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New York esophageal squamous cell carcinoma-1 and cancer immunotherapy

Immunotherapy

April 2015
7(4):411-39

DOI:10.2217/imt.15.3

Source
PubMed

Authors:

Ali Esfandiary

Monash University (Australia)

Soudeh Ghafouri-Fard

Shahid Beheshti University of Medical Sciences

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a known cancer testis gene with exceptional immunogenicity and prevalent expression in many cancer types. These characteristics have made it an appropriate vaccine candidate with the potential application against various malignancies. This article reviews recent knowledge about the NY-ESO-1 biology, function, immunogenicity and expression in cancers as well as and the results of clinical trials with this antigen.

. Recent clinical trials with New York esophageal squamous cell carcinoma-1 in cancer patients.

…

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411Immuno therapy (2015) 7(4), 411–439

ISSN 1750-743X

part of

Review

Immunotherapy

Review

2015

New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a known cancer testis

gene with exceptional immunogenicity and prevalent expression in many cancer types.

These characteristics have made it an appropriate vaccine candidate with the potential

application against various malignancies. This article reviews recent knowledge about

the NY-ESO-1 biology, function, immunogenicity and expression in cancers as well as

and the results of clinical trials with this antigen.

Keywords: cancer-testis antigen • immunogenicity • immunotherapy • NY-ESO-1

The gene coding for New York esophageal

squamous cell carcinoma 1 (NY-ESO-1), also

known as cancer/testis antigen 1B (CTAG1),

is a prototype of cancer testis (CT) gene fam-

ily. The main characteristics of the members

of this family are exclusive or selective expres-

sion in the testis among normal tissues and

expression in a wide variety of tumors [1] .

This expression pattern has made them suit-

able targets for cancer immunotherapy [2 ,3].

Testis is regarded as an immune privileged

site due to the presence of a blood–testis bar-

rier. The blood–testis barrier is an outcome

of presence of tight junctions between Ser-

toli cells along the basolateral aspect and

between capillary endothelial cells, lack of

APCs in seminiferous tubules and absence of

HLA class I expression on the surface of germ

cells. Therefore, expression of CT genes such

as NY-ESO-1 in tissues other than testis can

induce immune responses [4]. There are now

more than 100 gene families with such an

expression pattern. Not all of them have been

demonstrated to be able of eliciting immune

responses but are altogether called the CT

antigens (CTAs). Among them, NY-ESO-1

is considered to be the most immunogenic

and has become a striking target for cancer

vaccine strategies, which would employ the

immune system to selectively target and

remove the CTA-expressing tumor cells [5] .

Since its discovery in 1997, NY-ESO-1 has

been exempliﬁed as one of the fastest shifts

from molecular, cellular and immunological

description to clinical trials [6].

NY-ESO-1 history & biology

The NY-ESO-1 gene is located on the Xq28

region of the X chromosome and codes

for a number of products. This region car-

ries a disproportionately high number of

CT genes [7,8] . The expression of such CT

genes has been shown to be regulated by the

demethylation of the promoter regions as

well as histone modiﬁcations [8,9]. Recently,

it has been demonstrated that the epigenetic

regulation of the NY-ESO-1 gene needs the

chronological recruitment of the HDAC1-

mSin3a-NCOR, Dnmt3b-HDAC1-Egr1

and Dnmt1-PCNA-UHRF1-G9a complexes.

Therefore, a sequential epigenetic mecha-

nism including the histone deacetylation

and methylation, and the DNA methylation

processes is involved in this process [10] . Anti-

body against NY-ESO-1 was ﬁrst found in

the serum of a patient with squamous cell

carcinoma (SCC) of the esophagus. The

method used for such screening is named

‘SERological identiﬁcation of antigens by

recombinant EXpression cloning’ (SEREX).

In this method, serum of cancer-bearing

patients is screened against an expression

New York esophageal squamous cell

carcinoma-1 and cancer immunotherapy

Ali Esfandiary

& Soudeh Ghafouri-Fard*

Department of Medical Genetics, Shahid

Beheshti University of Medical Sciences,

Tehran 19857-17443, Iran

*Author for correspondence:

Tel.: +98 21238 72572

ghafourifard@razi.tums.ac.ir

For reprint orders, please contact: reprints@futuremedicine.com

412

Immunotherapy (2015) 7(4)

future science group

Review Esfandiary & Ghafouri-Fard

library for identifying the antibody repertoire of the

patient [8]. NY-ESO-1 is a 180 amino acid long protein

of 18 kDa, which contains a glycine-rich N-terminal

region and a very hydrophobic C-terminal region.

Although its C-terminal structure may imply the pres-

ence of a transmembrane domain, there is no evidence

of membrane association at the cellular level. Another

tumor antigen named LAGE-1 is shown to be strongly

homologous to NY-ESO-1. Both NY-ESO-1 and

LAGE-1 coding regions have numerous products from

alternative reading frames, including a smaller 109

amino acid product named CAMEL [11,12]. LAGE-1

expression in cancers is usually but not always in con-

junction with NY-ESO-1 or MAGE-A family mem-

bers [13] . However, in a study performed in the multiple

myeloma patients LAGE-1 was shown to be frequently

expressed despite the signiﬁcantly lower expression of

its close homologue NY-ESO-1 [14] . A third member of

the human NY-ESO-1 family, named ESO3, has been

located on the same region of chromosome X with

NY-ESO-1 and LAGE-1. However, its protein sequence

homology with NY-ESO-1 and LAGE-1 is less than 50

% and it is expressed ubiquitously in normal tissues so

is not a CT gene family member [15] .

NY-ESO-1 function

The only conserved feature in NY-ESO-1 is a Pcc-1

domain in its C-terminus (amino acids 89–164) which

is homologous to a yeast transcription factor involved

in cell cycle progression and polarized growth [16] .

Although the exact biological role of NY-ESO-1 is

not understood, it has been shown to interact spe-

ciﬁcally with another CTA, melanoma antigen gene

C1 (MAGE-C1) [17] . MAGE-C1 is a member of the

MAGE family with the major characteristic of hav-

ing MAGE homology domain (MHD), a large cen-

tral region conserved across its members. The MAGE

genes have been shown to be involved in cell cycle

progression, apoptosis and neurogenetic diseases [18].

As NY-ESO-1 expression in the testis is conﬁned to

spermatogonia and primary spermatocytes and is lost

during spermatid differentiation, it may have a possible

role in germ cell self-renewal or differentiation [8,19] .

NY-ESO-1 has been reported to be a cytoplasmic

protein in differentiated cells and cancer cell lines [20],

but in mesenchymal stem cells it localizes in nucleoli-

like structures. Nucleolar localization of NY-ESO-1

may suggest novel cellular function(s), in addition to

an association with other nucleolar proteins, such as

p53, p14ARF or nucleostemin [21] . The cellular local-

ization of NY-ESO-1 has been demonstrated in Bar-

rett’s esophagus (BE) and esophageal adenocarcinoma

(EAC) to be prominently within the cytoplasm, often

at an apical and luminal aspect. Such pattern of expres-

sion has suggested a possible role for it in a process of

vesicle trafﬁcking in BE and EAC, with paracrine

function linked with exocytosis into the esophageal

lumen [22] . Microvesicles which are shed from the cell

surface of cells are involved in cellular communication

and have been suggested to cause epigenetic repro-

gramming of target cells [23]. This process may partici-

pate in the replacement of the normal cell population

by a histologically nondysplastic but protumorigenic

mutant cell clone which is seen in BE and EAC [22,24].

In addition, vesicles may participate in protein storage

or transport [22] . Other studies aimed at demonstrating

subcellular localization of NY-ESO-1 have shown both

cytoplasmic and nuclear expression in head and neck

cancer samples, whereas cytoplasmic expression in dif-

fuse large B-cell testicular lymphoma specimens [25,26].

Finally, in intrahepatic cholagiocarcinoma samples,

NY-ESO-1 showed a predominantly, although not

exclusively, cytoplasmic staining [27].

NY-ESO-1 expression pattern in normal

tissues

NY-ESO-1 has been shown to be expressed in sper-

matogonia, primary spermatocytes [19] , oogonia and

placenta [28,29] . In the adult testis, its expression has

not been detected in postmeiotic cells or in the Sertoli

and Leydig cells [19] . NY-ESO-1 is among chromosome

X-encoded CTAs (CT-X antigens) whose expression has

been shown to appear as early as 13 weeks after gesta-

tion, increase with age and reach a plateau at around

22 weeks. In the fetal ovary, NY-ESO-1 positive oogo-

nia have been shown to be most abundant at around

24 weeks and quickly decrease afterward. NY-ESO-1

has been shown to be almost absolutely expressed in

OCT3/4-negative gonocytes coincident with the loss of

pluripotency [30] . NY-ESO-1 mRNA but not protein has

been shown at low levels in some other normal tissues

and the signiﬁcance of this ﬁnding in unclear [8,29].

NY-ESO-1 expression pattern in tumors

Expression of NY-ESO-1 has been assessed in different

histological types of tumors as well as cancer cell lines.

However, data obtained from tumor cell lines need to

be evaluated in human tumor samples to avoid over-

estimation of NY-ESO-1 expression. It is regarded as

a tumor associated antigen in many tumors [31,32]. The

highest expression has been shown in neuroblastoma

(82 %) [33] , synovial sarcoma (80%) [34] , melanoma

(46%) [35], cervical cancer (45%) [36] and epithelial

ovarian cancer (43%) [37] . If the expression rate and

speciﬁcity of this antigen in a certain tumor type is

high, it can be used as a tumor marker for such cancer.

However, for tumors with low expression rate of this

antigen such as oral SCC, it might be a useful addi-

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NY-ESO-1 & cancer immunotherapy Review

tional biomarker within a multiple marker system for

the diagnosis of disease [38] . In addition, NY-ESO-1

expression has been suggested as a diagnostically use-

ful tool for the distinction of synovial sarcoma from

other spindle cell neoplasms because of its strong and

diffuse expression in a majority of synovial sarcomas

but rare expression in other spindle cell neoplasms,

such as leiomyosarcoma, cellular schwannoma and

dermato ﬁbrosarcoma protuberans [39] . Other stud-

ies have shown high expression frequency of NY-

ESO-1 in myxoid and round cell liposarcoma [40–42]

implying that NY-ESO-1 is a sensitive and a speciﬁc

marker for myxoid and round cell liposarcoma among

mesenchymal myxoid neoplasms [41] .

