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Alexander EggermontRelated papers
The history of the smallpox vaccine
Journal of Infection, 2006
Smallpox was a highly virulent, contagious disease. Initial attempts to control the disease by variolation were controversial and dangerous. Variolation was the subject of some of the earliest published clinical trials. Vaccination was discovered by Edward Jenner in 1796. From initial skepticism by the medical community the uptake became so widespread that smallpox vaccination was made compulsory in England and Wales in 1853. Eventually, this led to the eradication of smallpox in 1980. Parallels can be drawn with modern vaccination and the smallpox vaccine especially with the current intense media scrutiny of modern vaccinations.
Vaccines Through Centuries: Major Cornerstones of Global Health
Frontiers in Public Health, 2015
Edward Jenner and the History of Smallpox and Vaccination
Baylor University Medical Center Proceedings, 2005
Vaccine development: A historical perspective
Biomedical Research
Inoculation, vaccination and public hygiene against smallpox.doc
I give here an historical view (from the XVIIIth to the XXth century) of hygiene policies adopted or rejected in different parts of the world (Europe and America). It starts from the beginning of the XVIIIth century, when the medications prescribed by Rhazes, the first physician who clearly diagnose the smallpox from 910, were still applied but the disease may be often fatal. However a new method of inoculation, which is hard to trace beyond the seventeenth century, began to be applied in Europe and America. According to the country its acceptation followed very different paths, going from the entire acceptation in New England till 1750, to the unconditional reject in France during the reign of Louis XV. However its acceptation by the population, the press, the doctors, the Churches and political power were clearly different. For example in New England Douglas (1722), the only Boston physician who had studied in Europe, claimed that inoculation aggravated the smallpox epidemics. In France de la Condamine in a paper to the Academy of science (1754) called the Faculties of Theology and medicine and senior magistrates to dispel the misgivings fomented against inoculation by ignorance. Despite its success he was forced to admit that his crusade had largely failed. Ironically, Louis XV fell victim of smallpox and died of it in 1774, after having blocked all attempts to eradicate it during his thirty years of reign. At the end of the XVIIIth century a new approach, this time by vaccination, was proposed by Jenner in 1798. Even if the population, the doctors, and the Churches were reticent at its beginning, they quickly accepted this practice and permitted its dissemination worldwide during the XIXth century. However a number of doctors, bacteriologists, biologists and national leagues would have preferred a more hygienic approach during this century. For example the Leicester Anti-Vaccination League founded in 1869 opposed the compulsory nature of vaccination, which they saw as an attack on personal freedom and developed a public-heath theory of the fight against epidemics. During the XXth century, the World Heath Organisation undertook the complete eradication of this disease from 1967. They declared in 1980 that the disease had been wiped off the face of the Earth. To accomplish this task, it used not only mass vaccination but in numerous cases, when it was insufficient, a strategy founded on hygiene procedures and isolation of patients to break the contagion chain. This fight against smallpox was a complex mix of acceptance or rejection by the population, the medical power, the political power, and mainly by the public hygiene policies followed during this long period of time and according to the country.
Utility of Vaccinations and the Body’s Immune System
2015
Vaccinations are biological substances used to stimulate the body’s immune system to develop immunity against certain pathogens. Vaccines are the most common methods used to prevent the widespread infection of diseases. Today, there are several vaccines used to prevent and control the spread of diseases such as the human papillomavirus (HPV) vaccine, influenza (flu) vaccine, and the chicken pox vaccination. The use of vaccines has been acknowledged as the reason for the eradication of smallpox and the reduction of certain diseases such as measles, tetanus and polio. In the late 1700s, it was Edward Jenner who discovered the small pox vaccination, as many other scientists, such as the French chemist and microbiologist Louis Pasteur struggled to find a cure for small pox.
OncoImmunology
ISSN: (Print) 2162-402X (Online) Journal homepage: https://www.tandfonline.com/loi/koni20
Trial watch
Peptide vaccines in cancer therapy
Erika Vacchelli, Isabelle Martins, Alexander Eggermont, Wolf Hervé Fridman,
Jerome Galon, Catherine Sautès-Fridman, Eric Tartour, Laurence Zitvogel,
Guido Kroemer & Lorenzo Galluzzi
To cite this article: Erika Vacchelli, Isabelle Martins, Alexander Eggermont, Wolf Hervé Fridman,
Jerome Galon, Catherine Sautès-Fridman, Eric Tartour, Laurence Zitvogel, Guido Kroemer &
Lorenzo Galluzzi (2012) Trial watch, OncoImmunology, 1:9, 1557-1576, DOI: 10.4161/onci.22428
To link to this article: https://doi.org/10.4161/onci.22428
Copyright © 2012 Landes Bioscience
Published online: 06 Dec 2012.
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REVIEW
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OncoImmunology 1:9, 1557–1576; December 2012; © 2012 Landes Bioscience
Trial watch
Peptide vaccines in cancer therapy
Erika Vacchelli,1,2,3,† Isabelle Martins,1,2,3,† Alexander Eggermont,2 Wolf Hervé Fridman,4,5,6,7 Jerome Galon,4,5,6,7,8
Catherine Sautès-Fridman,4,6,8 Eric Tartour,7,9 Laurence Zitvogel,2,10 Guido Kroemer1,4,6,7,11,‡,* and Lorenzo Galluzzi1,4,‡,*
1
Institut Gustave Roussy; Villejuif, France; 2Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France; 3INSERM, U848; Villejuif, France; 4Université Paris Descartes/Paris V;
Sorbonne Paris Cité; Paris, France; 5INSERM, U872; Paris, France; 6Centre de Recherche des Cordeliers; Paris, France; 7Pôle de Biologie;Hôpital Européen Georges Pompidou;
AP-HP; Paris, France; 8Université Pierre et Marie Curie/Paris VI; Paris, France; 9INSERM, U970; Paris, France; 10INSERM, U1015; CICBT507; Villejuif, France; 11Metabolomics Platform;
Institut Gustave Roussy; Villejuif, France
†
These authors contributed equally to this work.
‡
These authors share senior co-authorship.
Keywords: EGFR, MAGE-A3, NY-ESO-1, p53, RAS, WT1
Abbreviations: AML, acute myeloid leukemia; APC, antigen-presenting cell; BCG, bacillus Calmette-Guérin; BCR, B-cell receptor;
CDCA1, cell division cycle-associated 1; CEA, carcinoembryonic antigen; CHP, cholesterol-bearing hydrophobized pullulan;
CML, chronic myelogenous leukemia; CRC, colorectal carcinoma; CTA, cancer-testis antigen; CTL, cytotoxic T lymphocyte;
DC, dendritic cell; DEPDC1, DEP domain containing 1; EBV, Epstein-Barr virus; EGFR, epidermal growth factor receptor; FBP,
folate-binding protein; GAA, glioma-associated antigen; GBM, glioblastoma multiforme; GM-CSF, granulocyte macrophage
colony-stimulating factor; GnRH, gonadotropin releasing hormone; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV-8,
human herpesvirus 8; HPV, human papillomavirus; HSP, heat-shock protein; hTERT, human telomerase reverse transcriptase;
HTLV, human T lymphotropic virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IMP3, insulin-like growth factor II
mRNA-binding protein 3; KIF20A, kinesin family member 20A; KLH, keyhole limpet hemocyanin; LY6K, lymphocyte antigen
6 complex locus K; MAGE, melanoma-associated antigen; MART-1, melanoma antigen recognized by T cells 1; MDA, melanoma
differentiation antigen; MDS, myelodysplastic syndrome; MIATA, Minimal Information About T Cell Assays; MM, multiple
myeloma; MPHOSPH1, M phase phosphoprotein 1; MPLA, monophosphoryl lipid A; mTOR, mammalian target of rapamycin;
MUC1, mucin 1; NSCLC, non-small cell lung carcinoma; PMSA, prostate membrane-specific antigen; polyICLC, polyriboinosinicpolyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose; PSA, prostate-specific antigen; RCC, renal cell
carcinoma; RHAMM, receptor for hyaluronic acid-mediated motility; SART, squamous cell carcinoma antigen recognized by T
cells; SLP, synthetic long peptide; TAA, tumor-associated antigen; TARP, T-cell receptor gamma chain alternate reading frame
protein; TCR, T-cell receptor; TLR, Toll-like receptor; TRA, tumor rejection antigen; Treg, FOXP3 + regulatory T cell; URLC10,
upregulated in lung cancer 10; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; WT1, Wilms’ tumor 1
Prophylactic vaccination constitutes one of the most prominent
medical achievements of history. This concept was first
demonstrated by the pioneer work of Edward Jenner, dating
back to the late 1790s, after which an array of preparations that
confer life-long protective immunity against several infectious
agents has been developed. The ensuing implementation
of nation-wide vaccination programs has de facto abated
the incidence of dreadful diseases including rabies, typhoid,
cholera and many others. Among all, the most impressive
result of vaccination campaigns is surely represented by the
eradication of natural smallpox infection, which was definitively
certified by the WHO in 1980. The idea of employing vaccines as
anticancer interventions was first theorized in the 1890s by Paul
*Correspondence to: Guido Kroemer and Lorenzo Galluzzi;
Email: kroemer@orange.fr and deadoc@vodafone.it
Submitted: 10/02/12; Accepted: 10/02/12
http://dx.doi.org/10.4161/onci.22428
www.landesbioscience.com
Ehrlich and William Coley. However, it soon became clear that
while vaccination could be efficiently employed as a preventive
measure against infectious agents, anticancer vaccines would
have to (1) operate as therapeutic, rather than preventive,
interventions (at least in the vast majority of settings), and (2)
circumvent the fact that tumor cells often fail to elicit immune
responses. During the past 30 years, along with the recognition
that the immune system is not irresponsive to tumors (as it
was initially thought) and that malignant cells express tumorassociated antigens whereby they can be discriminated
from normal cells, considerable efforts have been dedicated
to the development of anticancer vaccines. Some of these
approaches, encompassing cell-based, DNA-based and purified
component-based preparations, have already been shown
to exert conspicuous anticancer effects in cohorts of patients
affected by both hematological and solid malignancies. In this
Trial Watch, we will summarize the results of recent clinical trials
that have evaluated/are evaluating purified peptides or fulllength proteins as therapeutic interventions against cancer.
