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Clinical Review & Education

JAMA Oncology | Review

Harnessing the Immune System as a Therapeutic Tool


in Virus-Associated Cancers
Rafael Santana-Davila, MD; Shailender Bhatia, MD; Laura Q. M. Chow, MD, FRCPC

Supplemental content
IMPORTANCE There are at least 7 viruses implicated in the pathogenesis of 10% to 15% of all
human cancers worldwide. Despite a high prevalence of infection with these viruses, only a
minority of infected individuals develop a subsequent malignant tumor, underscoring the
important role that host and environmental factors have in cancer development. This article
reviews the mechanisms of viral carcinogenesis, with an emphasis on the viral evasion of the
host immune system, and discusses how to harness the immune system effectively as a
therapeutic tool in select cancers.

OBSERVATIONS Immune evasion mechanisms of these viral infections have an important role
in carcinogenesis. Increased understanding of these mechanisms has paved the way for using
immunotherapy to treat virus-associated cancers. This study summarizes the use of adoptive
cell therapy, tumor vaccines, immune checkpoint inhibitors, and combination
immunotherapies in the treatment of select virus-associated cancers.

CONCLUSIONS AND RELEVANCE Immunotherapy is proving to be a useful strategy in the


Author Affiliations: Division of
treatment of virus-associated cancers. A greater understanding of the processes of immune Medical Oncology, Department of
evasion in chronic infections and malignant tumors will continue to help in the goal of Medicine, University of Washington,
optimizing immunotherapy, which will in turn translate into remission and long-term survival Seattle.
in this patient population. Corresponding Author: Rafael
Santana-Davila, MD, Division of
Medical Oncology, Department of
JAMA Oncol. doi:10.1001/jamaoncol.2016.4574 Medicine, University of Washington,
Published online November 3, 2016. 825 Eastlake Ave E, Seattle, WA
98109 (rafaelsd@u.washington.edu).

V
iruses infect living cells and co-opt the host replication ma- be construed as a biological accident in which the infection has a cen-
chinery to produce viral progeny that goes on to infect tral role but is not the only requirement. The mechanisms of viral on-
more cells. To thrive, viruses need to overcome the regu- cogenesis are outside of the scope of this review article, but we will
latory components of the cell cycle while avoiding the induction of summarize the most important concepts. On infection, viral onco-
apoptosis and the host immune surveillance. The mechanisms by genes hijack the cell cycle and drive the infected cell from its usual
which a virus establishes a chronic infectious state resemble many nondividing G0 phase into the replicating S phase to generate the
of the hallmarks of carcinogenesis.1,2 Hence, it is not surprising that resources needed for viral genome replication and transmission. With
chronic viral infections are associated with the development of sev- disruption of the cell cycle checkpoints and the antiapoptotic ma-
eral types of cancers. chinery, viruses can directly influence the oncogenic process by leav-
Virus-associated malignant tumors account for 10% to 15% of ing the cell at risk of acquiring carcinogenic mutations that initiate
all human cancers globally. Specifically, 7 viruses have been linked an oncogenic transformation.16 Indirectly, viruses can also contrib-
with human cancers, including Epstein-Barr virus (EBV), human pap- ute to carcinogenesis by inducing a chronic inflammatory state in in-
illomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), fected tissues, which promotes oxidative stress and inflammation.17
human herpesvirus 8 (formerly Kaposi sarcoma herpesvirus), hu- Increasing evidence suggests that evasion of innate and adaptive im-
man T-cell lymphotropic virus, and Merkel cell polyomavirus (MCPyV) munity has a fundamental part in viral tumorigenesis.16
(Table). In this review article, we focus on the mechanisms of im-
mune evasion in virus-associated malignant tumors and discuss po-
tential therapeutic strategies to harness the power of the immune
Immune Evasion in Viral Infections and Its
system against these cancers.
Association With Malignant Transformation
A natural function of the immune system, aside from protecting the
host from pathogens, is to recognize and eliminate dysfunctional cells
Mechanisms of Viral Carcinogenesis
through a process called immunosurveillance (eFigure 1 in the Supple-
Human infection with viruses is associated with the development of ment). For a cancer and a viral infection to persist, they have to cir-
a cancer in only a minority of cases. When it does, the occurrence can cumvent the immune system to avoid detection. The mechanisms