Table 1 demonstrates its expression in malignant

tissues as well as the frequency of occurrence of spon-

taneous immune responses in cancer patients. Most of

studies have used reverse transcription PCR (RT-PCR)

or immunohistochemistry (IHC). Higher frequency

of gene expression detected in a speciﬁc tumor type by

RT-PCR than IHC is due to higher sensitivity of RT-

PCR. An unexpected discrepancy between the mRNA

and protein expressions has been observed in medul-

loblastoma, which has been attributed to possible post-

transcriptional control of CTAs in this kind of cancer

or sample bias due to the heterogeneous expression of

CTAs at both the mRNA and protein level [43]. More

recent studies have used quantitative real-time PCR

(qRT-PCR) which has the advantage of providing quan-

tiﬁcation for levels of gene expression. Analysis of pro-

tein expression by IHC provides invaluable data about

the intratumoral distribution of NY-ESO-1, reveal-

ing its intratumoral heterogeneity [44]. However, it is

anticipated that antigens with relative homo geneity of

expression in a certain tumor are more suitable targets

for immunotherapy compared with those with scat-

tered expression [43]. The variations observed between

different protein studies in the frequency of NY-ESO-1

expression in a speciﬁc tumor type may be at least partly

due to different detection methods and different anti-

bodies used for NY-ESO-1 detection. Among antibod-

ies used in different studies, ES121 and E978 have been

shown not to bind to LAGE-1 regardless of the high

degree of homology between LAGE and NY-ESO-1.

On the contrary, D8.38 binds a peptide sequence com-

mon in both NY-ESO-1 and LAGE-1. Since NY-ESO-1

and LAGE-1 are not necessarily co-expressed in individ-

ual tumors, NY-ESO-1 expression frequencies tend to

be higher in studies that have used D8.38. [8]. A higher

false-negative rate is anticipated to occur in tissue micro-

array (TMA)-based analyses due to sampling error,

given that CTA expression in tumors is often focal [45].

NY-ESO-1 overexpression in astrocytoma, menin-

gioma and breast carcinoma has been shown to increase

in parallel with the malignancy grade of tumors [46–49].

However, the association between NY-ESO-1 expression

and tumor grade in breast cancer has not been conﬁrmed

in another study [50] . On the other hand, a signiﬁcantly

higher expression of NY-ESO-1 has been demonstrated

in triple negative breast cancers compared with estrogen

receptor (ER) positive tumors [51] . Correlation of NY-

ESO-1 expression with ER negativity in breast tumors

and a trend for its coexpression with basal cell mark-

ers have been conﬁrmed in other studies as well [52 ] . In

addition, NY-ESO-1 has been among CTAs with high

expression rate in BRCA-associated breast cancer [53] .

In malignant melanoma, NY-ESO-1 expression is more

frequently demonstrated in metastatic than in primary

tumors and its expression is associated with thicker pri-

mary lesions and a higher frequency of metastatic dis-

ease, pinpointing to a worse prognosis [54,55]. Contrary

to malignant melanoma samples, only a small percent-

age of desmoplastic melanoma and ocular melanoma

samples have been shown to express NY-ESO-1 [56,57] .

On the other hand, in non-Hodgkin’s lymphoma the

higher positivity for NY-ESO-1 has been observed in

early stage compared with advanced stage disease [58] . In

prostate cancer, a tight link has been observed between

NY-ESO-1 expression and ERG activation and (to a

lesser extent) PTEN- and 6q15-deletions [59] . In a sub-

set of tumors, NY-ESO-1 expression has been shown to

be lost during remission which is thought to be either

a means to evade T-cell-based immunosurveillance or

the result of reduced cell proliferation. In hepato cellular

carcinoma NY-ESO-1 expression has been associated

with metastasis [60,61] and worse outcome following sur-

gery with the possible mechanism of increasing tumor

cell migration [62]. In gastrointestinal stromal tumors,

the expression of NY-ESO-1 has been associated with

tumor progression under imatinib treatment [63]. In

head and neck cancer, simultaneous NY-ESO-1 expres-

sion in cytoplasm and nucleus has been suggested as a

marker of poor survival [25]. Finally, in multiple myeloma

NY-ESO-1 expression has been shown to be associated

with cytogenetic abnormalities and poor prognosis [64].

However, in a large population of patients with pha-

ryngeal cancer, prognosis tended to be better in patients

with NY-ESO-1 expression, but this correlation was not

statistically signiﬁcant [65] .

Although not all tumor cells express NY-ESO-1,

its expression can be upregulated using demethylating

agents such as decitabine. Such a treatment can con-

vert a nonimmunogenic tumor cell into an immuno-

genic target that would be competently recognized by

NY-ESO-1-speciﬁc T cells as shown in human glioma

cells [66].

In a recent study aimed at investigation of the mech-

anisms governing degradation of NY-ESO-1 in selected

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Immunotherapy (2015) 7(4)

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Review Esfandiary & Ghafouri-Fard

cancer cell lines, it has been demonstrated that inhibi-

tors of proteasome-mediated degradation can induce

the partitioning of NY-ESO-1 into a detergent insol-

uble fraction and increase localization of NY-ESO-1

at the centrosome. NY-ESO-1 region corresponding to

amino acids 91–150 has been shown to control both

stability and localization of NY-ESO-1. In brief, the

steady state level of NY-ESO-1 has been shown to be

regulated by proteasomal degradation. Consequently

NY-ESO-1 antigenic presentation and immunogenic-

ity can be induced by proteasome inhibitors which are

increasingly used as front-line treatment in cancer [67] .

NY-ESO-1 as a stem cell marker

CTAs are believed to participate in early stages of

embryonic development and in stem cell self-renewal.

It has been suggested that expression of these antigens

in tumor tissues is conﬁned to cells that preserve stem

cell properties. So CTAs expression may be character-

istics of cancer stem cells (CSCs) and can be regarded

as targets for interference in recurrence and metasta-

sis. Cancer cells in which CTAs are expressed may

have lost their differentiation capacity [1] . NY-ESO-1

is among CTAs whose expression has been detected

in both adult and fetal human mesenchymal stem

cells of the bone marrow but after differentiation of

osteocytes and adipocytes, their expression is down-

regulated [21] . NY-ESO-1 expression in mesenchymal

stem cells has been shown by immunoﬂuorescence

carried out on cultured cells derived from bone mar-

row aspirates and fetuses [21] . As NY-ESO-1 is now

being used in cancer vaccine treatment, its expression

in stem cells could be recognized as a potential dis-

advantage; however, immunotherapeutic approaches

targeting NY-ESO-1 have been reported to be well tol-

erated. This may be related to an essential difference

between the dot expression of NY-ESO-1 in normal

tissues and its diffuse expression in tumor tissues [22] .

Considering the fact that CT genes might be stem

cell markers, it is not surprising that the presence of

CT gene-expressing cells in tumor cell population

may be the result of clonal proliferation of an abnor-

mal CSC [68] . CSCs are a group of cells within tumors

which have stem-like features, express stem cell mark-

ers and are thought to be the sources of metastasis and

tumor relapse [69]. Expression of CT genes in CSCs

has clinical implications in the treatment of cancer

recurrences and metastasis [70]. In a study of CT genes

expression in CSC isolated from glioma cell lines and

tissues, it has been demonstrated that CT genes includ-

ing NY-ESO-1 are strongly and frequently expressed

in CSCs compared with differentiated cells. Moreover,

epigenetic studies in promoter regions of CT genes

including NY-ESO-1 revealed high histone acetylation

and hypomethylation in CSCs compared with differ-

entiated cells. Heterogeneous expression of CT genes

in the tumor mass is consistent with this epigenetic

pattern difference. Additionally, as the expression level

of HLA class I antigens was not changed by the dif-

ferentiation status, CTAs may present as surface anti-

gens in CSCs. Consequently, CT genes such as NY-

ESO-1 have been suggested as appropriate candidates

for targeted vaccine therapy against CSCs in glioma

patients [71] .

NY-ESO-1 immunogenicity

Spontaneous humoral and cellular immune responses

to NY-ESO-1 have been repeatedly identiﬁed in can-

cer patients whose tumor expresses this molecule

(Table 1). The spontaneous immune responses detected

in patients with NY-ESO-1 expressing tumors are

considered as markers for selection of cancer vaccine

recipients [72]. The timing and efﬁciency of elicited

immune responses differ widely between different can-

cer patients. For instance, it has been shown that about

half of patients with NY-ESO-1 expressing melanoma

tumors ultimately develop antibody responses against

NY-ESO-1 [73]. On the other hand, only a small per-

centage of multiple myeloma patients evidenced NY-

ESO-1 speciﬁc antibodies during disease progression.

Antibodies detected in multiple myeloma patients have

been shown to be able of activating complement and

increasing CTA uptake by APCs. So it has been con-

cluded that primary autoantibodies against NY-ESO-1

in these patients are capable of affecting cellular anti-

tumor immunity by formation and uptake of mono and

polyvalent immune complexes [74]. In a recent study

using a CTA microarray designed to screen for CTA

autoantibodies, NY-ESO-1 was the most frequent auto-

antibody identiﬁed in lung cancer sera [75]. In addition,

it has been shown that NY-ESO-1 speciﬁc antibody

titers concur with increased tumor burden and pro-

gression of the disease, so comprise markers of recur-

rent and/or progressive disease in some cancers such as

multiple myeloma, melanoma, prostate cancer, bladder

cancer, as well as hepatocellular carcinoma [74,76–80]. In

addition, the humoral response against NY-ESO-1 has

been shown to be a useful tumor marker in combina-

tion with conventional tumor markers for detection of

advanced gastric cancer and post-treatment tumor load

in seropositive patients [81] . In a study aimed at ﬁne-

mapping of naturally occurring NY-ESO-1 antibody

epitopes in melanoma patients sera it has been revealed

that humoral immune responses to NY-ESO-1 differs

widely in antibody speciﬁcity, intensity and antibody

subtypes in a way that multiple epitopes within the

N-terminus of NY-ESO-1 were responded to. On the

other hand the immune responses detected after vac-

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NY-ESO-1 & cancer immunotherapy Review

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers.

Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Hematologic Multiple myeloma Bone marrow 39/66 (59%)/gene-

expression proﬁling

47/55 (85%)/IHC/B9.8 Humoral response in 13/39

(33%) of mRNA positive cases/

ELISA CD8

T-cell responses in

2/3 (67%) patients who had

cytogenetic abnormalities

[64]

Bone marrow 4/55 (7.3%)/RT-PCR [82]

Bone marrow 13/39 (36%) /RT-PCR [14]

Bone marrow 13/50 (26%)/RT-PCR 2/27 (7%)/IHC/219-510-

23 and E978

Humoral response in 1/33 (3%)/

ELISA

[8 3]

Plasma cell myeloma Parafﬁn-embedded

bone marrow biopsies

– 17/203 (8%)/TMA (IHC)/

B978

[84]

Non-Hodgkin’s

lymphoma

B cell, T cell, non B and

T cell

– 3/97 (3.1%)/TMA (IHC)/

B978

Humoral response in 5/97

(5.2%)/ELISA

[58]

Diffuse large B-cell

testicular lymphoma

tumor tissue 9/24 (37.5%)/IHC/D8.38 [26]

Adult T-cell leukemia/

lymphoma

Primary tumor cells 35/57 (61%/RT-PCR) 100% of available

samples/IHC/E978

Humoral response in 5/43

(12%)/ELISA

[85]

CD8

T-cell responses in 5/9

(55.6%)

Light-chain

amyloidosis (AL

amyloidosis)

Bone marrow 0/38 (0%)/IHC/E978 1/35 (3%)/ELISA [86]

Bladder Transitional cell

carcinoma

59 superﬁcial (Ta and

T1) and 43 invasive

(≥T2)

46/102 (45%)/ RT-PCR [87]

Urothelial carcinoma 87 Ta, 49 T1, 214 T2–4 122/350

(35%)/qRT-PCR

[88]

Brain Astrocytoma Tumor tissues 14/14 (100%)/IHC/anti-

NY-ESO-1 mouse mAb

[89]

Medulloblastomas/

primitive

euroectodermal

tumors

Tumor tissues – 6/6(100%)/IHC/anti-NY-

ESO-1 mouse mAb

Medulloblastomas Tumor tissue 5/25 (20%)/RT-PCR 0/25(0%)/IHC/B978 [90]

Pediatric tumors 1/11 (9%)-qRT-PCR [91]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

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Review Esfandiary & Ghafouri-Fard

Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Brain (cont.) Meningioma 110 meningioma

samples collected from

99 patients (43 males

and 56 females) which

was 40 grade 1, 57

grade 2 and 13 grade 3

samples

5 /18 (27. 8%) / RT- PCR 108/110 (98.2%) IHC/

Anti-NY-ESO-1 mouse

mAb

High IgG response in 1/21 which

was grade 3/ELISA marked

degrees of T-cell inﬁltration in

30% of the tumors

No association between CD3

or CD8

T-cell inﬁltration and

NY-ESO-1 expression, recurrence

status or tumor grade

[92]

20 grade I and II, 6

atypical and malignant

meningiomas

3/26 (12%)/RT-PCR [93]

Glioma Tumor tissue 0/15 (0%)/RT-PCR [7]

Malignant glioblastoma

multiforme

0/42 (0%)/RT-PCR [93]

Breast Metastatic tumor 6/53 (11%)/IHC/NY-

ESO-1/CTAG1B-speciﬁc

rabbit polyclonal

antibody (NY45) or

ES121 or E978

[52]

Primary tumor 13/201 (6%)/IHC/NY-

ESO-1/CTAG1B-speciﬁc

rabbit polyclonal

antibody (NY45) or

ES121 or E978

Breast carcinoma BRCA-associated

tumors

10/26 (38%)/IHC/E978 [53]

Metastatic Humoral response in 2/26 (7.6%) [94]

Primary breast cancer 14/164 (8.5%)/TMA/

B9.8.1.1

[45]

Primary invasive 21/140 (15%)/TMA

(IHC)/E978

[48]

Invasive breast

carcinoma

ER-positive tumors 2/50 (4%)/IHC/E978 [51]

ER/PR/HER2 triple-

negative tumors

9/50 (18%)/IHC/E978

ER-negative tumors 47/265 (17.7%)/IHC/E978 [49]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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future science group

NY-ESO-1 & cancer immunotherapy Review

Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Breast (cont.) ER-positive tumors 4/189 (2%)/IHC/E978

Invasive ductal

carcinoma

ER/PR/HER2 triple-

negative tumors

43/225 (19%)/IHC/ E978

32/81 (40%)/IHC/

B9.8.1.1

[95]

26/1082 (2.4%)/TMA/

E978

[96]

Medullary breast

cancer

94 and 84% of patients

were ER negative

and PR negative,

respectively

11/9 (22%)/IHC/B9.8.1 [97]

12/ 98 (12%)/RT-PCR Humoral response in 4/100

(4%) / RAYS

[98]

Ductal carcinoma

in situ

4/128 (3%)/TMA/E978 Humoral response in 3/62 (5%)

response CD8

inﬁltrates in

5/28 (18%) of NY-ESO-1 positive

tumors

[96]

Lubolar carcinoma

in situ

0/128 (0%)/TMA/E978 CD79a

plasmocytes/B cells

inﬁltrates in 4/9 (44%) of

NY-ESO-1 positive tumors

Invasive ductal

carcinoma

26/1082 (2.4%)/TMA/

E978

Invasive lobular

carcinoma

0/194 (0%)/TMA/E978

Breast carcinoma 6/6 (100%)/qRT-PCR 4/6 (67%)/TMA/E978

Breast carcinoma 37/88 (42%)/RT-PCR,

conﬁrmed by qRT-PCR

1/88 (1%)/IHC/E978 or

ES121

Humoral and CD8

response in

1/62 (2%)

[99]

Benign breast lesion 21/31 (68%)/RT-PCR,

conﬁrmed by qRT-PCR

0/31 (0%)/IHC/E978 or

ES121

Humoral response in 0/9 (0%)

Primary invasive

breast cancer

Humoral response in 25/97

(26%)/ELISA

[10 0]

Ductal carcinoma

in situ

Humoral response in 3/40 (8%)/

ELISA

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Breast (cont.) Triple negative 151 ductal, 7 lobular,

10 other

27/168 (16%)/IHC/ES121 Humoral response in 8/11

(73%)/ELISA CD8

T-cell

response in 27/27 (100%)

[101]

/HER2

1/47 (2%)/IHC/ES121

Triple negative 5/50 (10%)/IHC/

polyclonal antibodies

[102]

Luminal A-like 2/50 (4%)/IHC/

polyclonal antibodies

Gastrointestinal

tumors

Gastrointestinal

stromal tumor

53 samples of stomach,

29 samples of small

bowel, 2 samples of

rectum and 1 sample of

mesentery1 sample of

adrenal gland

10/86 (12%)/IHC/E978 [63]

19 (54%) high risk

tumors, 5 (14%)

intermediate risk

tumors, 8 (23%) low

risk tumors and 3 (9%)

very low risk tumors

7/35 (20%)/IHC/E978 [103]

Gastric cancer 13 stage I, 17 stage II,

45 stage III, 24 stage IV

tumors and 2 cases of

recurrent disease

12/101 (12%)/RT-PCR 7/12 mRNA positives

(56%)/IHC/E978

Humoral response in 7/11 (6

mRNA positives stage III and IV,

1 mRNA negative) (63%)/ELISA

[10 4]

15/112 (13%)/RT-PCR CD8

T-cell responses in a subset

of patients

[105]

12/121 (10%)/RT-PCR 1/12 of mRNA positives

(8%)/IHC/E978

Humoral response in 1 mRNA

positive/82 (1%)/ELISA

[106]

Colorectal cancer Humoral response in 0/25 (0%) [94]

Humoral response in 5/74 (7%)/

SEREX

[107]

Gynecological Vulvar squamous cell

carcinoma

Primary tumors 1/76 (1.3%)/IHC/LS-

C17002

[108]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Head and neck Pharyngeal squamous

cell carcinoma

46 patients with

oropharyngeal and

44 patients with

hypopharyngeal

tumors

30/90 (33.3%)/IHC/

B9.8.1.1

[65]

Mouth, larynx and

pharynx squamous

cell carcinomas

15 mouth, 14 larynx

and 4 pharynx

squamous cell

carcinomas

4/33 (12%)/RT-PCR [10 9]

222 mouth, 94 pharynx

and 137 larynx cancers

4.3%/TMA (IHC)/E978 [25]

Larynx squamous cell

carcinoma

37 supraglottic, 23

glottic and 3 subglottic

neoplasms

6/63 (9.52%)/IHC/E978 [110]

Mouth squamous cell

carcinoma

18/65 (28%)/RT-PCR [38]

Squamous cell

carcinoma

3/57 (6%)/RT-PCR [111]

3/51 (6%)/RT-PCR Humoral response in 3/39 (8%)/

ELISA

[112]

Tongue squamous cell

carcinoma

13/53 (25%)/IHC [113]

Hepatobiliary Hepatoma 2/7 (29%)/RT-PCR [7]

Hepatocellular

carcinoma

10/38 (26.3%)/qRT-

PCR

3/10 (30%) of mRNA-

positive specimens/IHC/

ES121

[114]

Intrahepatic 20/89 (22%)/IHC/E978 [27]

Cholangiocarcinoma Intrahepatic 2/20 (10%)/RT-PCR [115]

Intra- and extra-hepatic 0/50 (0%)/TMA (IHC)/

E978

[116]

Gallbladder

carcinoma

1/32 (3%)/TMA (IHC)/

E978

[116]

3/146 (2%)/TMA (IHC)/

E978

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Hepatobiliary

(cont.)

20 stage I or II and 25

stage III or IV

7/45 (15.6%)/IHC/E978,

TNM stage of 3/7 was I

or II and 4/7 was III or IV

[117]

Hepatocellular

carcinoma

18/41 (43.9%)/RT PCR 3/18 (17%) of mRNA

positive samples/IHC/

ES121

Humoral response in 2/92 (2%)

Both were stage IIIA

[80]

17/62 (27.4%)/RT-PCR 25 /132(18.9%)/TMA

(IHC)

[61]

28/120 (23%)/IHC/E978 [62]

18 stage I–III and 18

stage IV

4/36 (1.1%/RT-PCR) [118]

31/73 (42.5%)/RT-PCR [60]

0/21 (0%)/RT-PCR [119]

12/30 (40%) /RT-PCR [12 0]

10/30 (33%)/RT-PCR 13.8% (24/174)/IHC [121 ]

19/64 (30%)/qRT-PCR [122]

9/34 (27%)/ RT-PCR Humoral response in 6/37

(16.2%)/ELISA 5 ≥ stage III and

1 stage II

[12 3]

12/49 (24%) /RT-PCR Humoral and NY-ESO-1-speciﬁc

functional CD4

and CD8

T-cell

response in 23/189 (12%)

[124]

28 /55 (51%)/RT-PCR Humoral response in 4/22

(18%)/ELISA CD8

T-cell

response in 10/28 (37.5%)

[125]

Pancreas 0/24 (0%)/RT-PCR 0 / 24 ( 0%) / R AYS [12 6]

0 / 96 (0%)/RAYS

0 /18 ( 0%) / R AYS

Kidney Chromophobe renal

cell carcinoma

6/18 (33%)/IHC/D8.38 [127]

Renal oncocytoma 15/17 (88%)/IHC/D8.38

Lung Lung carcinoma 2/12 (17%)/RT-PCR [7]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Lung (cont.) 3/50 (60%)/qRT-PCR [114]

Small cell lung

carcinoma

Humoral response in 4/43 (9%)/

ELISA

[12 8]