OncoImmunology
1557
Introduction
Jenner’s pioneering observations. Edward Anthony Jenner
(1749–1823) was an English physician nowadays considered
by many as the father of modern immunology.1,2 In the 1790s,
Jenner, who beyond medicine cultivated various interests spanning from natural history to air balloons, was practicing as a family doctor and surgeon in Berkeley (Gloucestershire), the small
town he was born in some 40 y earlier. In that period, Jenner
was particularly intrigued by the observation that milkmaids
were generally immune to smallpox, and he postulated that such
a protection would be conferred by the pus contained in blisters
that milkmaids developed along with cowpox (a disease similar to, yet much less virulent than, smallpox).1,2 In 1796, to test
his hypothesis, Jenner inoculated 8 year old James Phipps with
pus that he had scraped from the blisters of a cowpox-affected
milkmaid. Sometimes later, Jenner challenged James Phipps with
variolous material, i.e., material obtained from a smallpox pustule of a selected mild case (supposedly affected by the relatively
less virulent Variola minor smallpox virus). The boy developed
no signs of disease, nor did he after a further similar inoculation performed a few weeks later. Jenner pursued his investigations on additional 22 cases and then reported his findings to the
Royal Society, which accepted to publish them only after consistent revisions.1,2 The term “vaccination” (from the Latin adjective
“vaccinae,” which literally means “pertaining to cows, from cow”)
was coined by Jenner himself for the technique he had devised to
prevent smallpox, and only more than 50 years later it was attributed a more general meaning by the French microbiologist Louis
Pasteur, another pioneer in the history of vaccination.3,4
When Jenner first inoculated James Phipps, variolation, i.e.,
the inoculation of variolous material into healthy subjects as a
prophylactic measure against smallpox, was a well known procedure (it had been imported in 1721 from Turkey by Lady Mary
Wortley Montagu), yet was associated with a very high incidence of (often lethal) smallpox cases.1,2 Thus, Jenner was not
the first to realize that a sublethal smallpox or cowpox infection
can confer protection to subsequent, potentially lethal, challenges. Similarly, he was not the first who de facto inoculated
cowpox-derived material as a prophylaxis against smallpox, since
at least six investigators from the UK and Germany, including
the farmer Benjamin Jesty, had done so (with variable success)
earlier.5 Still, it is thanks to Jenner’s observations that the British
government eventually banned variolation and decided to provide cowpox-based vaccination free of charge (but optional)
nation-wide (Vaccination Act, 1840). This constituted the first
large-scale vaccination campaign of history, paving the way to a
series of similar measures taken worldwide and culminating with
the eradication of natural smallpox sources, as first certified by
a committee of experts in 1979 and confirmed by WHO one
year later.6 Since then, the development of efficient vaccines and
their widespread administration has strikingly abated the incidence of life-threatening infectious diseases including (but not
limited to) rabies, typhoid, cholera, measles, plague, chickenpox,
mumps, poliomyelitis and hepatitis B.3 Such an extraordinary
medical achievement has been possible also thanks to the critical
1558
contribution of Pasteur, who in the last decades of the 19th century demonstrated for the first time that the rationale behind
smallpox vaccination could be extended to several other infectious diseases.3,4
Ehrlich and Coley’s hypotheses. The hypothesis that—similar to infectious diseases—cancer could be treated with active
immunotherapy first arose nearly one century after Jenner’s
investigations, along with the work of the German physician
Paul Ehrlich and the American surgeon William Bradley Coley.3
On one hand, driven by the findings made a few years earlier by
Pasteur, Ehrlich (who is best known for the vaccination-unrelated concept of a “magic bullet” that would specifically kill cancer cells while sparing their normal counterparts) attempted to
generate immunity against cancer by injecting weakened tumor
cells, with no success.3 On the other hand, inspired by multiple sporadic cases of cancer patients who underwent complete
(and often long-lasting) regression following acute streptococcal
fevers, Coley became convinced that he could efficiently use bacteria to cure tumors. To this aim, Coley developed a mixture of
heat-killed Streptococcus pyogenes and Serratia marcescens bacteria
(best known as the Coley toxin), which he begun to test in cancer
patients as early as in 1896.7 This preparation de facto operates as
an adjuvant, facilitating the maturation of dendritic cells (DCs)
via Toll-like receptor (TLR)-transduced signals,8 rather than as
a bona fide tumor-specific vaccine. However, similar to other
relatively unspecific immunotherapeutic approaches such as the
administration of high-dose interleukin (IL)-2 to melanoma and
renal cell carcinoma (RCC) patients,9,10 Coley’s toxin soon turned
out to mediate potent antitumor effects.11,12 Of note, the use of
the Coley toxin has been suspended in the early 1960s, owing
to concerns following the thalidomide case (this antiemetic was
withdrawn 11 years after its approval by FDA as it was found
to be highly teratogenic, leading to more than 10,000 children
born with deformities worldwide).13 Still, both Coley and Ehrlich
represent true pioneers of modern oncoimmunology, theorizing
concepts that have been disregarded for nearly one century and
have received renovated interest only recently.14
The “self/non-self” dichotomy and the “danger theory”.
One of the major impediments against the rapid development
of tumor immunology as a self-standing discipline directly
stemmed from one of the most central concepts in immunology:
the “self/non-self” dichotomy, as first theorized by the Australian
virologist Sir Frank Macfarlane Burnet in 1949.15 This model has
surely been instrumental for the understanding of phenomena
that underpin graft rejection and several other disorders involving an immune component.16 However, it has also promoted the
(incorrect) view that tumors, de facto being self tissues, must be
non-immunogenic and (as a corollary) insensitive to immunotherapeutic interventions. The self/non-self model was first questioned in the late 1980s, when the cellular circuitries behind the
activation of T cells, and notably the requirement for antigen presentation, began to be elucidated.17 A few years later, the American
scientist Polly Matzinger proposed a revolutionary theory according to which the immune system would not simply react to nonself (while sparing self) constituents, but would rather respond
to situations of danger, irrespective of their origin.18 The first
OncoImmunology
Volume 1 Issue 9
corollary of such a “danger theory” was that trauma, cancer and
other conditions that had long been viewed as immunologically
silent de facto are capable of activating the immune system,18,19
a notion that nowadays is widely accepted.20,21 Approximately
in the same period, van der Bruggen and colleagues from the
Ludwig Institute for Cancer Research (Brussels, Belgium) were
the first to clone the gene coding for MZ2-E, a protein expressed
by multiple distinct melanoma cell lines as well as by tumors of
unrelated histological origin, but not by a panel of normal tissues.22 Moreover, cytotoxic T lymphocytes (CTLs) that specifically reacted against malignant cells in vitro were being found
in patients affected by a variety of hematological and solid neoplasms.22,23 Thus, in line with by Polly Matzinger’s model,18,19 it
appeared that the adult T-cell repertoire preserves the ability to
react against self antigens, at least in specific circumstances.