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Clinical Review & Education Review The Immune System as a Therapeutic Tool in Virus-Associated Cancers

Table. Epidemiology of Human Cancer Viruses and Their Associated Cancers

Virus Prevalence of Cancer Cancer Viral Association With Cancer


Epstein-Barr virus Found in 99% of the human population Burkitt lymphoma Epstein-Barr virus is implicated in 99% of cases in
the endemic form, 10%-15% in the sporadic form,
and 40% in the human immunodeficiency
virusassociated form3
Classic Hodgkin lymphoma Epstein-Barr virus is found in 40% of cases
Posttransplantation Most cases manifest early after transplantation, are
lymphoproliferative disease associated with immunosuppression, and are
Epstein-Barr virus related4
Diffuse large B-cell lymphoma Occurs in 20% of cases4
Nasopharyngeal carcinoma In its endemic form, virtually all patients are
Epstein-Barr virus positive. Most cases in nonendemic
forms are also Epstein-Barr virus positive, but human
papillomavirus has also been implicated5
Gastric cancer Gastric carcinoma associated with Epstein-Barr virus
has distinct clinicopathological features, occurs
mostly in men and in younger individuals, and
generally has a lymphoepithelioma-like histology.
Occurs in 8.7% of all gastric cancers6
Hepatitis B virus Varies by region. It is more common Hepatocellular carcinoma More than 50% of cases of cirrhosis and
in Africa and the Western Pacific, hepatocellular carcinoma are attributable to a viral
where the prevalence is 8.8% and 5.3%, etiology. Hepatitis B virus is responsible for 53% of
respectively. In the United States, the hepatocellular carcinoma cases
prevalence is estimated to be 0.3%7
Hepatitis C virus Varies by region. Central and East Asia Hepatocellular carcinoma Hepatitis C virus is responsible for 27% of cases of
and North Africa and the Middle East are hepatocellular carcinoma
estimated to have a high prevalence
(>3.5%). The prevalence in the United
States is 1.3%8
Human T-cell 20 Million people worldwide are type Adult T-cell leukemia or lymphoma The lifetime risk of progression to adult T-cell
lymphotropic virus 1 carriers. Most reside in endemic areas, leukemia or lymphoma in a patient who is human
such as southern Japan, Africa, the T-cell lymphotropic virus 1 positive is 2.1% for
Caribbean basin, and Latin America women and 6.6% for men9
Human papillomavirus More than 40 serotypes of the virus Cervical cancer Close to half a million women are diagnosed as
exist. Only a minority can cause cancer, having invasive cervical cancer worldwide every year.
with types 16 and 18 being responsible Human papillomavirus is associated with virtually all
for most cases. In the United States, of the cases
the seroprevalence of human Head and neck squamous cell A meta-analysis11 of 148 studies and 12 163 patients
papillomavirus 16 was 19% in men carcinoma showed that human papillomavirus was implicated
and 30% in women10 in 24.2% of cancers of the oral cavity, 45.8% of
oropharyngeal cancers, and 22.1% of
hypopharyngeal and laryngeal cancers
Anal squamous cell cancers Up to 93% of anal squamous cell carcinomas are
associated with human papillomavirus infection12
Other (primarily genital region Occurs in 65% of vaginal cancers, 50% of vulvar
cancers) cancers, and 35% of penile cancers12
Human herpesvirus 8, Ranges from 1%-3% of blood donors Kaposi sarcoma Kaposi sarcoma is associated with
formerly Kaposi in North America to >70% of individuals immunosuppression. Kaposi sarcoma herpesvirus
sarcoma herpesvirus in regions of Africa where Kaposi is the only known etiologic agent13
sarcoma herpesvirus is endemic13 Primary effusion lymphoma Primary effusion lymphoma is an uncommon
AIDS-related lymphoma13
Merkel cell Serum antibodies can be detected in Merkel cell carcinoma Sequences of this virus are integrated in 80% of
polyomavirus 80% of adults older than 50 y in the Merkel cell carcinoma cases15
United States14

