab in combination with valproic acid in
HPV-related cervical cancer. Patients receive valproic acid 12.5 mg/kg
once per day and avelumab 10 mg/kg IV every 2 weeks for up to
2 years.
A phase II clinical trial (NCT01693783) is investigating the role of
ipilimumab in 42 patients with recurrent or metastatic HPV-related
cervical cancer, 35 (83%) of whom had received prior radiotherapy,
and 21 (50%) had received 2 or 3 prior chemotherapy regimens.
Patients received ipilimumab IV over 90 min, every 3 weeks for 4 cy-
cles, in the absence of disease progression or unacceptable toxicity.
Patients achieving objective response or stable disease continue to re-
ceive maintenance therapy (ipilimumab IV every 12 weeks for four
courses in the absence of disease progression or unacceptable toxicity).
Results from this study showed that although ipilimumab was tolerable
in this population, with diarrhea being the main grade 3 toxic effect,
experienced by 33% of the patients, there was no significant response
induced by this agent in patients’ tumors, maybe due to the lack of
access to the tumor of activated immune cells. Out of the 34 evaluable
patients there was 1 PR (squamous cell carcinoma); 10 stable disease
(six squamous cell carcinoma and four adenocarcinoma); and 23 pro-
gressive disease. Median PFS was 2.5 months (95% CI, 2.1–3.2 months),
and the median OS was 8.5 months (95% CI, 3.6, upper limit not
reached). The main limitation of the study was the absence of a control
arm [36].
NCT03340376, an open-label, multicenter, randomized phase II
trial will evaluate the safety and efficacy of atezolizumab in patients
with recurrent cervical cancer in second-line therapy. Patients will be
randomized into three arms: group A will receive atezolizumab
1200 mg IV monotherapy every 21 days until progression of disease;
group B atezolizumab 1200 mg IV in combination with doxorubicin
75 mg/m2 every 3 weeks for a total of 6 cycles or until progression; and
group C will be treated with doxorubicin 75 mg/m2 alone for 6 cycles or
until progression. The primary endpoint is PFS and the secondary
endpoint is OS.
Promising results come from the adoptive cell transfer using auto-
logous tumor-infiltrating lymphocytes (TIL) treatment.
A current open-label, multicenter phase II clinical trial
(NCT03108495) is evaluating the efficacy and safety of such therapy in
patients with recurrent, metastatic, or persistent cervical carcinoma.
TIL are harvested from patient’s tumor and re-infused after a lympho-
depletion with cyclophosphamide and fludarabine. After a single au-
tologous TIL infusion, up to six doses of IL-2 (600,000 IU/kg) are given
to the patient. Preliminary data show a 44% ORR with disease control
rate of 89% at 3.5-month median study follow-up with 11/12 patients
maintaining their response [55].
L. Attademo, et al.
Platinum Chemotherapy Plus Paclitaxel With Bevacizumab and
Atezolizumab in Metastatic Carcinoma of the Cervix (NCT03556839) is
a randomized, open label, phase III trial assessing the effect of atezo-
lizumab in combination with bevacizumab and cisplatin/paclitaxel
chemotherapy on OS in metastatic (IVB stage), persistent or recurrent
cervical cancer. The use of bevacizumab is mandatory in this trial in
contrast to the KEYNOTE-826 study (discussed further in the text).
Patients in the experimental arm will receive cisplatin 50 mg/
m2 + paclitaxel 175 mg/m2 + bevacizumab 15 mg/kg + atezolizumab
1200 mg IV every 21 days. Women with a complete response after ≥ 6
treatment cycles will be able to continue maintenance therapy with
bevacizumab plus atezolizumab, upon investigator opinion. The study
is currently recruiting, and the estimated enrolled patients are 404.
The efficacy of pembrolizumab is being evaluated in phase III trials.
KEYNOTE-826 (NCT03635567) is a phase III, randomized, double-
blind, placebo-controlled study with the purpose to evaluate the effi-
cacy and safety of pembrolizumab plus platinum-based chemotherapy
for first-line treatment of persistent, recurrent or metastatic cervical
cancer compared to placebo in combination with platinum-based che-
motherapy regimen. In the experimental arm, on day 1 of each 21-day
cycle, patients will receive an IV infusion of pembrolizumab 200 mg
plus investigator choice of chemotherapy (paclitaxel 175 mg/m2 plus
cisplatin 50 mg/m2 with or without bevacizumab 15 mg/kg or pacli-
taxel 175 mg/m2 plus carboplatin [target AUC = 5], with or without
bevacizumab 15 mg/kg). Treatment is administered until disease pro-
gression or toxicity, for up to 35 cycles (approximately 2 years). The
primary endpoints of this study are PFS per RECIST 1.1 and OS.
Secondary endpoints are objective response, DOR, 12-month PFS, pa-
tient-reported quality of life, and safety. The trial has completed the
accrual.
Cemiplimab is an anti-PD-1 monoclonal antibody under investiga-
tion in NCT03257267 trial. This open-label, randomized, phase III
clinical study is evaluating the efficacy of IV cemiplimab every 21 days
in comparison with physician’s choice chemotherapy (topotecan,
gemcitabine, vinorelbine), in recurrent, persistent, and/or metastatic or
platinum-refractory cervical cancer patients, for which there is not a
curative-intent option (surgery or radiation therapy with or without
chemotherapy). The primary outcome is OS.