Tumor-associated antigens. Nowadays, MZ2-E, best known
as melanoma-associated antigen (MAGE)-A1, is considered as
the “founder” of the large family of tumor-associated antigens
(TAAs), i.e., antigens that, at least in some settings, are capable of eliciting a tumor-specific immune response manifesting
with the expansion of TAA-specific CTLs.24–27 Unfortunately,
TAA-directed immune responses are most often incapable of
mediating sizeable antineoplastic effects, owing to multiple reasons (see below).28 Still, the findings by van der Bruggen and
colleagues generated an intense wave of investigation worldwide,
not only leading to the identification of dozens, if not hundreds,
of additional TAAs, but also providing additional insights into
the mechanisms whereby TAAs, in selected circumstances, are
capable to break self-tolerance and elicit an immune response.29–31
So far, four distinct classes of TAAs have been described: (1) truly
exogenous, non-self TAAs; (2) unique, mutated TAAs; (3) idiotypic TAAs and (4) shared TAAs.
Exogenous TAAs. Bona fide non-self TAAs are specifically
expressed by neoplasms that develop as a result of (or concomitant with) viral infections. According to WHO, the viruses that
are currently known to be associated with human malignancies
are limited to the Epstein-Barr virus (EBV), which is linked
to lymphomas and nasopharyngeal cancer, hepatitis B virus
(HBV) and hepatitis C virus (HCV), both of which are associated with hepatocellular carcinoma, human papillomaviruses
(HPV), in particular HPV-16 and HPV-18, which are associated with head and neck, cervical and anal carcinomas, human
T lymphotropic virus Type 1 (HTLV-1) and Type 2 (HTLV-2),
which are linked to adult T-cell leukemia and hairy-cell leukemia, respectively, and human herpesvirus 8 (HHV-8), which is
associated with Kaposi’s sarcoma.32–34 The possibility to develop
recombinant vaccines against these viruses has been extensively
investigated in the last decade, and multiple clinical trials have
been concluded with encouraging results.35–39 In this context, a
special mention goes to Cervarix® and Gardasil®, two multivalent, recombinant anti-HPV vaccines that have been approved
by FDA in 2009 as preventive measures against HPV infection
and the consequent development of cervical carcinoma.40 The
success of Cervarix® and Gardasil® as compared with other vaccination strategies against viral cancers that have not yet moved
from the bench to the bedside, depends—at least in part—on the
www.landesbioscience.com
fact that both these vaccines were developed as fully preventive
measures, aimed at blocking de novo HPV infection, rather than
as at therapeutic strategy against established cervical carcinoma.
Indeed, both Cervarix® and Gardasil® induce high levels of neutralizing antibodies and result in the generation of HPV-specific
long-lasting memory B cells,41 which efficiently prevent infection, yet are less efficient in promoting T-cell responses that may
be beneficial for cervical carcinoma patients. In line with thin
notion, official documents report that Cervarix® is not efficient
against histopathological endpoints in HPV-infected women
(source http://www.fda.gov).
Unique TAAs. Malignant cells near-to-invariably accumulate
genetic alterations, which can be as gross as chromosomal rearrangements (e.g., t(9;22)(q34;q11), resulting in the very well
known Philadelphia chromosome and leading to chronic myelogenous leukemia, CML) or as specific as point mutations affecting the activity of tumor suppressor genes (e.g., ATM, TP53) or
oncogenes (e.g., ALK, EGFR, KRAS).42 Some of these alterations
(such as the Philadelphia chromosome and the resulting fusion
kinase BCR-ABL) are so prevalent among specific populations of
cancer patients that their detection decisively contributes to diagnosis.43,44 Others (such as R175H, R248W and R273H TP53
substitutions) are highly prevalent, too, yet affect a rather heterogeneous and very large population of patients, bearing malignancies that encompass (but are not limited to) breast, lung, gastric
and colorectal cancer.45 Irrespective of whether these changes
actually drive oncogenesis and tumor progression (driver mutations) or whether they appear alongside with carcinogenesis and
are retained by tumor cells (passenger mutations),46 non-synonymous mutations that affect exons are expected to generate new,
tumor-specific (unique) and potentially immunogenic antigens.47
In line with this notion, patients affected by neoplasms bearing
one of such unique TAAs have been shown to naturally develop
anti-TAA antibodies and/or TAA-specific CD8 + cells, although
these responses—in the near-to-totality of cases—are unable to
exert significant antitumor effects.48–50 As unique TAAs are only
expressed by malignant cells, immune responses arising against
their epitopes have a very low probability to result in autoimmune
reactions. In addition, the development of efficient immunotherapies against unique TAAs that are expressed by a wide array of
tumors would provide clinical benefits to a large population of
cancer patients. During the last two decades, the intense wave of
research stemming from these considerations has demonstrated
that targeting unique TAAs constitutes a meaningful immunotherapeutic approach against cancer.51–55
Idiotypic TAAs. One particular class of unique TAAs is constituted by idiotypic TAAs. Hematological malignancies arising
from B cells that have functionally rearranged immunoglobulin
(Ig)-coding genes are characterized by the cell surface expression of a clonal B-cell receptor (BCR). Such a BCR is de facto
a self protein, yet contains a unique variable region that defines
its specificity (idiotype), to which the immune system has never
been exposed, and hence that is potentially immunogenic.56 In
line with this notion, anti-idiotypic antibodies arise naturally in
the course of humoral immune responses (when high levels of
clonal Igs are produced by plasma cells), which they contribute to
OncoImmunology
1559
terminate.57,58 In 1972, Lynch et al. were the first to demonstrate
that peptides corresponding to idiotypic regions of the BCR
exposed by myeloma cells are capable of eliciting an efficient
immune response,59 de facto providing the rationale for the development of idiotypic anticancer vaccination. In practical terms,
this can be achieved not only by injecting purified peptides that
correspond to the idiotype expressed by malignant cells, but also
by means of anti-idiotype antibodies.60 The latter constitute bona
fide structural mimics of TAAs (which in this specific case—but
not in many other settings—are represented by the idiotype),
owing to the fact that antigens and the corresponding antibodies exhibit a consistent degree of complementarity.60 In general,
anti-idiotype antibodies are advantageous as compared with
purified peptides as they can be easily and cost-effectively produced in high amounts by immunizing laboratory animals with
TAA-targeting antibodies.60 Irrespective of how they are elicited,
anti-idiotype immune responses are patient- and tumor-specific,
implying (1) that the development of idiotypic anticancer vaccines requires the precise characterization of neoplastic cells on a
per patient basis, and (2) that the efficacy of this approach can be
fully compromised by the arisal of a new malignant cell clone as
well as by processes of somatic (hyper)mutation, which normally
affect the idiotype.61 Still, following the pioneer work by Lynch
and colleagues,59 the fact that idiotypes constitute a meaningful
target for the therapy of B-cell neoplasms has been validated in
multiple preclinical and clinical settings.62–65
Shared TAAs. Obviously, cancer cells express (and sometimes
overexpress) a majority of self antigens, which they share with the
normal tissue they originated from.66 According to the “self/nonself” theory, these antigens should not elicit an immune response,
due to central and/or peripheral tolerance mechanisms that are
in place to prevent autoimmune reactions.17 This prediction is
actually inaccurate, as (1) both antibodies and CD8 + T cells recognizing shared TAAs (e.g., wild type epidermal growth factor
receptor, EGFR and p53) appear to be enriched in the circulation
of cancer patients as compared with healthy subjects; 67,68 and (2)
a consistent fraction of paraneoplastic syndromes derives from
tumor-elicited autoimmune reactions targeting normal tissues.69
Thus, as postulated by the “danger theory,” self-shared TAAs are
capable of eliciting an immune response, most likely because they
are presented to the immune system in the context of appropriate activation signals.18,19 Such an immune response is frequently
held in check by local immunosuppressive mechanisms (see
below),70,71 and hence does not exert antitumor effects, yet it may
be functional at distant sites, thus underlying life-threatening
paraneoplastic syndromes.69 During the last two decades, great
efforts have been dedicated at understanding whether and based
on which strategies shared TAAs would constitute meaningful targets for the elicitation of antitumor immune responses.