of viral immune evasion vary according to the pathogen; however, inhibition of these pathways by the viral infection is an increased risk
they are strikingly similar to those used by cancers and include the for the infected cell to undergo a malignant transformation. Simi-
following: disruption of the innate immune system by impeding the larly, for a successful chronic infection, the adaptive immune sys-
production of interferon; inhibition of natural killer cells, dendritic tem needs to be evaded by the virus. Therefore, an immune mi-
cells, and macrophages; interruption of antigen presentation by in- croenvironment that supports a chronic infection can also potentially
fected cells; and creation of a suppressive immune microenviron- shorten the equilibrium phase and promote escape from immuno-
ment. Detailed common viral and cancer immune evasion strate- surveillance, leading to an active cancer.
gies are shown in Figure 1 and Figure 2.
The pathways of the innate immune and tumor suppressor sys-
tems share many similarities, such as the induction of interferon ex-
Immunotherapy of Virus-Associated Cancers
pression by pattern recognition receptors in viral infections or by
damage-associated molecular patterns in cancer, as well as the ac- The persistent expression of nonself viral antigens in cancer
tivation of tumor necrosis factor receptors and subsequent apop- cells,2,3,19 the recognition of these antigens by the host immune sys-
tosis of the infected or neoplastic cell by cellular effectors of the in- tem, and our increasing understanding of immune evasion mecha-
nate immune system.18 However, an unintended consequence of the nisms prevalent in the tumor microenvironment have provided a

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The Immune System as a Therapeutic Tool in Virus-Associated Cancers Review Clinical Review & Education

Figure 1. Similarities Between the Immune Microenvironment in Cancer and Chronic Infections

TIM3 LAG3
CTLA4
5

PDL1
4
MHC1
CTL

NK cell
Dendritic cell 3 TCR PD1

IL10
TGF NKG2D
Galectin
MHC1
PDL1
TNF receptor 1 2 MICA and
6 MICB
TLRs Neoplastic cell

Striking similarities exist in the mechanisms used by chronic viral infections and associated antigen 4; IL-10, interleukin 10; LAG3, Lymphocyte-activation gene 3;
malignant tumors to avoid the innate and adaptive immune system and include MICA, MHC class I polypeptide-related sequence A; MICB, MHC class I
(1) upregulation of PD-L1 and PD-L2 expression, (2) downregulation of MICA and polypeptide-related sequence B; NK, natural killer cell; NKG2D, Natural killer
MICB, (3) expression of anti-inflammatory cytokines, (4) downregulation of the group 2D; PD1, programmed death 1 receptor; PDL1, programmed death ligand 1;
immune response by dendritic cells, (5) differentiation of effector T-cells into TCR, T-cell receptor; TGF, transforming growth factor ; TIM3, T-cell
functionally impaired exhausted T-cells, and (6) targeting of tumor-suppressor immunoglobulin mucin-3; TLRs, Toll-like receptors; and TNF, tumor necrosis
pathways by viral oncoproteins. CTLA4 indicates cytotoxic T-lymphocyte factor. Further details are given in the legend to eFigure 2 in the Supplement.

