NcXHF

ECONOMOPOULOU, BOURHIS, AND PSYRRI
outcome in terms of locoregional control, PFS, and overall
survival (OS). 7 One study demonstrated that genomic analysis
in R/M HNSCC enables an assessment of the molecular
profıle in 38% of patients and might guide targeted treatment
selection. 8 Preclinical data support the combination of HPV
vaccines with anti-programmed cell death protein 1 (anti-
PD-1)–blocking antibodies to enhance the response to immunotherapy.
9 Finally, a large cohort study indicated that
the current TNM (turmor, node metastasis) staging system is
not suitable for HPV-associated HNSCC. 10
KEY POINTS
In vivo preclinical data suggest that HPV vaccination could
act as an immune-stimulating agent resulting in
improvement of response rates of HPV-positive
oropharyngeal cancers to anti-PD-1 checkpoint inhibitor.
A better-designed staging system of HPV-positive
carcinoma that also encompasses prognostic factors such
as age and tobacco use could alter treatment of these
patients.
A reduction in the overall treatment time of postoperative
radiotherapy in patients with head and neck squamous cell
carcinoma (HNSCC) with adverse factors for locoregional
failure does not improve outcomes in terms of locoregional
control, progression-free survival, and overall survival.
LUX-Head and Neck 1 clinical trials comparing the efficacy
of afatinib as monotherapy compared to single-agent
methotrexate as second-line treatment in HNSCC met its
primary endpoint showing an increase in progression-free
survival of 0.9 months with afatinib compared to
methotrexate, but in practical terms this modest effect is
of unknown clinical importance.
An individual patient data network meta-analysis of the
treatment of nonmetastatic nasopharyngeal carcinoma
suggests that incorporating induction chemotherapy or
adjuvant chemotherapy to chemoradiotherapy may further
improve the outcome in terms of tumor control probability
and survival over chemoradiotherapy alone.
HPV-ASSOCIATED OROPHARYNGEAL CANCERS
Therapeutic HPV Vaccine Increases Sensitivity of
Poorly Immunogenic Tumor to Anti-PD-1 Monotherapy
The immune system plays an important role in cancer development,
because tumor cells have the ability to evade immunosurveillance
through a variety of different mechanisms,
including reduced expression of tumor antigens, secretion of
immunosuppressive cytokines such as transforming growth
factor (TGF) beta, recruitment of immunosuppressive cells
such as regulatory T cells (Tregs), and overexpression of certain
ligands, such as programmed cell death ligand 1 (PD-
L1). 11 PD-L1 binds to the PD-1 receptor and activates the
PD-1 checkpoint pathway, which blocks the immune response
by downregulating T-cell effector functions. 12 Several
lines of evidence underscore the crucial role of an intact immune
system in controlling HPV infection and its associated
lesions. First, most healthy individuals infected with HPV are
capable of clearing the infection, and they do not develop
clinical manifestations. 13,14 Only a minority of infected individuals
is not capable of clearing the virus and subsequently
develops HPV-associated lesions. Second, immune cell infıltrates
frequently are found in HPV-associated regressing lesions,
whereas these cell types are absent in persistent
lesions. 15 Finally, immunocompromized individuals, such as
HIV-infected people, have documented higher rates of HPV
infection and associated lesions. 16 Because the immune system
plays a pivotal role in controlling HPV infection, therapeutic
vaccine strategies have been developed. Therapeutic
vaccines are aimed to treat HPV-infected cells, and this can
be accomplished by inducing a cellular T-cell immune response
that can recognize and eliminate these HPV-infected
cells. 17
HPV16 E6 and E7 proteins are ideal targets for cancer immunotherapy.
HPV16 E6 and E7 are foreign viral proteins
and are more immunogenic than a self-protein overexpressed
in cancer cells. Furthermore, they are continuously
expressed by all virus-infected cells. 18 Thus, DNA vaccines,
viral vector vaccines, bacterial vector vaccines, peptide vaccines,
and cell-based vaccines are attractive targets for investigation.
DNA vaccines are promising candidates for
therapeutic HPV vaccination in HPV-associated oropharyngeal
carcinoma (OSCC). 19 Strategies to increase the activity
of vaccines include using alternative administration routes,
eliminating the immunosuppressive tumor microenviroment,
and combining the vaccine with chemotherapy. In patients
with HPV-associated oropharyngeal cancers, a high
frequency of Tregs that inhibit cellular immune response often
are found in tumor biopsies. 20 In addition, Lyford-Pike et
al 21 demonstrated that the PD-1/PD-L1 pathway is involved
in immune resistance of HPV-associated HNSCC. 21 PD-1
antibodies that inhibit the interaction between PD-1 and
PD-L1 currently are being evaluated in clinical trials in a variety
of cancers, leading to renewed enthusiasm for immunotherapy
as a treatment modality. Pembrolizumab and
nivolumab have been approved recently for the treatment of
metastatic malignant melanoma. 22,23 The clinical response to
anti-PD-1 antibodies has correlated with PD-L1 expression
and with the presence of tumor-infıltrating lymphocytes in
several tumors, including HNSCC. 24 Furthermore, novel
anti-PD-L1 antibodies also are being evaluated in clinical trials
in HNSCC. In this setting, Pai et al 9 suggested that a possible
strategy to enhance responses to immune checkpoint
blockade might be attenuation of immune responses to the
host tumor by combining the HPV vaccine with a PD-1 antibody.
9 This strategy may facilitate PD-1 blockade–induced
T-cell function restoration. The authors created a mouse
model, with subcutaneous inoculation of tumor cells, that
was poorly immunogenic and resistant to anti-PD-1 antibody;
subsequently, they evaluated the impact of an HPV
vaccine on improvement or response rates to anti-PD-1
blockade. The mice then were treated with either anti-PD-1–
blocking antibody, CRT/E7 (detox) DNA vaccine, or a com-
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