Promising results have been obtained in both preclinical and
clinical models.52,72,73 Of note, although so-called “cancer-testis”
antigens (CTAs) are expressed not only by a variety of malignant
cells but also by germline cells,74 they are most often considered
as unique, rather than shared, TAAs, mostly due to the fact that
testes represent an immune privileged site and are de facto spared
by most, if not all, autoimmune reactions.75
1560
Considerations on the development of anticancer vaccines.
Along with the recognition that the immune system is not completely irresponsive to tumors (as it was initially thought to be)
and that malignant cells express antigens that are capable of eliciting a tumor-specific immune response, great efforts have been
dedicated to the development of anticancer vaccines.29 Thus, several approaches have been evaluated for their potential to elicit
efficient, tumor-specific immune responses, including (but not
limited to): recombinant TAAs, in the form of short synthetic
epitopes (expected to directly bind, and hence be presented
to T cells on, MHC molecules); recombinant full-length proteins (whose presentation requires the uptake and processing by
antigen-presenting cells, APCs) or tumor cell-purified preparations (containing TAAs alone or in complex with chaperon proteins), administered as such or via multiple delivery systems (e.g.,
nanoparticles, DC-derived exosomes, DC-targeting vectors);
TAA-encoding vectors; and DC preparations. The results of such
an intense wave of investigation/vaccine development have been
encouraging. Still, exception made for Cervarix® and Gardasil®
(which are approved for prophylactic use, see above), only one
product is currently commercialized as a therapeutic anticancer vaccine, namely, sipuleucel-T (also known as Provenge®), a
cellular preparation for the treatment of asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer.76 This is in strike contrast with the large array of vaccines
that have been developed against infectious agents during the
last century. Indeed, there are at least three major obstacles that
complicate the development of anticancer vaccines as compared
with prophylactic vaccines against infectious diseases. First: the
antigenic properties of cancer cells. Although a number of specific and potentially immunogenic TAAs have been identified (see
above), only a few of them operate as bona fide tumor rejection
antigens (TRAs) as they elicit an immune response that leads to
tumor eradication.26,77 Of note, it has recently been shown that
TRAs not necessarily correspond to TAAs that arise as a result
of driver mutations, indicating (1) that there is no direct correlation between the oncogenic potential of mutations and their
immunogenicity, and (2) that passenger mutations might generate
therapeutically useful targets for immunotherapy.78 Second: the
fact that anticancer vaccines must operate, in the vast majority of
cases, as therapeutic interventions. Conventional prophylactic vaccines against infectious agents elicit strong humoral responses and
promote the establishment of long-term B-cell memory.79 While
this results in an efficient protection against invading pathogens
(including HPV strains associated with cervical carcinoma, see
above), it has limited (if any) efficacy against established tumors.
Indeed, the rejection of established neoplastic lesions requires the
activation of robust cell-mediated immune responses, which can
be achieved only by specific vaccination strategies.3,80 In particular, the elicitation of cell-mediated immunity requires TAAs to be
conveniently processed by APCs, mainly DCs, and presented to
T cells in vivo in the context of appropriate stimulatory signals.30
This is a critical point and explains why vaccines are invariably
administered in the presence of adjuvants (encompassing classical
agents such as alum, montanide and incomplete Freund’s adjuvant
as well as recently developed TLR agonists like monophosphoryl
OncoImmunology
Volume 1 Issue 9
lipid A, MPLA and imiquimod).11,12 Indeed, in the absence of
activation signals, immature DCs present TAAs to T cells in the
context of inhibitory interactions, hence promoting the establishment of tolerance via multiple mechanisms.81–84 Third, the existence of distinct immunosuppressive pathways that are elicited
by tumor cells, both locally and systemically. Cancer cells not
only co-opt the stromal components of the neoplastic lesion to
serve their metabolic and structural needs,85,86 but also secrete a
wide array of mediators that (1) stimulate the bone marrow to
release specific subsets of (relatively immature) myeloid cells into
the bloodstream; (2) attract such cells and others to the tumor
microenvironment and promote their expansion; (3) condition
the differentiation program and/or functional behavior of tumorinfiltrating leukocytes.87–91 Overall, this results not only in the
establishment of a potently immunosuppressive tumor microenvironment but also in some extent of systemic immunosuppression,
and explains, at least in part, why natural TAA-directed immune
responses are near-to-always unable to exert antitumor effects.
Along the lines of our Trial Watch series,11,12,92–97 here we will
discuss recently published and ongoing clinical trials that have
investigated/are investigating the safety and efficacy of purified peptides or full-length proteins as therapeutic interventions
against cancer.
Hematological Malignancies
During the past 15 years, the safety and efficacy of recombinant peptides/proteins employed as therapeutic vaccines against
hematological neoplasms have been evaluated in a few clinical
trials. Peptides derived from Wilms’ tumor 1 (WT1), a transcription factor that is overexpressed by several neoplasms,98 have
been tested (most often combined with the carrier keyhole limpet hemocyanin, KLH) in CML patients (n = 1)99 acute myeloid
leukemia (AML) patients (n = 10 and n = 10),100,101 as well as in
a mixed cohort of AML and myelodysplastic syndrome (MDS)
patients (n = 19).102 A peptide derived from receptor for hyaluronic acid-mediated motility (RHAMM, a hyaluronate-binding protein that influences cell motility) has been evaluated in
AML, MDS and multiple myeloma (MM) patients (n = 10 and
n = 9).103,104 Idiotype vaccines have been investigated in cohorts
of myeloma (n = 5 and n = 6)105,106 and lymphoma (n = 20,
n = 16 and n = 177) patients.63,107,108 Finally, two clinical trials
have investigated the therapeutic potential of autologous, tumorderived heat-shock protein (HSP)-complexed antigens in CML
(n = 20) and non-Hodgkin’s lymphoma (n = 20) patients.109,110
Altogether, these studies demonstrated that recombinant TAAderived peptides are well tolerated by patients bearing hematological malignancies. These vaccines elicited TAA-specific immune
responses in a variable fraction of patients, some of whom also
exhibited partial or complete clinical responses.
Nowadays (September 2012), official sources list 11 recent
(started after January, 1st 2008), ongoing (not withdrawn, terminated or completed at the day of submission) Phase I-II clinical
studies assessing the safety and efficacy of recombinant peptides
as therapeutic interventions against hematological neoplasms
(Table 1). Six of these studies are investigating WT1-derived
www.landesbioscience.com
peptides, either as a standalone intervention or combined with
granulocyte macrophage colony-stimulating factor (GM-CSF) or
regimens for the depletion of immunosuppressive FOXP3 + regulatory T cells (Tregs), in cohorts of AML and MDS patients. The
remaining five studies involve MM patients or subjects affected
by various hematological malignancies, who are receiving, either
as single agents or in combination with various immunostimulatory strategies, peptides derived from the MAGE-A1-related
protein MAGE-A3,111 from mucin 1 (MUC1, an extensively glycosylated transmembrane protein that is overexpressed by a wide
variety of cancers),112 from the catalytic subunit of human telomerase reverse transcriptase (hTERT)113 or from the anti-apoptotic
protein survivin114 (source www.clinicaltrials.gov).
Neurological and Pulmonary Cancers
To the best of our knowledge, the first clinical trials investigating the safety and therapeutic potential of TAA-derived peptides
in brain and lung cancer patients have been completed in the
mid 2000s,115–118 followed by a few additional studies addressing the same question.119–123 In particular, a personalized multipeptide preparation combined with a mineral oil-based adjuvant
(Montanide ISA51) has been tested in glioma patients (n = 25),118
tumor-derived peptides complexed with HSPs have been evaluated
in astroglyoma, oligodendrocytoma and meningioma patients
(n = 5),120 and a WT1-derived 9mer has been tested in individuals
affected by glioblastoma multiforme (GBM) (n = 21).122 In addition, cohorts of non-small cell lung carcinoma (NSCLC) patients
have been treated with peptides derived from ERBB2/HER2
(a member of the epidermal growth factor receptor family frequently overexpressed in lung and breast cancer patients),124 in
combination with GM-CSF (n = 2 and n = 1),115,117 with hTERTderived peptides, combined with either GM-CSF or radiotherapy
(n = 26 and n = 23),119,123 and with peptides corresponding to
mutated regions of RAS (n = 18).121 Taken together, these studies
demonstrated that the administration of TAA-derived peptides
to patients affected by neurological or pulmonary malignancies
is safe and has the potential of inducing—in a fraction of cases—
immunological and clinical responses.