strong rationale for using immunotherapy to treat virus-associated mission for a median of 3.1 years after CTL infusion in 28 of 29 pa-
cancers. These immunotherapy efforts have focused on a multitude tients with high-risk or heavily pretreated, relapsed EBV-
of approaches aiming to render cancer cells more visible to the associated non-HL or HL. Thirteen of the 21 prior relapsed, resistant
immune cells, reinvigorate existing immune responses, generate patients demonstrated responses to therapy (11 with complete re-
new ones, or simply use the viral targets for selective delivery of sponse [CR] and 2 with partial response [PR]). A clinical trial using
cancer therapeutics to tumors. We highlight examples of the differ- this strategy is ongoing in patients with EBV-driven lymphoma who
ent approaches of adoptive cell therapy, tumor vaccines, immune have relapsed after allogeneic transplantation (NCT01956084 in the
checkpoint inhibitors (ICIs), and combination therapies below and in eTable in the Supplement). Epstein-Barr virusspecific CTLs are being
the eTable in the Supplement. evaluated in several ongoing studies for EBV-driven lymphoma and
other malignant cancers (NCT02057445, NCT00062868, and
Adoptive Cell Therapy NCT01636388 in the eTable in the Supplement). In a clinical trial of
Isolation of viral antigenspecific T cells from the peripheral blood patients with metastatic nasopharyngeal carcinoma (NPC), a cancer
or tumors of affected patients, followed by ex vivo expansion and strongly linked to EBV, transfer of autologous EBV-specific CTLs
adoptive transfer, has been extensively investigated as a treat- resulted in a response in 7 of 15 patients.20 Unlike PTLD or EBV-
ment for virus-associated cancers. Adoptively transferred T cells rec- driven lymphomas, NPC has expression of a limited array of EBV
ognize and destroy tumor cells expressing viral antigens to pro- antigens, with LMP2 being the most promising target. Recent
mote immediate tumor regression and subsequently expand and investigations have focused on optimizing T-cell expansion against
persist to provide a long-term protective response. Selected prom- LMP2 using novel adenovirus vectors21 and on sequencing ACT with
ising adoptive cell therapy (ACT) trials are summarized below. chemotherapy. In a study22 that combined 4 cycles of gemcitabine
Approximately 70% of posttransplantation lymphoprolifera- and carboplatin, followed by up to 6 cycles of LMP2-specific CTLs,
tive disorder (PTLD), 40% of classic Hodgkin lymphoma (HL), and in patients with metastatic or recurrent NPC, a response rate of 71%
20% of non-HL cases are associated with EBV.3 These malignant can- (3 CRs and 22 PRs) was observed in 35 patients.
cers are characterized by EBV gene expression in tumor cells and ex- Adoptive cell therapy is also being explored for several other
pression of EBV antigens, particularly the latent membrane pro- viral malignant cancers. In 9 patients with metastatic cervical can-
teins (LMPs) on the cell surface. In EBV-associated PTLD, infusion cer that had progressed through prior systemic therapy, autolo-
of virus-specific T cells has been successfully used against the neo- gous HPV tumor-infiltrating lymphocytes were isolated from frag-
plastic process, both with donor cytotoxic T lymphocytes (CTLs) in ments of metastatic tumors, expanded ex vivo, and administered
patients who have received allogeneic hematopoietic stem cell trans- after lymphocyte-depleting chemotherapy.23 One woman had a
plantation or with autologous CTLs in patients who are solid organ PR, and 2 patients were experiencing ongoing CRs up to 22 and 15
recipients.4 Cytotoxic T lymphocytes engineered to target LMP1 and months at the time of publication. Ongoing trials are using autolo-
LMP2 antigens administered adjuvantly were associated with re- gous HPV E6/E7 antigenspecific CTLs isolated from the peripheral

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Clinical Review & Education Review The Immune System as a Therapeutic Tool in Virus-Associated Cancers