Finally, avelumab is studied in combination with axitinib, a tyrosine
kinase inhibitor that also inhibits VEGF receptor, c-KIT and PDGFR
(NCT03826589), or with valproic acid (NCT03357757). The ALARICE
study (NCT03826589) is a proof-of-concept study, with the purpose to
assess the efficacy and safety of avelumab with axitinib in patients with
persistent or recurrent cervical cancer following platinum-based che-
motherapy. The study hypothesis is that the combination of these drugs
could significantly improve the ORR with acceptable toxicity compared
with traditional chemotherapy
Discussion
In the last decades, a better understanding of the interactions be-
tween the HPV infection and the host immune system response has
focused the interest on the use of immunotherapeutic drugs in cervical
cancer patients. Initial clinical trials were designed based on some
cervical cancer features related to a possible immunotherapy effec-
tiveness, such as a high tumor mutational burden, the expression of
oncoproteins E6 and E7 and the presence of CD4 and CD8 lymphocytic
infiltrate [36,38,39,56,57]. Elevated expression levels of PD-1 on T cells
and PD-L1 on monocytes in peripheral blood of cervical and CIN pa-
tients were positively associated with tumor stages reflecting the se-
verity of cancer [58].
In tissue samples from cervical intraepithelial neoplasia (CIN), in-
creased PD-L1 and PD-1 expression were correlated with HPV-posi-
tivity, increasing CIN grade, and tumor metastasis. Furthermore, up-
regulation of the PD-1/PD-L1 pathway was associated with decreased
expression of interferon-γ [33]. Finally, recurrent copy number gain of
8
Cancer Treatment Reviews 90 (2020) 102088
the genes encoding the PD-1 ligands was found in a subset of cervical
and vulvar squamous cell cancers suggesting a genetic basis for PD-L1
expression; these genetic changes were also suggested as possible
markers to identify candidate patients for therapies targeting PD-1
[35]. Amplification or gain of PD-L1 was found in 28 of 129 (22%)
cases in the database of The Cancer Genome Atlas (TCGA) for cervical
squamous cervical cancers [34].
Two studies reported that PD-1 was expressed in the tumor stroma
of cervical cancer in 60% (59/97) and in 47% (31/66) of the patients,
respectively [59,60]. While expression of PD-L1 in normal cervical
tissues was rarely found, several studies demonstrated positivity in
cervical carcinoma tissues with an incidence between 34 and 96%
[60–64]. PD-L1-positive immune cells were also reported in tumor-
draining lymph nodes [65]. In a cervical squamous cervical cancers
sample series, expression rates of PD-L1 were 59.1% on cancer cells and
47.0% on tumor-infiltrating lymphocytes [60].
An analysis by histology type reported that PD-L1 expression is
observed in 80% of squamous cervical cancers, suggesting that this
histotype could potentially benefit from immunotherapeutic approach
than the adenocarcinoma [66].
Based on these early results, pembrolizumab as a single agent was
investigated and then approved in 2018 by the FDA for use in patients
with recurrent or metastatic cervical cancer with disease progression
after chemotherapy, and tumor expression of PD-L1 (CPS ≥ 1) as de-
termined by an FDA-approved test. The drug is not approved in Europe.
In the metastatic setting, different immune check point inhibitors
are under evaluation as single agents or in combination with che-
motherapy or other molecularly target drugs. In particular, preclinical
and clinical studies showed that cytotoxic agents have im-
munomodulatory effects, with the potential of modifying the tumor
microenvironment and activating multiple pathways related to innate
and adaptive immune response [50]. Macrophages maturation and
differentiation, Natural Killer cell proliferation, increased levels of Toll-
like receptor 4 and enhanced expression of major histocompatibility
complex I (MHC-I) on tumor surface are immune stimulatory signals
observed during chemotherapy [50].
In the locally advanced setting, radiation therapy in combination
with immunotherapy is being evaluated as an attractive option in gy-
necologic cancers, as both immunomodulatory and abscopal effects
have been observed [67,68]. Two phase III clinical trials, on main-
tenance treatment with pembrolizumab and durvalumab added to
chemo-radiation are enrolling high-risk locally advanced patients
(FIGO 2014 stage IB2–IIB with node-positive disease) and all FIGO
stage III–IVA (either node-positive or node-negative disease) patients.
An important change of the standard of care could be expected if the
hypothesis of these trials was confirmed.
Evidence on monotherapy with other immunotherapeutic agents is
still limited, but preliminary encouraging data prompted the initiation
of phase III trials, which will better define the role of immunotherapy in
the setting of locally advanced and metastatic disease. In addition, the
translational part of such trials is investigating biomarkers identifying
patients with high probability of response or of early recurrence, which
would reduce useless or unwanted use of immunotherapy.
As an example of this field of research, an integrative analysis of
copy number alterations (CNA) and gene expression data from TCGA
cervical cancer was conducted to identify dysregulated genes triggered
by CNAs. The authors observed a strong association between five driver
genes (PI3KCA, PI3KCB, DVL3, WWTR1 and ERBB2) and immune cell
infiltration, suggesting their involvement in regulating immune re-
sponse [69,70].
In conclusion, immunotherapy will probably play an important role
in the future treatment of locoregional, recurrent or metastatic cervical
cancer provided that ongoing research will confirm the encouraging
results demonstrated in earlier studies. Finally, identification of pre-
dictive biomarkers will be an important goal both in locally advanced
and metastatic disease.
L. Attademo, et al.
Acknowledgements
Editorial assistance was provided by Laura Brogelli, MD, Barbara
Bartolini, PhD, and Aashni Shah, of Polistudium srl (Milan, Italy); this
assistance was supported by internal funds.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Conflicts of Interest
SP declares honoraria from AZ, MSD, Pfizer, Roche, Clovis, GSK,
Incyte. GV declares honoraria from AZ, MSD, Amgen, Roche, Clovis,
GSK. SCC, CP declare honoraria from AZ, Tesaro, Roche, Pharmamar.
MDN declares honoraria from Tesaro, MSD; LA, VT, RT, LM, DC, AS,
PP,SVS ,SL and SG have no conflicts of interest to declare.
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