Today (September 2012), official sources list 13 recent,
ongoing, Phase I-III clinical trials investigating the safety profile and efficacy of TAA-derived vaccines as therapeutic interventions against neurological neoplasms (Table 2). Six of these
studies involve GBM patients, 4 glioma patients, 1 astrocytoma
patients, 1 neuroblastoma patients and 1 individuals bearing
not-better specified brain tumors. In four trials, a peptide corresponding to the EGFR in-frame deletion mutant EGFRvIII
(rindopepimut, also known as CDX-110)125,126 is employed,
either as a single agent or in combination with GM-CSF, temozolomide or radiotherapy. Alternatively, patients are administered with glioma-associated antigens (GAAs), frequently
associated to the TLR3 activator polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose (polyICLC), with survivin-derived peptides, with
HSP-TAA complexes or with a multi-peptide vaccine containing 11 distinct TAAs (IMA950)127 (source www.clinicaltrials.
OncoImmunology
1561
Table 1. Clinical trials testing TAA-derived peptides as therapeutic interventions in patients affected by hematological neoplasms*
Tumor type
Trials
Phase
Status
Type
TAAs
Co-therapy
Not yet
recruiting
Ref.
NCT00725283
I
As single AA
NCT01051063
ALL
AML
5
Combined with
Treg depletion
NCT01513109
II
As single AA
NCT01266083
n.a.
Combined with
GM-CSF
NCT00665002
WT1
Combined with
GM-CSF
NCT00672152
MDS
Hematological
malignancies
Multiple
myeloma
Peptide
I-II
WT1
Recruiting
1
5
I
Recruiting
n.a.
Enrolling
by invitation
MUC1
As single AA
NCT01423760
I
Recruiting
MAGE-A3
As single AA
NCT01380145
Active,
not recruiting
CMV
hTERT
Survivin
Combined with
GM-CSF and PCV
NCT00834665
MUC1
Combined with
GM-CSF
NCT01232712
MAGE-A3
Combined with ASCT,
lenalidomide, and
immunostimulants
NCT01245673
I-II
Peptide
Peptide
Recruiting
II
AA, adjuvanted agent; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia, ASCT, autologous stem cell transplantation; CMV, cytomegalovirus N495 peptide; GM-CSF, granulocyte macrophage colony-stimulating factor; hTERT, human telomerase reverse transcriptase; MAGE-A3, melanoma-associated antigen A3; MDS, myelodysplastic syndrome; MUC1, mucin 1; n.a., not available; PCV, pneumococcal conjugate vaccine; poly ICLC,
polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose; TAA, tumor associated antigen; Treg, FOXP3+ regulatory
T cells; WT1, Wilms’ tumor 1. *started after January, 1st 2008 and not withdrawn, terminated or completed at the day of submission.
gov). In addition, official sources list 17 recent, ongoing,
Phase I-III clinical trials investigating the potential of TAAderived peptides for the treatment of lung cancer, mainly
NSCLC, patients (Table 2). These studies involve a variety of
recombinant vaccines, including (but not limited to) peptides
derived from MUC1, MAGE-A3, hTERT, kinesin family member 20A (KIF20A), cell division cycle-associated 1 (CDCA1),
vascular endothelial growth factor receptor 1 and 2 (VEGFR1
and VEGFR2) and CTAs (such as NY-ESO-1 and upregulated in lung cancer 10, URLC10).74 In the majority of cases,
peptides or full-length proteins are administered as standalone
adjuvanted agents, with the exceptions of trial NCT01579188,
in which hTERT-derived peptides are combined with GM-CSF,
trials NCT00409188 and NCT01015443, in which MUC1derived peptides are administered after a single dose of cyclophosphamide, and trial NCT00455572, in which recombinant
full-length MAGE-A3 is combined with radiotherapy, cisplatin (a DNA-damaging agent) or vinorelbine (a semi-synthetic
vinca alkaloid). Importantly, trial NCT00480025, in which
advanced NSCLC patients are treated with adjuvanted fulllength MAGE-A3 upon tumor resection, constitutes the (or
1562
at least one of the) largest clinical study(ies) ever commenced
to evaluate the efficacy of an immunotherapeutic intervention
against lung cancer.128 Another particularly intriguing approach
in this context is represented by trial NCT00655161, in which
NSCLC patients receive an inactivated strain of Saccharomyces
cerevisiae that has been engineered for the expression of mutant
RAS (GI-4000) (source www.clinicaltrials.gov).
Breast, Ovarian and Prostate Carcinoma
During the last two decades, the potential of recombinant vaccines employed as therapeutic interventions against breast,
ovarian and prostate carcinoma patients has been extensively
investigated. Thus, cohorts of breast carcinoma patients have
been administered with HER2-derived peptides in combination with GM-CSF (n = 31, n = 9, n = 9 and n = 195),115–117,129
with peptides derived from a specific splicing variant of survivin
(n = 14),130 with a broad panel of peptides naturally presented
by ovarian cancer cells in combination with GM-CSF (n = 7),131
with full-length CA15–3, CA125 and carcinoembryonic antigen
(CEA), three circulating markers of breast cancer recurrence,132
OncoImmunology
Volume 1 Issue 9
Table 2. Clinical trials testing TAA-derived peptides and/or full length proteins as therapeutic interventions in patients affected by neurological and
pulmonary malignancies
Tumor type
Trials
Phase
Status
Type
TAAs
Co-therapy
Ref.
Astrocytoma
1
0
Active,
not recruiting
Peptide
GAA
Combined with poly ICLC
NCT00795457
Brain cancer
1
I
Active,
not recruiting
Peptide
TAAs
As single AA
NCT00935545
Combined with various
immunostimulants
NCT01403285
Combined with GM-CSF
and radiotherapy
NCT01222221
Combined with
chemotherapeutics
NCT00626015
Combined with GM-CSF
NCT00643097
I
Recruiting
IMA950
Peptide
Glioblastoma
multiforme
I-II
6
EGFRvIII
Active,
not recruiting
II
III
Recruiting
n.a.
Recruiting
0
Glioma
4
I
Lung cancer
1
I-II
Active, not
recruiting
HSP complex
HSPPC96
Combined with temozolomide
NCT00905060
Peptide
EGFRvIII
Combined with GM-CSF
and temozolomide
NCT01480479
GAA
Combined with poly ICLC
NCT01130077
NCT00874861
Peptide
EGFRvIII
As single AA
NCT01058850
Survivin
Combined with GM-CSF
NCT01250470
NY-ESO-1
As single AA
NCT01584115
Recruiting
Recruiting
Peptide
AA, adjuvanted agent; EGFR, epidermal growth factor receptor; GAA, glioma-associated antigen; GM-CSF, granulocyte macrophage colony-stimulating
factor; HSP, heat-shock protein; HSPPC96, HSP-peptide vaccine 96; n.a., not available; poly ICLC, polyriboinosinic-polyribocytidylic acid stabilized with
poly-L-lysine in carboxymethylcellulose; TAA, tumor associated antigen; *started after January, 1st 2008 and not withdrawn, terminated or completed
at the day of submission.
combined with autologous breast cancer cells, allogeneic breast
cancer MCF-7 cells, GM-CSF and recombinant IL-2 (n = 42),133
and with Sialyl-Tn (a MUC1-associated carbohydrate) chemically coupled to KLH (n = 33).134 Some of these approaches
have alongside been tested in ovarian cancer patients,115,116,131,134
owing to the fact that breast and ovarian carcinomas share a
relatively consistent number of TAAs.135 Moreover, ovarian carcinoma patients have been treated with a synthetic form of an
immunodominant disaccharide of the Thomsen-Friedenreich
antigen conjugated to KLH (n = 10),136 with not better specified pre-designated or evidence-based peptides (n = 5),137 with
a p53-derived synthetic long peptide (SLP) coupled to immunostimulatory doses of cyclophosphamide (n = 10),138 and with
multiple courses of recombinant poxviruses encoding full-length
NY-ESO-1 (n = 22).139 Finally, prostate carcinoma patients
have received HER2-derived peptides, as such or in the form of
hybrids with a moiety of the MHC Class II-associated invariant
chain, plus GM-CSF (n = 40 and n = 32),140,141 prostate-specific
antigen (PSA)-derived peptides, as a single adjuvanted agent
(n = 5) or combined with GM-CSF (n = 28),142,143 full-length
NY-ESO-1 complexed with cholesterol-bearing hydrophobized
www.landesbioscience.com
pullulan (CHP) (n = 4, n = 4 and n = 2),144–146 an adjuvanted
globo H hexasaccharide-KLH fusion (n = 20),147 and a number
of multi-peptide preparations often, but not always, including
PSA- and squamous cell carcinoma antigen recognized by T cells
(SART)-derived peptides and combined with GM-CSF or estramustine phosphate, an alkylating estradiol derivative (n = 13,
n = 10, n = 16, n = 19 and n = 23).148–153 Altogether, these studies
demonstrated that the administration of recombinant peptides
or full length proteins to breast, ovarian and prostate carcinoma
patients is generally safe and can induce, in a fraction of cases,
immunological and clinical responses.