based tumor antigens fused to the cytotoxic signaling domains from


Figure 2. Common Mechanisms of Immune Evasion Between
Viral Infections and Cancer the TCR and to costimulatory signaling domains that optimally ac-
tivate the T cell. Chimeric antigen receptor T cells provide an off-
the-shelf strategy that does not require major histocompatibility
complex matching, thereby potentially enhancing the application
of this therapy to a wider group of patients. Chimeric antigen re-
ceptor T cells have generally been used in hematological CD19-
ER and Golgi
apparatus
positive malignant cancers (mostly acute lymphoblastic leukemia)
Proteasome
and with outstanding clinical results in early-phase trials, with com-
Viral or tumor
proteins TAP plete remission rates in excess of 70% in patients who had pro-
Peptides
gressed through the current standard of care.26 Given this initial suc-
HLA-1
cess, more mature efforts are under way to better define the role
of this treatment in acute lymphoblastic leukemia, and ongoing clini-
EBV EBV
EBNA HPV cal trials are exploring novel chimeric antigen receptor designs in
HPV
HCV Cancer other hematological and solid malignant cancers. A limitation of this
Cancer
therapeutic strategy is the need for an antigen that is expressed by
EBV tumors but not by healthy tissues. The presence of nonself, high-
HPV avidity target antigens on tumor cells of virus-associated cancers
KSHV
Cancer makes the receptor-engineered T-cell approach an attractive op-
tion for these cancers. A TCR targeting an epitope of HPV-16 E6 and
Evasion of the immune system is a critical step that chronic viral infections and E7 has been developed, and T cells expressing this receptor have
cancer need to establish in order to thrive. The mechanisms in how they achieve
it are largely dependent on the specific virus or malignancy but overall they
demonstrated recognition in cervical and oropharyngeal cancer cell
share many characteristics. A common mechanism of immune evasion is for the lines.27 This approach is being tested in clinical trials (NCT02280811
cancer or infected cell to become less visible, which may occur via loss of and NCT02858310 in the eTable in the Supplement).
tumor or viral antigen expression. For successful antigen presentation, a protein
is initially degraded by a proteasome with subsequent processing of viral and
tumor proteins by the proteasome into small peptides. The transporter Tumor Vaccines
associated protein (TAP) then transports the peptides into the endoplasmic Vaccination against tumor-associated antigens has been exten-
reticulum, where it is coupled to an MHC molecule and transported to the cell sively investigated because expression of nonself, high-avidity vi-
surface. To reduce the amount of viral and tumor antigens, and to escape
ral antigens in these cancers is an attractive target for vaccine strat-
cytotoxic T-lymphocytes (CTLs) and adaptive immune system activation,
viruses and tumors downregulate proteasome subunits, TAP, 2 microglobulin, egies. Vaccination efforts have already led to major advances in
and the MHC I heavy chain itself. EBNA indicates Epstein-Barr nuclear antigen; preventing viral infections, such as HPV and HBV in high-risk popu-
EBV, Epstein-Barr virus; ER, endoplasmic reticulum; HCV, hepatitis C virus; lations, leading to decreased incidence of virus-associated cancers
HLA-1, human leukocyte antigen; HPV, human papillomavirus; and KSHV, Kaposi
sarcoma herpesvirus. in these populations.28,29
Disappointingly, vaccination strategies demonstrated modest
to low activity in treating established cancers or chronic viral infec-
blood and subsequently genetically engineered with a mutant tions. In HPV infections, oncoproteins E6 and E7 are required for the
transforming growth factor receptor to improve efficacy of the transformation of epithelial cells.30 They are expressed at all stages
infused cells (NCT02379520 in the eTable in the Supplement) or with of premalignant and malignant transformation and therefore are ideal
a T-cell receptor (TCR) that targets the tumor-specific E6 oncoprotein targets for therapeutic vaccines. Vaccination with the E6 and E7
(NCT02280811 in the eTable in the Supplement). epitopes,31 E6/E7 DNA,32 or a fusion protein of E6 and E7 and the L2
In a study24 of HBV-associated hepatocellular carcinoma (HCC), viral capsid protein33 has been demonstrated to result in a partial or
15 patients underwent radical resection, followed by tumor- completeregressionofpremalignantlesions.Unfortunately,anHPV-16
infiltrating lymphocyte generation, expansion, and administration. synthetic peptide as an epitope vaccine was much less immuno-
At a median follow-up of 14 months, only 3 patients had experi- genic when used in patients with recurrent cervical cancer and did not
enced recurrence, which is encouraging compared with historical confer a survival benefit compared with historical controls.34 A vac-
controls. Similarly, in a study25 of Merkel cell carcinoma (MCC), a pa- cine using a modified live attenuated Listeria monocytogenes bioen-
tient was treated with autologous polyclonal MCPyV-specific CD8- gineered to secrete an HPV-16 E7 fusion protein was associated with
positive T cells, combined with intralesional interferon beta, single- an encouraging 39% (10 of 26 patients) survival rate at 1 year.35
fraction radiotherapy, and low-dose interleukin 2, resulting in a PR The less than impressive therapeutic results with vaccine therapy
and a progression-free survival of 1.5 years. An ongoing phase 1/2 in virus-associated malignant cancers may be in part due to the lack
trial is exploring this strategy in patients with MCC (NCT02584829 of antigenic proteins in tumorigenesis; however, the main chal-
in the eTable in the Supplement). lenge of therapeutic vaccines is in how to overcome the immuno-
The above-mentioned ACT efforts have generally involved T cells suppressive cancer microenvironment. To overcome this chal-
that target antigens through native TCRs. Recently, there has been lenge, immunomodulation is being studied with vaccine adjuvants,
considerable interest in using T cells with a genetically modified TCR chemotherapeutic agents, radiotherapy, indoleamine 2,3-
or a chimeric antigen receptor that target antigens expressed in tu- dioxygenase inhibitors, ICIs, agonists of selected tumor necrosis fac-
mors. Chimeric antigen receptors are synthetic molecules com- tor receptor family members, and inhibitors of immunosuppres-
posed of immunoglobulin variable regions that recognize membrane- sive cytokines.36