0/4 (0%)/ RT-PCR [129]

Large cell carcinoma 2/9 (22%)/RT-PCR [13 0]

(8/45) 17.8/TMA (IHC)/

D8.38

[131]

(4/38) 10.5%/TMA

(IHC)/D8.38

[131]

5/37 (14%)/RT-PCR [13 0]

Adenocarcinoma 3/25 (12%)/qRT-PCR Humoral response in 3/90

(3.3%) and 5/60 (8.3%) of

patients from the USA and

Japan, respectively

[132]

2/53 (3.8%)/RT-PCR [133]

10.8%/IHC/B9.8.1.1 [134]

9/57 (16%)/IHC/E978 [135]

Humoral response in 9/62

(15%)/ELISA

[12 8]

Adenosquamous

carcinoma

1/3 (33%)/RT-PCR [130]

11/41 (27%)/RT-PCR

8/41 (19%)/RT-PCR [133]

Squamous cell

carcinoma

23.3%/IHC [134]

15/75 (20%)/IHC/E978 [135]

Humoral response in 16/55

(29%)/ELISA

[12 8]

4/12 (33%)/RT-PCR [130]

Undifferentiated lung

carcinoma

Humoral response in 6/15

(40%)/ELISA

[12 8]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Lung (cont.) 40 adenocarcinoma

and 40 squamous cell

carcinoma

18.5%/IHC/B9.8.1.1 [136]

11/141 (7.8%) / RT- PCR 13/157 (8.3%)/IHC/E978 [133]

9/87 (10.3%)/ELISA [75]

Non-small-cell lung

cancer (NSCLC)

Early stage, primary 11.8%(20/169)/IHC/E978 [43]

1/42 (2%)/RT-PCR [129]

7/33 (21%)/RT-PCR [137]

139 /523 (27%)/RT-PCR [138]

20/63 (32%)/RT-PCR [139]

25/239 (10%)/RT-PCR [14 0]

Primary operable

tumor

Humoral response in 1/24

(4.2%)/ELISA

[94]

Melanocytic Head and neck

melanoma

40 initial, 15 recurrent

and 15 metastatic

melanomas

17/70 (24%)/IHC/ES121 [141]

Esophageal

melanoma

primary tumors 6/6 (100%)/IHC/ESO121 [14 2]

Conjunctival

melanoma

0/15 (0%)/IHC/E978 [57]

Uveal melanoma 0/32 (0%)/IHC/E978

Desmoplastic

melanoma

3/32 (9%)/IHC/E978 [56]

Primary tumor 45%/IHC/E978 [35]

Metastatic tumor 45%/IHC/E978

50/120 (42%)/qRT-PCR 48/120 (40%)/IHC/E978 [143]

Stage I and stage II

primary cutaneous

melanoma

120/321(37%)/IHC/E978 [73]

12/38 (38%)/TMA (IHC) [131]

23/67 (37%)/RT-PCR [7]

Primary tumor 0/20 (0%)/RT-PCR [14 4]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Melanocytic

(cont.)

Distant metastasis 4/10 (40%)/RT-PCR

Locoregional

metastasis

7/22 (32%)/RT-PCR

2/20 (10%)/qRT-PCR [114]

Metastatic tumor 14/63 (23%)/RT-PCR [1 45]

10/23 (44%)/RT-PCR [14 6]

143/202 (71%)/RT-PCR [147]

Melanoma Metastatic Humoral response in 12/127

(9.4%)/ELISA

[94]

Humoral response in 3/44 (7%)/

SEREX

[148]

2/9 (2%)/RT-PCR Humoral response in 2/9 (2%)/

ELISA CD8

T-cell responses/

ELISPOT

[149]

Humoral response in 17/148

(11%)/ELISA HLA-DP4 in 16/17

(94%) of seropositive patients

CD4

T cells speciﬁc for the NY-

ESO-1 epitopes were generated

from 5 of 6 melanoma patients

with NY-ESO-1 Ab

[150]

Humoral response in 13/31

(42%)/ELISA CD4

T cell 11/13

(85%) of seropositive patients/

ELISPOT

[151]

22/39 (56%)/IHC/E978 [152]

Primary tumor 8/61 (13%)/IHC/E978 [54]

Metastatic tumor 18/56 (32%)/IHC/E978

Esophageal Adenocarcinoma 4 well differentiated,

14 moderately

differentiated,

4 moderately poorly

differentiated and

5 poorly differentiated

4/27 (15%) including

2 moderately

differentiated; 1

moderately-poorly

differentiated; 1 poorly

differentiated/IHC/E978

[22]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Esophageal

(cont.)

26 stages I–II, 15 stages

III-IV

17/41 (41%)/ RT-PCR [153]

Metastatic 53/55 (96%)/IHC/D8.38 [15 4]

Squamous cell

carcinoma

32/109 (29%)/TMA [155]

6/9 (67%)of mRNA

positive samples/IHC/

ES121

[114]

41/123 (33%)/RT-PCR 21/24 (87.5%) of mRNA

positive samples/IHC/

ES121 and E978

Humoral response in 2/51 (4%)/

ELISA CD8

T-cell response in 1/2

seropositives/ELISPOT

[156]

67 squamous

cell carcinoma,

1 adenocarcinoma,

1 small cell carcinoma

18/56 (32%)/IHC Humoral response in 9/69

(13%)/western blot

[157]

28/76 (26.8%)/RT-PCR CD8

T-cell responses in a subset

of patients

[105]

202 squamous

cell carcinoma,

6 adenocarcinoma,

4 adenosquamous

carcinoma and

1 undifferentiated

carcinoma

44/213 (21%)/IHC/E978 [158]

Prostate 8.8% of 8761 tumors

(5.8% weak, 2.5%

moderate and 0.5%

strong expression)/TMA

(IHC)/E978

[1 59]

Stage C (15/53) or D

(38/53)

20/53 (38%)/RT-PCR Humoral response in 1/30

(3.3%) stage D1 and 9/110

(8.2%) stage D2 patients/ELISA

CD8

T-cell response in 2/3

seropositives (67%) CD8

T cell

[160]

Prostate cancer Localized 2/66 (3%)/IHC/B8.38 Humoral response in 1/112 (1%)/

ELISA and western blot

[77]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Prostate (cont.) Hormone refractory

prostate cancer

7/48 (15%)/IHC/B8.38 Humoral response in 18/95

(17%)/ELISA and western blot

Humoral response in 4/20

(20%)/SEREX and ELISA

[161]

9/23 (39%)/ RT-PCR Humoral response in 12/23

(52%) patients and in 5/9 (55%)

of NY-ESO-1 expressing tumors/

ELISA

[162]

78/92 (85%)/IHC/D8.38 [127]

3/20 (15%)/IHC/D8.38

Benign prostate

hyperplasia

0/23 (0%)/RT-PCR Humoral response in 0/23 (0%)/

ELISA

[162]

Ovarian Ovarian germ cell

tumor

0/60 (0%)/IHC [163]

50/117 (43%)/IHC/ES121 [16 4]

Primary tumor 16/230 (7%)/IHC/E978 [165]

Recurrent tumor 7/80 (9%)/IHC/E978

2/8 (25%)/RT-PCR [7]

Ovarian carcinoma 2/20 (10%)/qRT-PCR [114]

Metastatic Humoral response in 4/32

(12.5%)/ELISA

[94]

Epithelial ovarian

cancer

37/48 (77%)/RT-PCR 37/48 (77%)/IHC/ES121 Humoral response in 12/48

(25%) and 11/37 (30%) of

expression positive patients/

ELISA (NY-ESO-1 and LAGE-1 are

serologically undifferentiable)

[37]

Humoral and speciﬁc CD8

T-cell

response in 10/14 (71%)

[166]

High-grade serous

ovarian cancer

5/34 (15%)/IHC/E978 Humoral response in (9/35) 26% [167]

Serous carcinoma 10/53 (19%)/IHC/D8.38 [168]

Cervical Squamous and adeno/

adenosquamous

46/94 (48%) and 6/15

(40%) of untreated

and recurrent tumors

respectively/IHC/D8.38

[169]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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Cancer type Tumor subtype Sample type mRNA expression/

technique

Protein expression/

technique and mAb

Humoral and cellular immune

response/technique

Ref.

Sarcoma Myxoid/round cell

liposarcoma

4 metastatic and 21

primary tumors

6/6 (100%)/qRT-PCR 25/25 (100%)/IHC/E978 [42]

7/8 (88%)/qRT-PCR 16/18 (89%)/IHC/E978 [40]

36/38 (95%)/IHC/E978 [41]

Extra-cardiac soft

tissue myxoma

0/39 (0%)/IHC/E978

Extraskeletal myxoid

chondrosarcoma

0/12 (0%)/IHC/E978

Lipoma 0/20 (0%)/IHC/E978

Low-grade

ﬁbromyxoid sarcoma

0/7 (0%)/IHC/E978

Myxoﬁbrosarcoma 0/10 (0%)/IHC/E978

Synovial sarcoma 38/50 (76%)/IHC [170]

Stage IV sarcoma 41/50 (82%)/IHC [171]

Chondrosarcoma 5 metastatic, 3 locally

recurrent, 3 disease

free

1/11 (9%)/qRT-PCR

which was metastatic

[172]

9 subtypes 13/36 (36%)/RT-PCR 9/36 (11%)/IHC/ES121 Humoral and CD8

T-cell

responses in 1/4 (25%) of

synovial sarcoma samples/ELISA

and ELISPOT

[1 73]

Angiosarcoma 2/20 (10%)/IHC [171]

Ewing sarcoma 0/18 (0%)/IHC

Dermatoﬁbrosarcoma

protuberans

2/20 (10%)/IHC

Testicular Testicular germ cell

tumors

Seminal ﬂuid 49/57 (86%)/IHC/D8.38 [174]

Seminona (classical) 12/73 (16%)/IHC/E978 [30]

Diffuse large B-cell

testicular lymphoma

9/24 (37%) IHC [26]

Penile Carcinoma 29/30 (97%)/IHC/D8.38 [175]

ELISA: Enzyme-linked immunosorbent assay; ELISPOT: Enzyme-linked immunospot; ER: Estrogen receptor; IHC: Immunohistochemistry; mAb: Monoclonal antibody; PR: Progesterone receptor;

(q)RT-PCR: (Quantitative) reverse transcription PCR; RAYS: Recombinant antigen expression on yeast surface; SEREX: Serological analysis of recombinantly expressed clones; TMA: Tissue microarray.

Table 1. New York esophageal squamous cell carcinoma-1 expression and immunogenicity in different cancers (cont.).

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cination were more focused than naturally induced

ones [72] .