Nowadays (September 2012), official sources list 16 recent,
ongoing Phase I-III clinical trials assessing the safety and efficacy
of recombinant peptides in breast carcinoma patients (Table 3).
A majority of these studies involve the administration of HER2derived peptides, either as adjuvanted standalone interventions
or combined with additional immunostimulatory agents, including low doses of cyclophosphamide, GM-CSF and polyICLC.
Alternatively, vaccination regimens based on CDCA1-, CEA-,
hTERT-, KIF20A-, MUC1-, survivin-, URLC10- and WT1derived peptides are being evaluated (source www.clinicaltrials.
OncoImmunology
1563
Table 2 (Continued). Clinical trials testing TAA-derived peptides and/or full length proteins as therapeutic interventions in patients affected by neurological and pulmonary malignancies
Tumor type
Trials
Phase
Status
Type
TAAs
Co-therapy
Ref.
Neuroblastoma
1
I
Active, not
recruiting
Peptide
GD2L
GD3L
Combined with KLH and oral
β-glucan
NCT00911560
n.a.
Enrolling by
invitation
MUC1
Peptide
CDCA1
KIF20A
URLC10
NSCLC
15
FL protein
Unknown
NCT01069575
NCT01219348
URLC10
NCT01069640
MAGE-A3
Combined with CDDP,
radiotherapy or vinorelbine
NCT00455572
CDCA1
URLC10
VEGFR1/2
NCT00874588
TTK
URLC10
VEGFR1/2
NCT00633724
Peptide
KOC1
TTK
URLC10
I-II
As single AA
NCT00674258
URLC10
VEGFR1/2
NCT00673777
RAS
NCT00655161
CTAs
NCT01592617
Vector
II
As single AA
IDO
Recruiting
I
NCT01423760
Recruiting
hTERT
Combined with GM-CSF
NCT01579188
MUC1
Combined with
cyclophosphamide
NCT00409188
FL protein
MAGE-A3
As single AA
NCT00480025
Recruiting
Peptide
MUC1
Combined with
cyclophosphamide
NCT01015443
Recruiting
Peptide
As single AA
NCT01069653
Peptide
Not yet recruiting
III
SCLC
1
I
CDCA1
KIF20A
AA, adjuvanted agent; CDCA1, cell division cycle-associated 1; CDDP, cisplatin; CTA, cancer-testis antigen; FL, full-length; GM-CSF, granulocyte macrophage colony-stimulating factor; hTERT, human telomerase reverse transcriptase; IDO, indoleamine 2, 3-dioxygenase; KIF20A, kinesin family member
20A; KLH, keyhole limpet hemocyanin; KOC1, K homology domain containing protein overexpressed in cancer; MAGE-A3, melanoma-associated
antigen A3; MUC1, mucin 1; n.a., not available; NSCLC, non-small cell lung carcinoma; SCLC, small cell lung cancer; TAA, tumor associated antigen;
URLC10, upregulated gene in lung cancer 10; VEGFR, vascular endothelial growth factor receptor. *started after January, 1st 2008 and not withdrawn,
terminated or completed at the day of submission.
gov). In addition, official sources list 8 recent, ongoing, Phase I-II
clinical trials investigating TAA-derived peptides for the therapeutic vaccination of ovarian (3 studies) and prostate (5 studies) carcinoma patients (Table 3). The trials enrolling ovarian carcinoma
patients involve the administration a p53-derived SLP combined
with pegylated interferon (IFN), full-length NY-ESO-1 adjuvanted with MPLA or a peptide derived from folate-binding protein (FBP, which is often overexpressed by ovarian neoplasms)154
in association with GM-CSF. The studies recruiting prostate
1564
carcinoma patients are based on peptides derived from T-cell
receptor gamma chain alternate reading frame protein (TARP, a
nuclear protein overexpressed in a large proportion of prostate carcinomas),155,156 administered either as a single agent or combined
with ex vivo TARP peptide-pulsed DCs, peptides derived from
prostate membrane-specific antigen (PMSA, a glycoprotein specifically expressed by normal and malignant prostate cells), CDCA1derived epitopes, a synthetic peptide derived corresponding to
amino acids 22–31 of mouse gonadotropin releasing hormone
OncoImmunology
Volume 1 Issue 9
(GnRH), or full-length NY-ESO-1, all given as standalone adjuvanted interventions (source www.clinicaltrials.gov).
Melanoma
Together with RCC, melanoma constitutes by far the clinical setting in which immunotherapeutic interventions have been most
extensively investigated, at least in part due to the fact that both
these neoplasms naturally generate immune responses and appear
to be very sensitive to immunostimulatory interventions, even as
unspecific as the systemic administration of high-dose IL-2.9,10
This intense research effort has lead not only to an improved
understanding of the biology of melanoma cells, but also to the
detailed characterization of a wide panel of melanocyte differentiation antigens (MDAs), underpinning the development of
potential anticancer vaccines.157 The safety and therapeutic profiles of many of such vaccination strategies have been tested in
clinical trials starting from the late 1990s. These studies involved
peptides derived from MDAs including, but not limited to: the
Type I transmembrane glycoprotein gp100 (n = 22, n = 15, n = 26,
n = 12, n = 60, n = 25, n = 24, n = 8, n = 11, n = 51, n = 12,
n = 121, n = 197 and n = 185),158–171 the 18 KDa transmembrane
protein melan A (also known as melanoma antigen recognized by
T cells 1, MART-1) (n = 1, n = 3, n = 15, n = 28, n = 12, n = 60,
n = 25, n = 6, n = 24, n = 8, n = 11, n = 12, n = 17, n = 18 and
n = 15),159,161,163–166,168,172–178 several members of the MAGE-A protein family such as MAGE-A1, MAGE-A3 and MAGE-A10 (n
= 24, n = 51, n = 121 and n = 197),164,167,169,170 and tyrosinase, an
enzyme required for melanin synthesis (n = 18, n = 43, n = 15,
n = 26, n = 60, n = 25, n = 24, n = 11, n = 51, n = 121, n = 197
and n = 18).159,160,162–164,166,167,169,170,177,179,180 In addition, clinical trials enrolling melanoma patients have been performed to assess
the safety profile and therapeutic potential of NY-ESO-1-derived
peptides (n = 37, n = 8, n = 13 and n = 121),169,181–183 hTERTderived peptides (n = 25),184 full-length recombinant NY-ESO-1
(n = not available, n = 51, n = 1, n = 1 and n = 18),144,145,185–187 HSPcomplexed antigens (n = not available),188 and subsequent courses
of recombinant poxviruses encoding full-length NY-ESO-1
(n = 25).139 Most often, MDA- and/or TAA-derived peptides were
administered as part of multi-peptide preparations and combined
with immunostimulatory interventions including conventional
adjuvants, GM-CSF, IL-2 and cyclophosphamide. In line with
the high sensitivity of melanoma cells to immunostimulatory
approaches, the vast majority of these clinical trials reported no
significant side effects and satisfactory rates of durable clinical
responses.
Today (September 2012), official sources list 25 recent, ongoing Phase I-III clinical trials assessing the safety and efficacy of
recombinant peptides/proteins in melanoma patients (Table 4).
Most of these studies are based on various MDA- or TAA-derived
peptides, given either as single adjuvanted agents or combined
with additional immunostimulatory interventions including, but
not limited to, IL-2, IL-12, pegylated IFNα, IFNγ, GM-CSF,
TLR agonists (e.g., polyICLC, imiquimod, resiquimod, lipopolysaccharide) and monoclonal antibodies targeting CD40 or
PD1. In this setting, particularly interesting strategies are being
www.landesbioscience.com
undertaken by trial NCT01331915, investigating the safety
and anticancer profile of a recombinant, detoxified toxin from
Bordetella pertussis coupled to a tyrosinase epitope,189 and by
trial NCT00706992, testing the clinical potential of a replication-defective recombinant canarypox virus encoding a melan
A-derived epitope coupled to T cells genetically engineered to
express a melan A-targeting T-cell receptor (TCR)190 (source
www.clinicaltrials.gov).