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Immune Checkpoint Inhibitors nivolumab and pembrolizumab resulted in ORRs of 87% and 65%,
The many monoclonal antibodies developed to block the pro- respectively.42,43 A follow-up phase 2 study44 in heavily pretreated
grammed death 1 (PD1) checkpoint via the interaction between PD1 patients showed a response rate of 66% (53 of 80 patients) to single-
(nivolumab and pembrolizumab) and its ligand PDL1 (avelumab and agent nivolumab. This trial led to the approval of nivolumab for pa-
durvalumab) or those that block the interaction between cytotoxic tients having HL with progressive disease after autologous trans-
T-lymphocyteassociated antigen (CTLA) 4 and B7 (ipilimumab and plantation and brentuximab vedotin therapy. The role of EBV in these
tremelimumab) are dramatically revolutionizing the treatment of responses is unknown because tissue analysis results were avail-
many solid malignant cancers. Given the abundant evidence for im- able in just 10 patients and only 1 patient had evidence of EBV relat-
mune exhaustion in chronic viral infections and in virus-associated edness; therefore, its applicability to patients with EBV-associated
cancers, these agents are being extensively investigated as a thera- lymphomas continues to be a subject of ongoing investigation.42
peutic strategy in this setting. In addition, ICIs demonstrated efficacy in a phase 1/2 trial of niv-
The ability of ICIs to act on the viral infection itself was demon- olumab in 47 patients with advanced HCC, including 23 patients with
strated clearly in the benign setting in a trial of 54 patients with per- virus-associated disease (12 HCV and 11 HBV).45 A favorable in-
sistent chronic HCV infection, despite prior interferon alpha terim analysis demonstrated good tolerability, with sustained re-
therapy.37 A single dose of nivolumab led to decreased HCV viral ti- sponses, including an ORR of 19% (8 of 42 patients), with 6 PRs (14%)
ters in 11% to 15% of patients, and 1 patient with resistance to prior and 2 CRs (5%).45 Intriguingly, 5 of the 6 PRs were in virus-infected
therapies maintained negative RNA levels at 1 year after the study. patients (4 HCV and 1 HBV), whereas the 2 CRs were in uninfected
This effect was further demonstrated in a trial of 21 patients with HCC patients.45 An ongoing randomized phase 3 trial (CheckMate 459)
and chronic HCV infection treated with tremelimumab, showing an comparing nivolumab vs sorafenib in the first-line setting of ad-
overall response rate (ORR) of 17.6%, and induced a significant de- vanced HCC treatment is under way (NCT02576509 in the eTable
crease in viral load, with 3 patients having a transient complete vi- in the Supplement).
ral response during follow-up.38 Several other efforts are ongoing Head and neck squamous cell carcinoma (HNSCC) is an attrac-
using ICIs to overcome immune exhaustion in chronic viral infec- tive disease for investigating ICIs because of immunogenicity from
tious states, including in human immunodeficiency virus infections a high mutation rate (related to alcohol and smoking carcinogens)
in which overexpression of PD1 in infected T cells contributes to T- and its association with HPV infection in a substantial subgroup of
cell dysfunction, thereby adding to the immunosuppression and in- patients. In part based on the impressive durable responses, with
creased incidence of malignant cancers associated with this an ORR of 18% observed in a phase 1 clinical trial of pembrolizumab
disease.39 in 132 patients,46 the US Food and Drug Administration has ap-
Because viral infections and malignant cancers share similar im- proved its use for patients with HNSCC after progression on plati-