Historically, the ﬁrst peptides from NY-ESO-1 rec-

ognized by CD8

T cells were identiﬁed in a mixed

tumor lymphocyte culture. The 155–163 (Q9T),

157–165 (S9C) and 157–167 (S11L) peptides were

shown to be restricted by the HLA-A2 molecule.

Among them peptide Q9T was not frequently immuno-

genic and S9C and S11L had overlapping reactivities.

In addition, in vitro stimulation with both S9C and

S11L led to cross-reactive responses [176] . Afterwards,

different programs of vaccination using S9C and

S11L have been performed and their efﬁcacy on the

induction of NY-ESO-1 peptide speciﬁc CD8

T-cell

responses has been conﬁrmed [177] . The potency of

other NY-ESO-1 peptides to elicit immune responses

has been evaluated in other studies. For instance, in a

survey of naturally occurring CD4

T-cell responses

against NY-ESO-1 in cancer patients, NY-ESO-1 pep-

tide 80–109 has been shown to be the most immu-

nogenic. NY-ESO-1 epitopes eliciting a CD4

T-cell

response have been peptide 87–98 presented by HLA

class II, peptide 108–119 restricted by HLA-DP4,

peptides 121–132 and 145–156 presented by HLA-

DR7 [151] and 119–143 presented by HLA-DR52b [178] .

In another study, immunodominant regions identiﬁed

in the NY-ESO-1 protein include peptide 79–102 and

peptide 115–138 for CD4

T cells and peptide 85–108

for CD8

T cells [152] . There are currently at least 21

distinctive epitopes illustrated in the context of at least

ﬁve HLA class II alleles [179] .

Cytotoxic T lymphocyte (CTL) against NY-ESO-1

epitopes has been assessed in tumor inﬁltrating

lympho cytes (TIL) as well. TILs are a heterogeneous

population of cells within tumors whose impact on the

outcome of cancer is an issue of debate. However, it

is speculated that their function is often compromised

due to accumulation of immunoregulatory cells and

different tumor escape mechanisms [180] . In a study

it has been revealed that although CTAs such as NY-

ESO-1 are frequently expressed in non-small-cell lung

cancer (NSCLC), CTL reactivity against their epit-

opes in TILs from nonimmunized NSCLC patients is

rare [181] . Another study has revealed an insigniﬁcant

correlation between NY-ESO-1 expression and T-cell

inﬁltration in NSCLC suggesting that the spontane-

ous immune response is not sufﬁcient against this anti-

gen [133] . In a more recent study, it has been demon-

strated that the number of inﬁltrating dendritic cells

(DCs) is higher in NSCLC patients whose tumors are

negative for NY-ESO-1 compared with those show-

ing positivity for NY-ESO-1. So it has been suggested

that NY-ESO-1 positive tumor cells would escape host

immune response in a manner which is similar to tumor

stem cells. However, no correlation was found between

DC and CTL inﬁltrations in these patients [135] . How-

ever, in epithelial ovarian cancer patients it has been

demonstrated that TILs correlate with NY-ESO-1

speciﬁc autoantibodies. Consequently, it has been sug-

gested that autoantibodies may collaborate with TILs

to affect clinical outcomes in these patients [182] . How-

ever, another study in epithelial ovarian cancer has

shown that although intraepithelial CD8

TILs and

a high CD8

/Treg ratio are associated with favorable

prognosis, this favorable prognostic effect is not cor-

related with concurrent expression of NY-ESO-1 [16 4] .

In hepatocellular carcinoma, the number of intratu-

moral FOXP3

regulatory T cells (Tregs) has been

shown to be higher in CTA positive samples (including

those positive for NY-ESO-1) suggesting inhibition of

immune response in such tumors [116] . More studies

are needed to evaluate the correlation of CTA expres-

sion with the function of TILs including cytotoxic and

Tregs.

It has been shown that human DCs that were incu-

bated with NY-ESO-1: monoclonal anti-NY-ESO-1

antibody (12D7) immune complexes efﬁciently stimu-

lated NY-ESO-1

157–165

/HLA-A2-speciﬁc human CD8

T cells to produce IFN-γ. In addition, the incubation

of DCs with NY-ESO-1:12D7 immune complexes has

been shown to result in the maturation of DCs [183] . It

has been demonstrated that more than 90% of patients

with circulating anti-NY-ESO-1 antibodies also devel-

oped an NY-ESO-1-speciﬁc CD8

T cells that were

not detected in patients in whom anti-NY-ESO-1

antibodies were absent [18 4] . NY-ESO-1 can be used

as an antigen in stem cell transplantation with T-cell

receptor (TCR)-engineered hematopoietic stem cells

as well as adoptive cell therapy with TCR-engineered

differentiated T cells. In a recent study, it has been

shown that hematopoietic stem cells engineered with

a TCR that recognizes NY-ESO-1 can successfully

differentiate to functional CD8

T cells in human-

ized mice. Interestingly, CD8

T cells harvested from

spleens of this mouse model could expand in vitro and

recognize NY-ESO-1 expressing targets 3 months post

transplant. Such an approach allow continuous supply

of T cells targeting a tumor antigen solving the prob-

lem seen when terminal differentiation results in dis-

appearance of injected mature tumor-targeted T cells

from hosts [185] .

Immunotherapeutic approaches against NY-ESO-1

have extensively focused on cellular effectors which

are induced by vaccination or expanded ex vivo and

transferred to the patients [18 6] . For improvement of

efﬁcacy of T cell cancer vaccines, it is important to ﬁnd

mechanisms for optimal priming of NY-ESO-1 spe-

ciﬁc CTLs. As shown in a transgenic mouse model, the

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Table 2. Recent clinical trials with New York esophageal squamous cell carcinoma-1 in cancer patients.

Adjuvant Number of patients, cancer

type

Immunogen Immune response (compared

with natural prevaccination

responses)

Clinical Trial

Phase

ISCOMATRIX 6 HLA-B7

melanoma

patients

HLA-B7-restricted

NY-ESO-1

60–72

CD8

: 1 increased, 2 induced 1

1 transitional cell carcinoma

of bladder, 42 melanoma and

3 breast cancer patients

Recombinant

NY-ESO-1

Ab: 38 induced, 4 stabilized,

4 increased response

27 metastatic melanoma

patients

Recombinant

NY-ESO-1

Ab: 19 induced, 7 stabilized

CD4

: 4 stabilized, 3 induced

CD8

: 12 stabilized, 3 induced

39 melanoma patients Ab: 5 stable, 34 induced

Cholesterol-bearing

hydrophobized pullulan

complexed

1 melanoma patient with

multiple metastases

NY-ESO-1 Ab: increased CD4

: induced

CD8

: induced

8 esophageal cancer patients NY-ESO -1 Ab: 5 induced, 1 increased,

1 stabilized CD4

: 4 induced,

2 increased, 1 stabilized

CD8

: 2 induced, 2 increased,

2 stabilized

1 melanoma patient, 4

esophageal and 4 prostate

cancer patients

NY-ESO-1 Ab: 6 induced, 2 increased,

1 stabilized

1 melanoma patient, 4

esophageal and 4 prostate

cancer patients

NY-ESO-1 Ab: 6 induced, 2 increased,

1 stabilized CD4

: 5 induced,

1 increased, 1 stable CD8

4 induced, 2 increased, 1

stabilized

8 esophageal cancer patients Recombinant

NY-ESO-1

Ab: 4 induced, 2 stabilized 1

8 esophageal and 2 prostate

cancer patients

Recombinant

NY-ESO-1

Ab: 5 increased, 4 induced 1

13 esophageal cancer

patients

NY-ESO-1 Ab: 5 induced, 2 increased 1

12 esophageal cancer

patients

Ab: 5 induced, 7 increased

Ipilimumab 15 metastatic melanoma

patients

– Ab: 3 increased, 2 induced,

10 negative CD4

: 5 induced,

1 stabilized CD8

: 5 induced

20 advanced melanoma

patients

– Ab: 5 induced, 5 increased,

8 stabilized, 1 decreased

CD4

: 5 induced, 4 increased,

3 stabilized CD8

: 4 induced,

3 increased, 3 stabilized,

1 decreased

46 metastatic melanoma

patients

– Ab: 4 induced, 2 increased,

2 stabilized

Ab: Antibody; BCG: Bacille de Calmette et Guérin; GM-CSF: Granulocyte-macrophage colony stimulating factor; IFA: Incomplete freund’s adjuvant; OLP: Overlapping

long peptides; MBV: Mixed bacterial vaccine; Poly-ICLC: Polyinosinic–polycytidylic acid-stabilized by lysine and carboxymethyl cellulose.

Data taken from [197] .

www.futuremedicine.com

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NY-ESO-1 & cancer immunotherapy Review

Adjuvant Number of patients, cancer

type

Immunogen Immune response (compared

with natural prevaccination

responses)

Clinical Trial

Phase

Recombinant

vaccinia-NYESO-1 and

recombinant fowlpox-

NY-ESO-1 vaccine

12 melanoma, 4 sarcoma,

2 head and neck, 1

breast, 1 ovarian, 1

prostate, 1 teratoma and 1

endometrial cancer patients

Recombinant

vaccinia-NYESO-1

and recombinant

fowlpox-NY-ESO-1

vaccine

Ab: 6 induced, 5 stabilized

CD4

: 6 induced, 6 stabilized

CD8

: 14 induced, 5 stabilized

Blood dendritic cells

generated with Flt3

ligand and CD40 ligand

6 melanoma patients NY-ESO-1

157–165

CD8

: 2 induced Pilot

endogenous T-cell

therapy

6 sarcoma patients NY-ESO-1

157–165

CD8

: 6 induced Pilot

Toll-like receptor 7

agonist imiquimod

9 malignant melanoma

patients

Recombinant

NY-ESO-1

Ab:4 induced CD4

: 6 induced

CD8

: all negative

Pilot

BCG and GM-CSF 6 urothelial carcinoma

patients

Recombinant

NY-ESO-1

Ab: 4 induced,1 increased

CD4

: 6 induced CD8

: 1

induced

Poly-ICLC 11 ovarian cancer patients OLP from NY-ESO-1 Ab: 10 induced or increased

CD8

: 10 induced or increased

CD4

: 11 induced or increased

Montanide ISA-51 (IFA) 13 ovarian cancer patients OLP from NY-ESO-1 Ab: 6 induced or increased

CD8

: 8 induced or increased

CD4

: 13 induced or increased

4 HLA-A2

patients with

metastatic skin melanoma

3 synthetic peptides

(including NY-

ESO-1

157–165

)

CD8

: 4 increased 1

4 HLA-DP*0401/0402 patients

(2 baseline seronegative

and 2 baseline seropositive

ovarian epithelial cancer

patients)

NY-ESO-1

157–170

NY-ESO

-1157–170

peptide-speciﬁc

CD4

Th1 Cells induced in all

patients without depletion of

CD4

CD25

T-cell vaccination

18 HLA-DP4

epithelial cancer

patients with minimal disease

burden

NY-ESO

157–170

Ab: 2 induced, 3 stabilized

CD4

: 13 induced, 2 stabilized

CD8

: 4 induced

CpG 7909 /PF3512676 9 epithelial ovarian cancer

patients

NY-ESO-1

157–165

CD8

: 6 induced 1

11 melanoma, 3 breast, 3

sarcoma, 1 ovarian cancer

patient

Recombinant

NY-ESO-1

Ab: 17 induced, 1 stabilized

CD4

: 17 induced CD8

8 induced, 1 increased

3 melanoma patients Analogue peptide

NY-ESO-1

157–165V

CD8

: 3 increased Pilot

7 melanoma, 4 non-small-

cell lung cancer, 1 sarcoma,

1 ovarian, 1 breast cancer

patient

NY-ESO-1

157–165

Ab: 5 stabilized, 1 induced

CD8

: 8 induced

Ab: Antibody; BCG: Bacille de Calmette et Guérin; GM-CSF: Granulocyte-macrophage colony stimulating factor; IFA: Incomplete freund’s adjuvant; OLP: Overlapping

long peptides; MBV: Mixed bacterial vaccine; Poly-ICLC: Polyinosinic–polycytidylic acid-stabilized by lysine and carboxymethyl cellulose.