Gastrointestinal, Pancreatic and Colorectal Tumors
The results of the first clinical trials investigating the safety and
efficacy of TAA-derived peptides or proteins as therapeutic interventions in cohort of patients affected by gastrointestinal, pancreatic and colorectal neoplasms have been published no earlier than
in 2004.191,192 Since then, the following therapeutic and clinical
settings have been investigated: survivin-derived peptides, given to
colorectal carcinoma (CRC) (n = 15) or pancreatic cancer (n = 1)
patients as a single adjuvanted agent,192,193 a multi-peptide vaccine
including epitopes from distinct SART proteins administered to
CRC patients as a standalone adjuvanted intervention (n = 10),191
a personalized, peptide-based vaccine, given to CRC patients in
combination with uracil, tegafur and calcium folinate (n = 8),194
a personalized combination of maximum 4 peptides derived from
16 distinct TAAs including (but not limited to) HER2, CEA,
PAP, PSA, SART2 and SART3, given to advanced gastric carcinoma or CRC patients in combination with a 5-fluorouracil
derivative (n = 11),195 full-length NY-ESO-1, administered as a
CHP complex to esophageal cancer patients (n = 4, n = 8, n = 4
and n = 8),144–146,196 an artificially synthesized helper/killer-hybrid
epitope long peptide derived from MAGE-A4, given as a dually
adjuvanted standalone intervention to a patient with CRC pulmonary metastasis,197 and three peptides derived from the protein
kinase TTK, lymphocyte antigen 6 complex locus K (LY6K), and
insulin-like growth factor II mRNA-binding protein 3 (IMP3),
administered in incomplete Freund’s adjuvant to esophageal cancer patients (n = 10 and n = 60).198,199 In all these settings, vaccination with TAA-peptides was well tolerated and, in multiple
instances, it also elicited immunological and clinical responses.
Nowadays (September 2012), official sources list 9 recent,
ongoing Phase I-II clinical trials investigating the safety and efficacy of recombinant peptides/proteins in esophageal cancer (5
trials), gastric cancer (1 trial), pancreatic carcinoma (5 trials) and
CRC (4 trials) patients (Table 5). CHP-complexed full-length
NY-ESO-1 as a single agent as well as peptides derived from
common TAAs such as CDCA1, TTK, URLC10, VEGFR1 and
VEGFR2, either as standalone interventions or combined with
TLR9 agonists, are being tested in esophageal cancer patients.
The safety and therapeutic profile of VEGFR1-derived peptides,
as single agents, is being investigated in gastric carcinoma patients.
CRC patients are being enrolled in trials involving MUC1derived peptides combined with either chemoradiation therapy
plus cyclophosphamide or polyICLC, peptides derived from the
CTA RNF43, given as standalone agents, as well as GI-4000 (an
inactivated strain of S. cerevisiae engineered for the expression
of mutant RAS, see above), in combination with conventional
OncoImmunology
1565
Table 3. Clinical trials testing TAA-derived peptides and/or full length proteins as therapeutic interventions in patients affected by breast, ovarian and
prostate carcinoma
Tumor type
Trials
Phase
Status
Type
Active,
not recruiting
n.a.
0
Recruiting
I
Breast cancer
16
Peptide
TAAs
Co-therapy
Ref.
HER2
MUC1
Combined with CpG
ODNs and/or GM-CSF
NCT00640861
CEA
CTAs
HER2
As single AA
NCT00892567
Combined with poly ICLC and tetanus
toxoid peptide
NCT01532960
CMV
hTERT
Survivin
Combined with basiliximab,
GM-CSF and prevnar
NCT01660529
MUC1
Combined with poly ICLC
NCT00986609
CDCA1
DEPDC1
KIF20A
MPHOSPH1
URLC10
As single AA
NCT01259505
FRα
Combined with cyclophosphamide
NCT01606241
HER2
As single AA
NCT01632332
HER2
Combined with lapatinib
NCT00952692
Active,
not recruiting
Combined with GM-CSF
I-II
III
Ovarian cancer
3
I-II
Not
yet recruiting
Recruiting
Recruiting
I
NCT01355393
Combined with anti-HER2
mAb and GM-CSF
NCT01570036
WT1
As single agent
NCT01220128
HER2
Combined with GM-CSF
NCT01479244
FBP
Combined with GM-CSF
NCT01580696
NY-ESO-1
As single AA
NCT01584115
Peptide
p53
Combined with gemcitabine
and pegylated IFNα-2b
NCT01639885
PSMA
TARP
Combined with poly ICLC
NCT00694551
TARP
Combined with ex vivo
TARP peptide-pulsed DCs
NCT00972309
Peptide
Recruiting
I-II
Combined with rintatolimod and/or
GM-CSF
Peptide
Active,
not recruiting
5
NCT00791037
FL protein
n.a.
Prostate cancer
Combined with GM-CSF
and cyclophosphamide
HER2
Recruiting
II
NCT00841399
NCT00854789
Unknown
LAGE1
NY-ESO-1
CDCA1
GnRH
NCT00711334
As single AA
NCT01225471
NCT00895466
AA, adjuvanted agent; CDCA1, cell division cycle-associated 1; CEA, carcinoembryonic antigen; CMV, cytomegalovirus pp65 peptide; CTA, cancer-testis
antigen; DC, dendritic cell; DEPDC1, DEP domain containing 1; FBP, folate binding protein; FL, full length; FR, folate receptor; GM-CSF, granulocyte
macrophage colony-stimulating factor; GnRH, gonadotropin releasing hormone; hTERT, human telomerase reverse transcriptase; IFN, interferon;
KIF20A, kinesin family member 20A; mAb, monoclonal antibody; MPHOSPH1, M-phase phosphoprotein 1; MUC1, mucin 1; n.a., not available; poly ICLC,
polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose; PMSA, prostate membrane-specific antigen; ODN,
oligodeoxynucleotide; TAA, tumor associated antigen; TARP, T-cell receptor gamma chain alternate reading frame protein; URLC10, upregulated in lung
cancer 10; WT1, Wilms’ tumor 1. *started after January, 1st 2008 and not withdrawn, terminated or completed at the day of submission.
1566
OncoImmunology
Volume 1 Issue 9
Table 4. Clinical trials testing TAA-derived peptides and/or full-length proteins as therapeutic interventions in melanoma patients
Tumor type
Trials
Phase
Status
Type
TAAs
Co-therapy
Ref.
NCT00977145
Recruiting
Peptide
Class I-restricted
peptides
Combined with IFNγ
n.a.
Combined with imiquimod
NCT01264731
MAGE-A3
As single AA
NCT01425749
gp100
MART-1
NY-ESO-1
Combined with poly ICLC
± anti-CD40-mAb
NCT01008527
gp100
Combined with
pegylated IFNα-2b
NCT00861406
MAGE-A3
Combined with dacarbazine
NCT00849875
Not
yet recruiting
Class I-restricted
peptides
Combined with
LPS or poly ICLC
NCT01585350
Combined with
anti-PD1 mAb
NCT01176461
Recruiting
gp100
MART-1
NY-ESO-1
PRAME
As single AA
NCT01149343
As single AA
NCT01584115
Combined with poly ICLC
NCT01079741
0
Recruiting
Peptide
Active,
not recruiting
I
Peptide
FL protein
Recruiting
Peptide
I-II
Melanoma
NCT01176474
NY-ESO-1
LAG3
MAGE-3.A2
NA-17
NY-ESO-1
NCT01308294
As single AA
25
Unknown
Vector
Tyrosinase
NCT01331915
Peptide
MAGE-3.A1
NA17.A2
Combined with GM-CSF, IFN-α,
IL-2 and imiquimod
MAGE-A3
As single AA
NCT01191034
NCT00896480
NCT00942162
Active,
not recruiting
II
Peptide
Recruiting
MART-1
Combined with anti-MART-1TCRexpressing PBLs ± IL-2
NCT00706992
Not better specified
Combined with GM-CSF and a
tetanus helper peptide
NCT00938223
gp100
MAGE-3
As single AA ± resiquimod
NCT00960752
gp100
MAGE-3.1
MART-1
NA17-A2
Combined with
daclizumab ± IL-12
NCT01307618
Combined with GM-CSF,
imiquimod and temozolomide
NCT01543464
As single AA ± poly ICLC
NCT01437605
As single AA ± IL-2
NCT0126660
As single AA
NCT00796445
IDO
survivin
MAGE-A3
III
Active,
not recruiting
Peptide
MAGE-A3
AA, adjuvanted agent; FL, full-length; GM-CSF, granulocyte macrophage colony-stimulating factor; gp100, glycoprotein 100; IDO, indoleamine 2,
3-dioxygenase; IFN, interferon; IL, interleukin; LAG3, lymphocyte-activation gene 3; LPS, lipopolysaccharide; mAb, monoclonal antibody; MAGE,
melanoma-associated antigen; MART-1, melanoma antigen recognized by T-cells 1; n.a., not available; PBL, peripheral blood lymphocyte; poly ICLC,
polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose; PRAME, preferentially expressed antigen in melanoma;
TAA, tumor associated antigen; TCR, T-cell receptor. *started after January, 1st 2008 and not withdrawn, terminated or completed at the day of submission.
www.landesbioscience.com
OncoImmunology
1567
Table 5. Clinical trials testing TAA-derived peptides and/or full-length proteins as therapeutic interventions in patients affected by esophageal, gastric,
pancreatic and colorectal carcinoma
Tumor type
Colorectal
carcinoma
Trials
Phase
Status
I
Unknown
4
Type
TAAs
Co-therapy
Ref.