mune evasion strategies and immunosuppression, the ability of ICIs num-containing chemotherapy. A response rate of 32% was ob-
to potentially simultaneously target the viral infection and modu- served in 28 HPV-positive patients; however, small numbers of study
late the cancer makes this therapeutic class particularly attractive. participants prevent meaningful conclusions.47 CheckMate 141, a
One of the most impressive examples of ICI efficacy in a virus- phase 3 study48 that randomized 361 patients with HNSCC who had
associated cancer was demonstrated in a phase 2 study40 of che- progressed through platinum-based chemotherapy to either niv-
motherapy-naive patients with MCC treated with pembrolizumab. olumab or the investigators choice of docetaxel, cetuximab, or
An ORR of 56% (14 of 25 patients) was observed, with PRs in 10 pa- methotrexate, was stopped early because of reports of meeting over-
tients and CRs in 4 patients. Responses were durable, with a me- all survival end points favoring nivolumab. In an interim analysis of
dian duration of 33 weeks, and the 6-month progression-free sur- 63 patients, patients with HPV-related disease treated with niv-
vival was 67%. Intriguingly and somewhat unexpectedly, the olumab had an improved median overall survival of 9.1 months com-
response rates were high in patients with MCPyV-positive tumors pared with 4.4 months with chemotherapy (hazard ratio, 0.56; 95%
(63% [10 of 16]) and in patients with MCPyV-negative tumors (44% CI, 0.32-0.99), demonstrating the activity of nivolumab in this virus-
[4 of 9]). This finding suggests underlying immunogenicity in both related subset of HNSCC.48 Both pembrolizumab and nivolumab are
of these subgroups, albeit by different mechanisms. The MCPyV- likely to have an important role in the future therapy of HNSCC, and
positive tumors appear to have a low mutational burden, with im- approaches looking at combining these agents with anti-CTLA4 an-
mune responses likely directed against viral antigens, whereas the tibodies and other ICIs are ongoing, as well as assessing their use in
MCPyV-negative tumors have a high mutational load, with UV ra- the neoadjuvant and adjuvant settings. In addition, an ongoing phase
diationassociated mutational signatures likely leading to neoanti- 1 trial is assessing 3 courses of ipilimumab after treatment with ce-
gen-directed immune responses.15 Another phase 2 trial investigat- tuximab and intensity-modulated radiotherapy for patients with
ing the use of avelumab in 88 patients with chemotherapy- squamous cell carcinoma of the head and neck (SCCHN) with or with-
refractory metastatic MCC reported an ORR of 31.8%, including 8 out markers of HPV infection (NCT01935921 in the eTable in the
patients with CRs.41 Similar to the pembrolizumab study,40 the vi- Supplement). Because of the promising activity in HPV-related
ral status did not appear to influence response (26.1% in MCPyV- SCCHN, ICIs are also being explored in a number of trials in HPV-
positive patients vs 35.5% in MCPyV-negative patients). Ipili- associated cervical cancer. Ipilimumab has been studied in patients
mumab is also being studied as an adjuvant systemic therapy in a with metastatic or recurrent cervical carcinoma in a phase 1/2 study,
randomized trial vs observation in patients with resected MCC with a preliminary analysis reporting an ORR of 9% (3 of 32).49
(NCT02196961 in the eTable in the Supplement). The ability of ICIs to specifically treat virus-associated malig-
Similar to MCC, the anti-PD1 antibodies have also demon- nant cancers is being determined in CheckMate 358 (NCT02488759
strated dramatic efficacy in HL. In separate early trials, treatment with in the eTable in the Supplement), which is using nivolumab