Data taken from [197] .

Table 2. Recent clinical trials with New York esophageal squamous cell carcinoma-1 in cancer patients (cont.).

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Th1 cytokines IFN-γ and IL-2 play important roles in

CTL priming. In addition, the inﬂammatory chemo-

kines CCL4 (MIP-1b) and CCL3 (MIP-1a) contrib-

ute in chemoattraction of primed CD4

T and CD8

T cells to mature DCs and to DC–CD4 conjugates,

respectively [187] .

Applications in clinical trials

A tumor antigen is considered as an appropriate can-

didate for cancer immunotherapy if it has the fol-

lowing characteristics: speciﬁc and stable expression

in the tumor, absence from normal tissues and being

necessary for the survival of the cancer cell [188] . NY-

ESO-1 represents one of the ideal tumor antigens in

this ﬁeld. Preclinical models as well as early stage clini-

cal trials with NY-ESO-1 speciﬁc T cells have dem-

onstrated promising results. Cancer vaccine trials with

NY-ESO-1 have been performed in different molecu-

lar forms. Most clinical trials with NY-ESO-1 tumor

vaccines have used either individual HLA restricted

epitopes or whole protein, with or without adjuvants.

Enhanced T- and B-cell responses to this antigen have

been observed in most of them post vaccination. NY-

ESO-1 peptide vaccines with HLA-A2 restricted pep-

tides have been used in clinical trials and CD8

T-cell

responses have been elicited post vaccination [189] . One

of the earliest clinical trials in patients with NY-ESO-1

tumors studied the immunogenicity of NY-ESO-1

peptides S9C and S11L along with granulocyte-

macrophage colony-stimulating factor as an adjuvant.

The results showed NY-ESO-1-speciﬁc CD8

T-cell

responses to S11L and S9C in most vaccinated patients

without preexisting immunity to NY-ESO-1 [190 ,191]. A

clinical trial with NY-ESO-1 has been performed using

a His-tagged recombinant full-length protein alone or

with a saponin based adjuvant (ISCOMATRIX), in

NY-ESO-1 positive melanoma patients with minimal

residual disease. High titer anti-NY-ESO-1 antibody

responses have been induced in all patients vaccinated

with NY-ESO-1 ISCOMATRIX but in only 25 % of

those who got NY-ESO-1 protein without adjuvant. In

addition, circulating CD4

and CD8

T cells speciﬁc

for a variety of NY-ESO-1 epitopes were induced [192] .

The same vaccine formulation has been used recently

in stage IV or unresectable stage III melanoma patients.

Contrary to minimal residual disease, advanced mela-

noma patients showed no clinical response to vaccina-

tion which has been attributed to higher proportion

of circulating Tregs in such patients [193] . Recombi-

nant vectors encoding NY-ESO-1 in addition to other

tumor antigens and even short hairpin RNA have

been used in preclinical models to enhance immune

system activation [194] . In addition, NY-ESO-1 pro-

tein complexed with cholesteryl pullulan (CHP),

CHP-NYESO- 1 has been administered in combina-

tion with the truncated 146HER2 protein with CHP,

CHP-HER2 to esophageal cancer patients. The results

indicate well-toleration as well as induction of NY-

ESO-1- and HER2-speciﬁc antibody responses which

show feasibility of protein cancer vaccines targeting

multiple antigens [195] . A summary of more recent clin-

ical trials which used NY-ESO-1 peptides with differ-

ent adjuvants has been shown in Table 2. In brief, NY-

ESO-1 vaccination has been shown to efﬁciently prime

an antibody, CD8

and CD4

T-cell response to NY-

ESO-1. However, because of the direct cytotoxic effect

Adjuvant Number of patients, cancer

type

Immunogen Immune response (compared

with natural prevaccination

responses)

Clinical Trial

Phase

Decitabine (decitabine

and doxorubicin

liposome)

12 epithelial ovarian cancer

patient

Vaccine (NY-

ESO-1- GM-

CSF,

Montanide)

Ab: 5 induced, 3 stabilized,

2 not available, 1 increased,

1 negative CD4

: 5 stabilized,

2 induced, 2 became negative,

2 not available, 1 negative

CD8

: 6 negative, 2 induced,

2 not available, 2 stabilized

MBV 6 melanoma, 2 prostate,

1 bladder, 1 head and neck,

2 sarcoma patients

– Ab: 7 stabilized, 1 induced, 1

increased, 1 decreased CD4

all were unchanged CD8

: all

were unchanged

NY-ESO-1 expressing

autologous tumor cells

4 metastatic melanoma

patients

NY-ESO-1

p157–165

CD8

: 3 induced, 1 increased Pilot

Ab: Antibody; BCG: Bacille de Calmette et Guérin; GM-CSF: Granulocyte-macrophage colony stimulating factor; IFA: Incomplete freund’s adjuvant; OLP: Overlapping

long peptides; MBV: Mixed bacterial vaccine; Poly-ICLC: Polyinosinic–polycytidylic acid-stabilized by lysine and carboxymethyl cellulose.

Data taken from [197] .

Table 2. Recent clinical trials with New York esophageal squamous cell carcinoma-1 in cancer patients (cont.).

www.futuremedicine.com

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future science group

NY-ESO-1 & cancer immunotherapy Review

of CD8

T cells against tumor cells, CTL mediated

immunity by MHC class I-restricted tumor peptides

is the focus of most cancer vaccine studies. As it is dif-

ﬁcult to induce fully activated CTL by tumor vaccine

therapy using MHC class I binding peptides, different

adjuvants are used in addition to MHC class I-binding

peptides to improve the efﬁciency of tumor vaccine

therapy. Furthermore, it has been demonstrated that

CD4

T cells have a critical role in the priming and

maintenance of CD8

T cells [19 6] .

In general, long-term vaccination with NY-ESO-1

protein has resulted in broader and more pronounced

immune responses. While short-term intensive vacci-

nation with peptides has elicited the strongest CD8

T-cell responses to single epitopes [6]. An important

issue to be considered to reach better efﬁciency of

vaccination is the format of the vaccine. It has been

shown in a mouse H-2

MHC background that genetic

(plasmid DNA), but not full length protein vaccine

can induce a protective prophylactic anti-tumor CTL

immune response in vivo. In addition, peptide vaccina-

tion using nominal MHC class I epitope adjuvanted

with a Toll-like receptor agonist such as stabilized RNA

has been demonstrated to induce some anti tumor pro-

tection. Clinically relevant anti-NY-ESO-1 immune

response is attributed to CTL but not antibodies

against NY-ESO-1 [198] . In humans, induction of CTL

responses following NY-ESO-1 protein vaccination

has been shown to be usually limited to the existence

of HLA-B35 and HLA-Cw3 MHC class I alleles [199] .

Therefore, an efﬁcient anticancer cytotoxic immune

response against NY-ESO-1 after protein vaccination

is not probable to occur in most humans. As shown by

Parvanova et al., genetic vaccine is capable of mount-

ing a clinically relevant immune response against NY-

ESO-1. It has been suggested that antigen processing

of NY-ESO-1 can make different MHC class I epitopes

when the protein is an exogenous antigen as compared

with an endogenous one [200] . In addition, TCR based

gene therapies targeting NY-ESO-1 has been shown

to be an effective treatment modality for patients with

metastatic melanoma and synovial cell sarcoma [201,202] .

The IHC staining proﬁling of tumors is important in

proper patient selection for such targeted adoptive cell

transfer immunotherapy clinical trials [55] .

Several clinical trials conducted in NY-ESO-1 posi-

tive patients have resulted in clinical responses. For

instance, in a study conducted in patients with metastatic

NY-ESO-1-expressing cancers, intra dermal immuniza-

tion with NY-ESO-1 peptides resulted in stabilization

of disease and regression of individual metastases in a

subset of patients [203]. In addition, vaccination with

recombinant vaccinia/fowlpox NY-ESO-1 vaccines

could result in favorable change in the natural course

of the disease in several patients with melanoma [204].

A recent study has shown a favorable clinical outcome

with overall survival times up to more than 43 months

in patients with NY-ESO-1 or LAGE-1 expressing

tumors who were vaccinated with NY-ESO-1 peptide,

CpG 7909 and Montanide ISA-51 [205]. Another study

aimed at safety and immuno genicity assessment of

NY-ESO-1b peptide and montanide ISA-51 vaccina-

tion in patients with high-risk epithelial ovarian can-

cer, complete clinical remission was observed in three

patients at 25, 38 and 52 months [206]. Another study

has demonstrated the induction of NY-ESO-1 immu-

nity and some favorable clinical outcomes in esopha-

geal cancer patients vaccinated with NY-ESO-1 pro-

tein. However, vaccination could not inhibit ultimate

tumor growth [207] . In spite of early clinical responses

seen after NY-ESO-1-speciﬁc immunotherapy, tumor

recurrence has occurred in some cases. The mechanism

of such recurrence is not clariﬁed yet. However, loss of

heterozygosity (LOH) in the major histocompatibility

complex (MHC) involving the HLA-A locus has been

observed in a murine xenograft model of NY-ESO-1

multiple myeloma in which tumor recurred after adop-

tive transfer of NY-ESO-1 speciﬁc CD8

T cells. So

loss of MHC expression from the cell surface has been

suggested as a possible mechanism for immune escape

from NY-ESO-1-speciﬁc T-cell therapy [208].

