Immunotherapy orchestrates radiotherapy in composing abscopal effects: A strategic review in metastatic head and neck cancer

Abstract

The treatment of metastatic head and neck squamous cell carcinoma (HNSCC) with a combination of radiotherapy (RT) and immunotherapy can augment treatment response and symptomatic relief. Combination therapy can also trigger a non-targeted tumor control event called the abscopal effect. This effect can be demonstrated by treatment with anti- programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti- cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies in combination with hypofractionated RT. Individual studies and clinical trials have revealed that combination radio-immunotherapy improves overall treatment response by successful initiation of the abscopal effect, which extends the treatment effects to non-targeted lesions. Growing attention to the abscopal effect may inspire innovations in current radiotherapy toward more effective and less toxic radiobiological treatment modalities for advanced HNSCC. We review the latest findings on the abscopal effect with emphases on therapeutic modalities and potential applications for treating metastatic HNSCC.

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*Address correspondence: Dr. Liang-Ting Lin, Department of Health Technology
and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong
SAR, China. E-mail: lt.lin@polyu.edu.hk (L.-T. Lin).
Conflicts of interest: The authors declare that they have no conflicts of interest
related to the subject matter or materials discussed in this article.
Journal of Chinese Medical Association. (2020) 83: 113-116.
Received October 24, 2019; accepted October 25, 2019.
doi: 10.1097/JCMA.0000000000000234.
Copyright © 2019, the Chinese Medical Association. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/)
Immunotherapy orchestrates radiotherapy in
composing abscopal effects: A strategic review in
metastatic head and neck cancer
Mohammady Akbora, Kai-Feng Hungb,c, Yi-Ping Yangb,d, Shih-Jie Choud,e, Ping-Hsing Tsaib,e,
Chian-Shiu Chienb,e, Liang-Ting Lina,*
aDepartment of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China;
bDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; cDepartment of Dentistry, School of
Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC; dSchool of Pharmaceutical Sciences, National Yang-Ming University,
Taipei, Taiwan, ROC; eInstitute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC
1. HEAD AND NECK SQUAMOUS CELL CARCINOMA
EPIDEMIOLOGY AND CLINICAL FEATURES
Head and neck squamous cell carcinoma (HNSCC) is the sixth
most common malignancy. Among 630,000 patients diag-
nosed with HNSCC each year, >350,000 die.1 HNSCC is the
third most common cause of cancer death and the fth leading
cause of overall mortality worldwide.2 HNSCC is more com-
mon in males than in females, and the incidence rate is esti-
mated at 20 per 100,000 people in the regions of Central and
Eastern Europe, Spain, Italy, France, Hong Kong, the Indian
subcontinent and Brazil, and among African Americans in the
United States.3 Tobacco use, betel leaf and nut chewing, alcohol
consumption, poor oral hygiene, and ultraviolet radiation are
widely considered to be risk factors of HNSCC.2 The human
papilloma virus, Epstein-Barr virus, and p53 malfunction are
also associated with HNSCC occurrence.4,5 Notably, autopsy
data show that distant metastasis is found in up to 46.7% of
HNSCC patients.6 Lungs, bones, mediastinal lymph nodes,
brain, liver, skin, and peritoneum are common metastatic sites,
among which the lungs are the most common.6,7
Clinically, radiotherapy (RT), surgical resection, chemother-
apy, and targeted therapy are treatment approaches for HNSCC.