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Clinical Review & Education Review The Immune System as a Therapeutic Tool in Virus-Associated Cancers

monotherapy or nivolumab plus ipilimumab in several virus- tain complete remission. This method should (1) remove immune
associated malignant cancers, including EBV-related NPC or EBV- suppression (by attenuating immunesuppressive mediators, such
related gastric cancer, MCC, HPV-related gynecological (cervical, as suppressor cells, or through inhibitory receptor blockade), (2) in-
vaginal, or vulvar) cancers, and HPV-positive SCCHN. Results from duce immunogenic cancer cell death (combining chemotherapy, ra-
this ongoing study will substantially influence our knowledge of the diotherapy, targeted therapy, and cellular therapy), (3) enhance an-
effectiveness and limitations of ICIs to treat virus-associated cancers. tigen-presenting cell function (immune adjuvants), and (4) promote
activation, potentiation, and survival of memory T cells and macro-
phage effector function.50
We need to improve immunologic responses and cure rates in
Conclusions
these diseases and must better define which patients will derive the
Treatment directed at enhancing the immune system to attack can- most benefit to limit toxicity and progression of disease. Biomark-
cer and efforts to revert the mechanisms of immune evasion have ers are under early exploration for validation as predictive markers
proven recently to be a successful strategy in most cancers. Be- of response and survival in a number of diseases. These biomarkers
cause of their etiology and the central role of immune evasion in virus- include PDL1 (with or without incorporation of inflammatory and tu-
associated cancers, immunotherapy is being widely studied as a treat- mor cell staining), PDL2, the interferon gamma gene signatures,51,52
ment strategy, with impressive results changing treatment paradigms mutational heterogeneity and mutation load,53 TCR repertoire
and adding to the therapeutic armamentarium. heterogeneity, 54 and circulating lymphocyte levels. 55 Serum-
Although an unprecedented benefit in subgroups across many specific and tissue-specific viral markers and quantitative viral lev-
diseases is observed, immunotherapy (particularly single-agent treat- els are still being assessed as prognostic and predictive markers in
ments) is still not effective in most patients. This finding reflects the conjunction with the above biomarkers in many immunotherapy
heterogeneity of immune biology and the complex mechanisms of investigations.50 In a rapidly evolving world of immunotherapy for
immune evasion in both virus-induced and nonvirus-induced ma- solid tumors, successful targeting of the immune system in virus-
lignant cancers. mediated cancers would not only benefit patients with these can-
A multipronged approach will be needed to potentially induce cers but also have far-reaching implications for the broader field of
immunologic responses, improve their depth and durability, and ob- cancer immunotherapy against nonviral cancers.

ARTICLE INFORMATION studies paid to the University of Washington from antibody to HCV seroprevalence. Hepatology. 2013;
Accepted for Publication: August 23, 2016. Novartis, Bristol-Myers Squibb, Merck, Eli Lily/ 57(4):1333-1342.
ImClone, AstraZeneca/MedImmune, Genentech, 9. Qayyum S, Choi JK. Adult T-cell
Published Online: November 3, 2016. VentiRx, Pfizer, Incyte, and NCCN/GlaxoSmithKline.
doi:10.1001/jamaoncol.2016.4574 leukemia/lymphoma. Arch Pathol Lab Med. 2014;
No other disclosures were reported. 138(2):282-286.
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