Conclusion

Considering the vast expression of NY-ESO-1 in

tumors of different histological types and spontane-

ous humoral and cellular responses detected in a sig-

niﬁcant number of such patients, various studies have

focused on designing potent NY-ESO-1 based vaccine

formulations. Such vaccines have been used in numer-

ous clinical trials with promising results in a subset

of patients. As recurrence has occurred in a number

of patients after primary responses to such vaccines,

attempts are done to ﬁnd the molecular mechanism of

such recurrences. The results of these studies would

help to deﬁne ‘selection criteria’ for patients entering

clinical trials.

Future perspective

NY-ESO-1 is the most immunogenic CTA identiﬁed

up to date. It has been applied in a number of clinical

trials with variable results. Trials with better responses

in patients have helped to understand the optimal tim-

ing and vaccine formulation to elicit immune responses.

However, existing vaccines still need improvement,

both in antigen and in adjuvant formulations [6]. The

wide spectrum of NY-ESO-1 expression in different

tumors is the main advantage of it as a high percentage

of cancer patients can beneﬁt from a certain vaccine.

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Immunotherapy (2015) 7(4)

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Review Esfandiary & Ghafouri-Fard

Attempt to design an efﬁcient vaccine for NY-ESO-1

should focus on designing a vaccine with any potential

epitope which can be naturally processed or delivered

to the cytoplasm of APCs, have an acceptable half life

once injected and is primed in an environment which

avoid the rise of regulatory cells [6]. An important

approach to overcome the mechanisms used by tumors

to evade the immune system is combination therapy.

One possible combination would be the use of DNA

methylation inhibitors combined with immunother-

apy. Such agents can enhance the expression of CTAs

such as NY-ESO-1 on cancer cells, thus increasing the

recognition of cancer cells by antigen-speciﬁc T cells.

Another possibility is the use of immunomodulatory

antibodies such as anti-CTLA-4 mAb ipilimumab

in combination with CTA-based vaccines. Such an

approach has been shown to enhance poly functional

NY-ESO-1-speciﬁc T-cell responses in treated mela-

noma patients [209] . Future clinical trials would beneﬁt

from such agents in conjunction with tumor vaccines.

In addition, vaccines designed against multi-antigens

including NY-ESO-1 and other immunogenic CTAs

will be beneﬁcial in overcoming immune evasion of

tumors.

Financial & competing interest disclosure

The authors have no relevant afliations or nancial involve-

ment with any organization or entity with a nancial inter-

est in or nancial conict with the subject matter or mate-

rials discussed in the manuscript. This includes employment,

consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this

manuscript.

Executive summary

• New York esophageal squamous cell carcinoma-1 (NY-ESO-1) is the most immunogenic cancer-testis antigen

identiﬁed up to date.

• It has been shown to be expressed in a wide variety of tumor tissues with the highest expression frequency in

neuroblastoma, synovial sarcoma, melanoma, cervical cancer and epithelial ovarian cancer.

• Spontaneous humoral and cellular immune responses against NY-ESO-1 have been detected in cancer patients.

• The safety and efﬁciency of NY-ESO-1 vaccines have been assessed in a number of clinical trials.

• NY-ESO-1 has been shown to be a promising target for immunotherapy of many cancers.

• NY-ESO-1 may be a potential biomarker for early recurrence in some cancers.

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The potential value of cancer‐testis antigens in ovarian cancer: Prognostic markers and targets for immunotherapy

Article

Full-text available

Jun 2024

Background Tumor immunotherapy has become an important adjuvant therapy after surgery, radiotherapy, and chemotherapy. In recent years, the role of tumor‐associated antigen (TAA) in tumor immunotherapy has become increasingly prominent. Cancer‐testis antigen (CTA) is a kind of TAA that is highly restricted in a variety of tumors and can induce an immune response. Aims This review article aimed to evaluate the role of CTA on the progression of ovarian cancer, its diagnostic efficacy, and the potential for immunotherapy. Methods We analyzed publications and outlined a comprehensive of overview the regulatory mechanism, immunogenicity, clinical expression significance, tumorigenesis, and application prospects of CTA in ovarian cancer, with a particular focus on recent progress in CTA‐based immunotherapy. Results The expression of CTA affects the occurrence, development, and prognosis of ovarian cancer and is closely related to tumor immunity. Conclusion CTA can be used as a biomarker for the diagnosis and prognosis evaluation of ovarian cancer and is an ideal target for antitumor immunotherapy. These findings provide novel insights on CTA in the improvement of diagnosis and treatment for ovarian cancer. The successes, current challenges and future prospects were also discussed to portray its significant potential.

The role of the NY-ESO-1 in the prognosis of gastric cancer

Article

Full-text available

Dec 2023

Gastric cancer (GC) is one of the most common malignancies worldwide and the fourth leading cause of cancer-related deaths. GC is a multifactorial disease influenced by both environmental and genetic factors. Its most critical features include invasiveness and high metastatic potential. Metastasis is a complex process, and our understanding of the mechanisms involved remains incomplete. Growing evidence suggests that cancer-testis antigens (CTAs) play a crucial role in the metastatic potential of various tumors. Several studies have linked CTA expression with lower tumor differentiation, higher metastatic potential, and poor chemotherapy response. New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen, part of the CTA group, is expressed in tumor tissues, while its expression in normal tissues is restricted to spermatogonia. This study aimed to determine the expression of NY-ESO-1 in primary adenocarcinoma of the stomach, both with and without metastasis in regional lymph nodes, and to compare it with TNM stage, age, gender, and survival. We analyzed gastric cancer tissue from 53 node-negative and 55 node-positive primary gastric carcinoma patients for NY-ESO-1 expression using immunohistochemical assay. The results were correlated with clinicopathological parameters and survival. Patients with positive NY-ESO-1 expression in primary tumors had a median survival of 19.0 months (range 14.1 – 24.0), in contrast to those with negative expression, who had a median survival of 52.0 months (range 0.0 – 133.3) (chi-square 7.99, P = 0.005). T status, N status, and NY-ESO-1 expression were all independently associated with shorter survival. No significant difference in NY-ESO-1 expression in primary tumors was observed concerning lymph node metastasis status. In summary, our findings suggest that increased expression of NY-ESO-1 could potentially serve as a prognostic biomarker for gastric cancer.

Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy

Article

Full-text available

Mar 2020
J TRANSL MED

Introduction: Cancer Immunotherapy has recently emerged as a promising and effective modality to treat different malignancies. Antigenic profiling of cancer tissues and determination of any pre-existing immune responses to cancer antigens may help predict responses to immune intervention in cancer. NY-ESO-1, a cancer testis antigen is the most immunogenic antigen to date. The promise of NY-ESO-1 as a candidate for specific immune recognition of cancer comes from its restricted expression in normal adult tissue but frequent occurrence in multiple tumors including melanoma and carcinomas of lung, esophageal, liver, gastric, prostrate, ovarian, and bladder. Main body: This review summarizes current knowledge of NY-ESO-1 as efficient biomarker and target of immunotherapy. It also addresses limitations and challenges preventing a robust immune response to NY-ESO-1 expressing cancers, and describes pre-clinical and clinical observations relevant to NY-ESO-1 immunity, holding potential therapeutic relevance for cancer treatment. Conclusion: NY-ESO-1 induces strong immune responses in cancer patients but has limited objective clinical responses to NY-ESO-1 expressing tumors due to effect of competitive negative signaling from immune-checkpoints and immune-suppressive tumor microenvironment. We propose that combination therapy to increase the efficacy of NY-ESO-1 specific immunotherapeutic interventions should be explored to unleash the immune response against NY-ESO-1 expressing tumors.

NY-ESO-1 expression in solid tumors predicts prognosis: A systematic review and meta-analysis

Article

Full-text available

Nov 2019

Background: New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a member of the cancer testis antigen family. NY-ESO-1 has documented potential as an effective target for cancer immunotherapy. The prognostic value of NY-ESO-1 expression in solid tumors, however, remains controversial because of inconclusive data. Methods: For this analysis, the Medline, Embase, and Cochrane Library databases were searched up to February 2018 for studies investigating NY-ESO-1 expression in solid tumors and overall survival (OS), progression-free survival (PFS), or disease-free survival (DFS). Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from each study. Pooled HRs and CIs were calculated using the Mantel-Haenszel fixed effects or random effects model. Results: A total of 23 studies were included in the analysis. The combined HR (95% CI) estimates for OS, PFS, and DFS were 1.41 (95% CI: 1.24-1.61; I = 0%), 1.62 (95% CI: 1.42-1.84; I = 17%), and 0.95 (95% CI: 0.56-1.59; I = 57%), respectively. Conclusions: NY-ESO-1 expression in solid tumors is associated with worse OS and PFS. Studies are still needed to provide more evidence.

Immune Checkpoint Blockades in Triple-Negative Breast Cancer: Current State and Molecular Mechanisms of Resistance

Article

Full-text available

May 2022

Immune checkpoint blockades (ICBs) have revolutionized cancer treatment. Recent studies have revealed a subset of triple-negative breast cancer (TNBC) to be considered as an immunogenic breast cancer subtype. Characteristics of TNBC, such as higher mutation rates and number of tumor-infiltrating immune cells, render the immunogenic phenotypes. Consequently, TNBCs have shown durable responses to ICBs such as atezolizumab and pembrolizumab in clinic. However, a significant number of TNBC patients do not benefit from these therapies, and mechanisms of resistance are poorly understood. Here, we review biomarkers that predict the responsiveness of TNBCs to ICB and recent advances in delineating molecular mechanisms of resistance to ICBs.

PLGA Nanoparticles Co-encapsulating NY-ESO-1 Peptides and IMM60 Induce Robust CD8 and CD4 T Cell and B Cell Responses

Article

Full-text available

Feb 2021

Tumor-specific neoantigens can be highly immunogenic, but their identification for each patient and the production of personalized cancer vaccines can be time-consuming and prohibitively expensive. In contrast, tumor-associated antigens are widely expressed and suitable as an off the shelf immunotherapy. Here, we developed a PLGA-based nanoparticle vaccine that contains both the immunogenic cancer germline antigen NY-ESO-1 and an α-GalCer analog IMM60, as a novel iNKT cell agonist and dendritic cell transactivator. Three peptide sequences (85–111, 117–143, and 157–165) derived from immunodominant regions of NY-ESO-1 were selected. These peptides have a wide HLA coverage and were efficiently processed and presented by dendritic cells via various HLA subtypes. Co-delivery of IMM60 enhanced CD4 and CD8 T cell responses and antibody levels against NY-ESO-1 in vivo. Moreover, the nanoparticles have negligible systemic toxicity in high doses, and they could be produced according to GMP guidelines. Together, we demonstrated the feasibility of producing a PLGA-based nanovaccine containing immunogenic peptides and an iNKT cell agonist, that is activating DCs to induce antigen-specific T cell responses.