RT was considered the primary treatment in the rst half of the
last century due to limited availability of antibiotics and anesthe-
sia. As availability of these increased, surgery and chemotherapy
became preferred rst-line treatments due to the adverse effects
and poor outcomes of RT.8 The introduction of intensity-mod-
ulated RT and image-guided RT helped to improve response
rates and reduce toxicity. Recently, immune checkpoint tar-
geted therapy became an effective treatment choice.8 Advanced
laryngohypopharyngeal squamous cell carcinoma, a type of
HNSCC, was routinely treated by surgery with adjuvant RT in
past decades;9,10 however, this had the potential to cause serious
impairment of laryngeal function, which compromised patients’
quality of life and led to social isolation.11–13 RT combined with
chemotherapy and immunotherapy is therefore considered an
attractive method for treating HNSCC patients with advanced
and/or unresectable tumors.14
2. RADIATION THERAPY AND THE ABSCOPAL
EFFECT IN CANCER THERAPY
The therapeutic effect of RT is mediated not only by direct
energy deposition to the exposed target but also by the so-called
abscopal effect wherein distal lesions respond to the local treat-
ment. The specic pathway of the abscopal effect is still under
debate despite documentation of a similar RT-driven bystander
effect associated with cytokines, immunogenic signals, and
extracellular vesicles.15,16 Putative mechanisms that involve
Abstract: The treatment of metastatic head and neck squamous cell carcinoma (HNSCC) with a combination of radiother-
apy (RT) and immunotherapy can augment treatment response and symptomatic relief. Combination therapy can also trigger a
non-targeted tumor control event called the abscopal effect. This effect can be demonstrated by treatment with anti-programmed
death 1/programmed death ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte–associated antigen 4 antibodies in combination with
hypofractionated RT. Individual studies and clinical trials have revealed that combination radio-immunotherapy improves overall
treatment response by successful initiation of the abscopal effect, which extends the treatment effects to non-targeted lesions.
Growing attention to the abscopal effect may inspire innovations in current RT toward more effective and less toxic radiobiological
treatment modalities for advanced HNSCC. We review the latest findings on the abscopal effect with emphases on therapeutic
modalities and potential applications for treating metastatic HNSCC.
Keywords: Abscopal effect; Checkpoint inhibitor; Head and neck cancer; Immunotherapy; Radiotherapy
<zdoi: 10.1097/JCMA.0000000000000234>

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Akbor et al. J Chin Med Assoc
cytokines, the immune system, and pseudo-abscopal effects have
been described.17 Faguet et al18 reported that clastogenic factors
are secreted from the irradiated cells and subsequently cause
chromosomal destruction to the unirradiated cells. This tumor-
suppressing effect has been shown to last in irradiated animals
for up to 10 weeks. Asur et al19 revealed that tumor necrosis fac-
tor alpha, ceramide, and tumour necrosis factor-related apopto-
sis-inducing ligand are induced by RT and are associated with
apoptosis in the epithelial and endothelial portions of the cancer
microenvironment. Peters et al20 suggested that the use of high-
dose spatially fractionated radiotherapy (GRID) may contribute
to both bystander and abscopal effects. Similar outcomes shown
by Kanagavelu et al21 indicated that lattice RT led to absco-
pal effects in syngenic Lewis Lung Carcinoma animal models.
Indeed, GRID is effective in the treatment of advanced massive
tumors.22 Lattice RT translates GRID therapy into advanced 3D
conformational RT with the help of modern radiation oncol-
ogy instruments.23 To date, the mechanism of communication
between primary and metastatic lesions remains unknown, but
it is generally agreed that the immunogenic effect of radiation
exposure is the primary component.24
3. THE ROLE OF PALLIATIVE RADIOTHERAPY IN
METASTATIC HNSCC
RT is the usual adjuvant modality for curative and palliative
treatment of metastatic HNSCC (mHNSCC).25 An accumulating
number of studies reveal that although the prognosis of mHN-
SCC is poor, some patients benet from prolonged disease-free
survival after RT to either the metastatic site or the primary
lesion.26 RT has thus been increasingly applied to patients with
mHNSCC in recent years,27 with a variety of available treatment
regimens (Table1).
Generally, the prescription for stage III or IV HNSCC is 70 Gy
in 35 fractions for curative treatment; however, a range of 20–30
Gy in ve fractions is often used for palliative cases. Mohanti et
al28 recommended a total dose of 20 Gy in ve fractions, resulting
in average outcomes of 37% tumor response and symptom relief
between 47% and 59%. A split course was introduced by Stevens
et al, which was composed of two cycles of 25 Gy in 10 fractions,
reaching a total of 50 Gy. The tumor response and symptom relief
were apparently enhanced to 82% and 85%, respectively.29 Corry
et al circulated the outcomes of the “Quad Shot regimen,” which
comprised three courses of bis in die (BID, meaning twice a day),
giving 3.7 Gy per fraction for two successive days to achieve a
total of 44.4 Gy in 12 fractions. The Quad Shot regimen contrib-
uted to clinical outcomes of 50%–70% tumor response and 80%
symptom relief.30 Porceddu et al25 described a regimen of 30–36
Gy in ve to six twice-weekly fractions, where an overall response
of 80% and symptom response of 62% were achieved. Agarwal
et al31 described an intensive palliative RT regimen delivering 40
Gy in 16 fractions, which demonstrated a treatment response rate
of 73% and symptom relief of 75%. Case reports in palliative
care therefore show that a higher total dose with a hypofraction-
ated dosing regimen may produce favorable outcomes in terms of
overall response and symptom relief.
4. COMBINED RADIO-IMMUNOTHERAPY IS
ESSENTIAL FOR THE ABSCOPAL EFFECT
The abscopal effect is a desired but rare event in radiation oncol-
ogy.32 Checkpoint inhibitory target therapy and the abscopal
effect return to focus with the combination of anti-programmed
death 1 (PD-1), anti-programmed death ligand 1 (PD-L1), and
anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)
treatments. Ipilimumab (a CTLA-4 checkpoint inhibitor) and
Nivolumab (a PD-1 checkpoint inhibitor) have been shown to
have complementary functions in the treatment of metastatic
melanoma.33 Ipilimumab is effective for cancer patients with
overexpression of antitumor immunity molecules and has been
identied as the primary agent contributing to overall survival
(OS) in metastatic melanoma patients.34,35 Nivolumab has been
approved as a second-line therapy for mHNSCC by the Food
and Drug Administration.36 Anti-PD-1/PD-L1 monotherapy
is associated with greater clinical benet in tumors expressing
PD-L1. The addition of anti-CTLA-4 therapy has the potential
to enhance antitumor activity of anti-PD-1/PD-L1 agents in
both PD-L1 positive and PD-L1 negative tumors.37
Radiotherapy plays a role in the recruitment of T cells in the
tumor microenvironment,38 secretion of cytokines, enhanced
tumor antigen presentation,39,40 and increased expression of
PD-L1 in irradiated tumors.41 Induction of the abscopal effect
has been published in both pre-clinical and clinical data.41–43 In
animal experiments, concurrent RT and anti-CTLA-4 antibody
therapy can successfully induce the abscopal effect.44,45 In addi-
tion, PD-1 blockade after completion of RT has been reported to
initiate elimination of retained tumors.41 Dual checkpoint block-
ade (anti-CTLA-4 and anti-PD-L1) in combination with RT has
Table 1
Palliative radiotherapy prescriptions and outcomes for metastatic HNSCC
Study RT regimen Outcomes
Mohanti et al28 20 Gy as 4 Gy per day for 5 days ORR: 37%, SR: 47%–59%
Stevens et al29 50 Gy as 25 Gy per cycle for 2 cycles, 2.5 Gy per fraction ORR: 82%, SR: 85%
Corry et al30 44.4 Gy BID as 3.7 Gy per fraction for 2 days per course for 3 courses ORR: 50%–70%, SR: 80%
Porceddu et al25 30–36 Gy as 6 Gy per fraction twice weekly for 3 weeks ORR: 80%, SR: 62%
Agarwal et al31 40 Gy as 2.5 Gy per fraction for 3 weeks ORR: 73%, SR: 75%
ORR= Overall response rate; PS= Patient satisfaction; SR= Symptom relief; Gy= Gray; BID= twice a day
Table 2