The expression, modulation and use of cancer-testis antigens as potential biomarkers for cancer immunotherapy

Article

Nov 2020

Cancer-testis antigens (CTA) are tumor antigens, present in the germ cells of testes, ovaries and trophoblasts, which undergo deregulated expression in the tumor and malignant cells. CTA genes are either X-linked or autosomal, favourably expressed in spermatogonia and spermatocytes, respectively. CTAs trigger unprompted humoral immunity and immune responses in malignancies, altering tumor cell physiology and neoplastic behaviors. CTAs demonstrate varied expression profile, with increased abundance in malignant melanoma and prostate, lung, breast and epithelial cell cancers, and a relatively reduced prevalence in intestinal cancer, renal cell adenocarcinoma and malignancies of immune cells. A combination of epigenetic and non-epigenetic agents regulates CTA mRNA expression, with the key participation of CpG islands and CpG-rich promoters, histone methyltransferases, cytokines, tyrosine kinases and transcriptional activators and repressors. CTA triggers gametogenesis, in association with mutated tumorigenic genes and tumor repressors. The CTAs function as potential biomarkers, particularly for prostate, cervical, breast, colorectal, gastric, urinary bladder, liver and lung carcinomas, characterized by alternate splicing and phenotypic heterogeneity in the cells. Additionally, CTAs are prospective targets for vaccine therapy, with the MAGE-A3 and NYESO-1 undergoing clinical trials for tumor regression in malignant melanoma. They have been deemed important for adaptive immunotherapy, marked by limited expression in normal somatic tissues and recurrent up-regulation in epithelial carcinoma. Overall, the current review delineates an up-dated understanding of the intricate processes of CTA expression and regulation in cancer. It further portrays the role of CTAs as biomarkers and probable candidates for tumor immunotherapy, with a future prospect in cancer treatment.

Extracellular vesicles in urological malignancies: an update

Article

Dec 2019

Extracellular vesicles (EVs) have an essential functional role in local tumour progression, metastatic spread and the emergence of drug resistance in bladder, kidney and prostate cancer. Thus, EVs could be diagnostic, prognostic and predictive biomarkers for these malignancies. Virtually all biomolecules (including DNA, mRNA, microRNA, long non-coding RNA, proteins and lipids) packaged into EVs have been tested as biomarkers in blood and urine samples. The results are very heterogeneous, but promising biomarker candidates have been identified. Differing methods of EV isolation, characterization and analysis of their content have been used owing to a lack of international consensus; hence, comparing study results is challenging. Furthermore, validation of potential biomarkers in independent cohorts or prospective trials has rarely been performed. Future efforts to establish EV-derived biomarkers need to adequately address these points. In addition, emerging technologies such as mass spectroscopy and chip-based approaches can identify surface markers specific for cancer-associated EVs and will enable specific separation from blood and urine EVs, which probably will improve their performance as biomarkers. Moreover, EVs could be harnessed as therapeutic drug delivery vehicles for precise and effective anticancer therapy.

Cellular immune responses against cancer-germline genes in cancers

Article

Jul 2019

Background: Cancer-germline genes are a class of genes that are normally expressed in testis, trophoblast and few somatic tissues but abnormally expressed in tumor tissues. Their expression signature indicates that they can induce cellular immune responses, thus being applied as targets in cancer immunotherapy. Objectives: To obtain the data of cellular immune responses against cancer-germline genes in cancer. Methods: We searched PubMed/Medline with the key words cancer-germline antigen, cancer-testis antigen, CD4+ T cell, CD8+ T cell and cancer. Results: About 40 cancer-germline genes have been shown to induce T cell specific responses in cancer patients. Melanoma, lung and breast cancer are among the mostly assessed cancer types. Several epitopes have been identified which can be used in immunotherapy of cancer. Conclusion: Cellular immune responses against cancer-germline genes are indicative of appropriateness of these genes as therapeutic targets.

Humoral immune responses against cancer-testis antigens in human malignancies

Article

Apr 2019

Background: Cancer-testis antigens (CTAs) are a class of cancer antigens with extensive expression in human cancers. Many researchers have detected antibody responses against these tumor antigens in serum of cancer patients. Objectives: To evaluate the relevance of humoral immune responses against CTAs in clinical outcome of cancer patientsMETHODS: We searched PubMed/Medline with the key words cancer-testis antigen, antibody, humoral response and cancer. Results: Humoral immune responses against CTAs have been detected in several human malignancies including skin, breast, brain and ovarian cancers. Some studies have shown associations between the presence of these responses in patients and patients' survival. Conclusion: Humoral immune responses against CTAs are putative biomarkers for cancer detection and follow-up.

The PTEN pathway in Tregs functions as a critical driver of the immunosuppressive tumor microenvironment and tolerance to apoptotic cells

Article

Full-text available

Nov 2015

The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intra-tumoral immune suppression driven by a specialized form of regulatory T cell (T reg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize T regs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a T reg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing T regs , and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immuno-suppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in T regs is disrupted.

Stem cells and cancer immunotherapy: Arrowhead’s 2 annual cancer immunotherapy conference

Article

Full-text available

Mar 2014

Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.

Clinical Significance of Immunohistochemical Expression of Cancer/Testis Tumor-associated Antigens (MAGE-A1, MAGE-A3/4, NY-ESO-1) in Patients with Non-small Cell Lung Cancer

Article

Jan 2014

This paper deals with the clinical significance of the immunohistochemical expression of MAGE-A1, MAGE-A3/4 and NY-ESO-1 antigens in patients with non-small cell lung cancer (NSCLC).

Expression of cancer testis (CT) antigens in human BRCA-associated breast cancers: Potential targets for immunoprevention?

Article

May 2011

Prospective study on the expression of cancer testis genes and antibody responses in 100 consecutive patients with primary breast cancer

Article

Jan 2008

To determine the expression of cancer testis (CT) genes and antibody responses in a nonselected population of patients with primary breast cancer, we investigated the composite expression of 11 CT genes by RT-PCR in fresh biopsies of 100 consecutive cases of primary breast carcinoma and by immunohistology in selected RT-PCR-positive cases. Antibody responses against 7 CT antigens were analyzed using recombinant antigen expression on yeast surface. In 98 evaluable cases, SCP-1 and SSX-4 were expressed most frequently (both 65%), followed by HOM-TES-85/CT-8 (47%), GAGE (26%), SSX-1 (20%), NY-ESO-1 (13%), MAGE-3 (11%), SSX-2 (8%), CT-10 (7%), MAGE-4 (4%) and CT-7 (1%). One CT gene was expressed by 90% of the cases; 79% expressed > or =2, 48% > or =3, 29% > or =4, 12% > or =5, 6% > or =6, 3% > or =7, 2% > or =8 and one case coexpressed 9 antigens. Of 100 serum samples screened for CT antigen-specific antibodies, antibodies against NY-ESO-1 were detected in 4 patients, against SCP-1 in 6 patients and against SSX-2 in 1 patient, while no antibodies were detected against MAGE-3, CT-7 and CT-10. Expression of CT genes or antibody responses was not correlated with clinical parameters (menopausal status, tumor size, nodal involvement, grading, histology and estrogen receptor status) or the demonstration of CT gene expression at the protein level, by immunohistology. Our results show that breast carcinomas are among the tumors with the most frequent expression of CT antigens, rendering many patients potential candidates for vaccine trials.

Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1

Article

Jan 2011

Simultaneous cytoplasmic and nuclear protein expression of MAGE-A family and NY-ESO-1 cancer-testis antigens represents an independent marker for poor survival in head & neck cancer

Article

Feb 2014

Humoral immune responses of cancer patients against 'Cancer-Testis' antigen NY-ESO-1: Correlation with clinical events

Article

Oct 1999

Humoral immune responses against the "Cancer-Testis" (CT) antigen NY-ESO-1 are frequently observed in patients with NY-ESO-1 expressing tumors. This is in contrast to other known tumor antigens (TA) defined by antibody or cytotoxic T cell (CTL) reactivity, i.e., MAGE-1, MAGE-3, SSX2, Melan A, and tyrosinase. No NY-ESO-1 antibody has been detected in healthy controls and patients with NY-ESO-1 negative tumors. In this study, we have assessed the NY-ESO-1 serum antibody response in patients with NY-ESO-1 positive tumors of different histological types and stages using Western blotting and an ELISA. Of the 12 patients analyzed, 10 had demonstrable NY-ESO-1 antibodies at the start of the study. All patients were followed for changes in NY-ESO-1 antibody titers during the course of tumor treatment and clinical evolution. In 4 patients, an increase of NY-ESO-1 antibody titer was observed with progression of disease or extensive tumor necrosis under treatment. One patient showed a stable NY-ESO-1 antibody titer over 3 years along with gradual regression of a large tumor mass. In 5 patients, a decrease of NY-ESO-1 antibody was detected: in 1 patient after curative tumor resection, in 3 patients with partial regression of metastatic disease under chemo- and immunotherapy, and in another patient with a NY-ESO-1 negative tumor relapse. Our results indicate that the induction and maintenance of NY-ESO-1 antibody is dependent on the presence of NY-ESO-1 expressing tumors. Furthermore, changes in NY-ESO-1 antibody titers correlate with the evolution of NY-ESO-1 positive disease.

Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers

Article

Jan 2000

Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses

Article

Apr 2000

NY-ESO-1, a member of the cancer-testis family of antigens, is expressed in a subset of a broad range of different human tumor types. Patients with advanced NY-ESO-1-expressing tumors frequently develop humoral immunity to NY-ESO-1, and three HLA A2-restricted peptides were defined previously as targets for cytotoxic CD8(+) T cells in a melanoma patient with NY-ESO-1 antibody. The objectives of the present study were (i) to develop enzyme-linked immunospot (ELISPOT) and tetramer assays to measure CD8(+) T cell responses to NY-ESO-1, (ii) to determine the frequency of CD8(+) T cell responses to NY-ESO-1 in a series of HLA-A2 patients with NY-ESO-1 expressing tumors, (iii) to determine the relation between CD8(+) T cell and humoral immune responses to NY-ESO-1, and (iv) to compare results of NY-ESO-1 ELISPOT assays performed independently in two laboratories with T cells from the same patients. NY-ESO-1 ELISPOT and tetramer assays with excellent sensitivity, specificity, and reproducibility have been developed and found to correlate with cytotoxicity assays. CD8(+) T cell responses to HLA-A2-restricted NY-ESO-1 peptides were detected in 10 of 11 patients with NY-ESO-1 antibody, but not in patients lacking antibody or in patients with NY-ESO-1-negative tumors. The results of ELISPOT assays were concordant in the two laboratories, providing the basis for standardized monitoring of T cell responses in patients receiving NY-ESO-1 vaccines.

New York esophageal squamous cell carcinoma-1 and cancer immunotherapy

Abstract and Figures

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