The reported cases of combined radio-immunotherapy triggering the abscopal effect
Study Radiotherapy Immunotherapy
Shinde et al50 QUAD SHOT, 3.7 Gy BID for 2 days (total 14.8 Gy), with 2 additional courses in 1-month
intervals, reaching 44.4 Gy
Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies
Bahig et al51 Patients received 3 to 5 SBRT fractions, with 15 Gy in 1 to 5 fractions Durvalumab (1500 mg IV every 4 weeks) and
tremelimumab (75 mg IV for a total of 4 doses)

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Review Article. (2020) 83:2 J Chin Med Assoc
also been shown to stimulate immune mechanisms.46 Abscopal
effects are increasingly being documented, particularly in the
context of the combination of immune checkpoint blockade and
radiation.47–49
A case report by Shinde et al showed that the abscopal effect
in HNSCC can be triggered when RT is combined with ipili-
mumab (anti-CTLA-4 monoclonal antibody). A regimen of
ipilimumab and nivolumab administered concurrently every 3
weeks for four cycles, however, resulted in negative outcomes.
An RT regimen, “QUAD SHOT” for palliation was then given
with 3.7 Gy BID for 2 days (total dose 14.8 Gy) to the pri-
mary site and 3.3Gy BID for 2 days (total dose 13.2 Gy) to
the microscopic areas at high risk for disease. No radiation was
given to the lung, which was the secondary metastatic site of
HNSCC. Two weeks after irradiation, the primary lesion and
bulk left neck adenopathy had decreased by about 25%, and
the metastatic pulmonary nodule had decreased by about 50%.
The QUAD SHOT regimen was repeated two more times at one-
month intervals, and nally the patient was cured.50 Notably,
the same QUAD SHOT dosage did not reect any sign of the
abscopal effect in the absence of ipilimumab administration.22
Following the same strategy, Bahig et al initiated combined
radio-immunotherapy to investigate its anticancer effects. Up to
15 Gy per fraction was given by stereotactic body radiotherapy
(SBRT), accompanied by the systemic infusion of durvalumab
and tremelimumab. Rather than demonstrating direct evidence of
the abscopal effect, the OS and progression-free survival partially
supported the point-of-view that the local SBRT may work syn-
ergistically with systemic anti-PD-L1 administration51 (Table2).
5. DISCUSSION
The abscopal effect is described as the regression of metastatic
tumor mass at a distant location from the radiation site. RT
regimens delivered with higher total doses and hypofractiona-
tion show no evidence of the abscopal effect despite benets in
tumor control and symptom relief. Monotherapy using mono-
clonal antibodies is sometimes unable to control tumor growth,
whereas combining it with RT leads to the non-targeted effect.
Remarkably, immunotherapy with anti-PD-1/PD-L1 and anti-
CTLA-4 antibodies in combination with RT shows enhance-
ment of the abscopal effect in several tumor-bearing animal
models for colon and colorectal cancers, mammary adenocarci-
noma, and melanoma.41,45,46,52,53
There is concern that the abscopal effect from radio-immu-
notherapy is actually a consequence of systemic administration
of monoclonal antibodies. Accumulating evidence indicates that
plenty of immunogenic markers are released after local RT, but
few studies identify possible mediators involved in the com-
munication between primary and metastatic lesions. Growing
interest in extracellular vesicle-mediated biological effects will
potentially draw more attention from researchers, but very lim-
ited information is available thus far. We believe that further
investigation of radio-immunotherapy as well as the abscopal
effect may improve clinical outcomes for patients.
ACKNOWLEDGMENTS
This study was funded by the Shenzhen Basic Research Funding
Scheme (JCYJ20170818103614207), Science and Technology
Innovation Commission of Shenzhen Municipality, China.
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