RNF43
As single AA
NCT00641615
GI-4000
Combined with bevacizumab
and/or FOLOFOX or FOLFIRI
NCT01322815
Combined with chemoradio-therapy
and cyclophosphamide
NCT01507103
Combined with poly ICLC
NCT00773097
NY-ESO-1
As single AA complexed
with CHP
NCT01003808
IMP3
LY6K
TTK
As single AA
NCT00682227
KOC1
TTK
URLC10
VEGFR1/2
Combined with cisplatin
and 5-FU
NCT00632333
Combined with CpG ODNs
NCT00669292
CDCA1
KOC1
URLC10
As single AA
NCT01267578
VEGFR1
As single AA
NCT01227772
hTERT
Combined with gemcitabine,
GM-CSF and tadalafil
NCT01342224
VEGFR1/2
Combined with gemcitabine
Peptide
II
Recruiting
MUC1
Active,
not recruiting
FL protein
I
Unknown
Esophageal
carcinoma
5
Peptide
TTK
I-II
URLC10
Recruiting
II
Gastric cancer
Pancreatic
carcinoma
1
I-II
Recruiting
I
Active,
not recruiting
Peptide
NCT01266720
5
Peptide
Unknown
NCT00639925
VEGFR1
As single AA
NCT00683358
VEGFR1/2
Combined with gemcitabine
NCT00655785
I-II
5-FU, 5-fluorouracil; AA, adjuvanted agent; CDCA1, cell division cycle-associated 1; CHP, cholesterol-bearing hydrophobized pullulan; FL, full-length;
FOLFIRI, folinic acid, 5-FU, irinotecan; FOLFOX, folinic acid, 5-FU, oxaliplatin; GM-CSF, granulocyte macrophage colony-stimulating factor; hTERT,
human telomerase reverse transcriptase; IMP3, insulin-like growth factor II mRNA-binding protein 3; KOC1, K homology domain containing protein
overexpressed in cancer; LY6K, lymphocyte antigen 6 complex locus K; MUC1, mucin 1; ODN, oligodeoxynucleotide; poly ICLC, polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose; TAA, tumor associated antigen; URLC10, upregulated in lung cancer 10; VEGFR,
vascular endothelial growth factor receptor. *started after January, 1st 2008 and not withdrawn, terminated or completed at the day of submission.
chemotherapy or bevacizumab (a VEGF-targeting monoclonal
antibody). Finally, peptides derived from hTERT and VEGFR1/2
are being tested in pancreatic carcinoma patients, in combination
with GM-CSF plus tadalafil (a phosphodiesterase Type 5 inhibitor currently approved for the therapy of erectile dysfunction and
commercialized under the label of Cialis®) and/or gemcitabine (a
nucleoside analog) (source www.clinicaltrials.gov).
Renal, Bladder and Reproductive Tract Tumors
So far, a few clinical studies have investigated the profile of
TAA-derived peptides or proteins employed as therapeutic interventions in cohort of patients affected by RCC and distinct malignancies of the reproductive tract, including cervical carcinoma,
endometrial cancer, uterine sarcoma and vulvar intraepithelial
1568
neoplasia.137,200–204 In particular, multi-peptide vaccination strategies involving up to six peptides derived from a broad panel of
RCC-associated antigens have been tested, invariably in combination with immunostimulatory interventions (including IL-2,
IFNα, GM-CSF and low-dose cyclophosphamide), in RCC
patients (n = 10 and n = 96).203,204 In addition, the efficacy of
peptides corresponding to distinct regions of the HPV-16 protein
E7 has been evaluated in patients affected by cervical carcinoma
or vulvar intraepithelial neoplasia, most often as standalone adjuvanted agents or combined with pan-HLA-DR-binding T helper
epitopes (n = 19, n = 18 and n = 15).200–202 Finally, not better specified pre-designated or evidence-based peptides have been tested
in a cohort of patients affected by cervical carcinoma or various
other neoplasms of the reproductive tract (n = 9).137 The administration of recombinant peptides combined to immunostimulatory
OncoImmunology
Volume 1 Issue 9
Table 6. Clinical trials testing TAA-derived peptides and/or full-length proteins as therapeutic interventions in patients affected by bladder carcinoma
and tumors of the reproductive tract
Tumor type
Bladder cancer
Endometrial
cancer
Reproductive
tract cancer
Trials
3
1
Phase
II
I-II
Status
Type
TAAs
Co-therapy
Ref.
Enrolling
by invitation
Peptide
MAGE-A3
As single AA ± BCG
NCT01498172
Recruiting
FL protein
MAGE-A3
Unknown
Peptide
DEPDC1
MPHOSPH1
As single AA
Recruiting
Peptide
FBP
Combined with GM-CSF
NCT01580696
FL protein
NY-ESO-1
Combined with GM-CSF,
decitabine and doxorubicin
NCT00887796
Active,
not recruiting
Seven TAAs
As single AA
NCT01095848
FRα
Combined with
cyclophosphamide
NCT01606241
Virus
NY-ESO-1
Combined with GM-CSF
and rapamycin
NCT01536054
Peptide
Survivin
Combined with
cyclophosphamide
NCT01416038
I
Peptide
6
Recruiting
I-II
NCT01435356
NCT00633204
NCT01673217
AA, adjuvanted agent; BCG, bacillus Calmette-Guérin; DEPDC1, DEP domain containing 1; FBP, folate-binding protein; FL, full-length; FR, folate receptor;
GM-CSF, granulocyte macrophage colony-stimulating factor; MAGE-A3, melanoma-associated antigen A3; MPHOSPH1, M-phase phosphoprotein 1; TAA,
tumor associated antigen. *started after January, 1st 2008 and not withdrawn, terminated or completed at the day of submission.
interventions was well tolerated by RCC patients and yielded
immunological responses that, at least in some cases, were associated with improved patient survival.203,204 Conversely, E7-derived
peptides induced potent immune responses that, in one trial,
led to viral clearance from cervical scrapings by the fourth vaccine course,200 yet were unable to promote efficient antitumor
immunity.137,200–202 These results are in line with the fact that—
according to official sources—preventive anti-HPV vaccines (i.e.,
Cervarix® and Gardasil®) are not efficient against histopathological endpoints when used as therapeutic agents in HPV-infected
women (source http://www.fda.gov).
Today (September 2012), official sources list 10 recent, ongoing Phase I-II clinical trials investigating the safety and efficacy
of recombinant peptides/proteins in bladder carcinoma (3 trials) and reproductive tract cancer (7 trials) patients (Table 6).
In the former clinical setting, MAGE-A3-derived peptides,
recombinant full-length MAGE-A3 or epitopes derived from
DEP domain containing 1 (DEPDC1) and M phase phosphoprotein 1 (MPHOSPH1) are being tested, either as standalone
adjuvanted agents or in combination with the bacillus CalmetteGuérin (BCG), an attenuated strain of Mycobacterium bovis that
is currently employed against superficial bladder carcinoma.205 In
the latter clinical setting, 2 studies involve full-length NY-ESO-1
combined with GM-CSF, the demethylating agents decitabine
and doxorubicine (an anthracycline that has recently been shown
to promote the immunogenic death of tumor cells),20,206,207 two
studies involve a lyophilized liposomal preparation containing
either seven different TAA-derived peptides (DPX-0907, given
as a standalone adjuvanted agent) or survivin-derived epitopes
(administered in combination with cyclophosphamide), one
www.landesbioscience.com
study involves the administration of folate receptor α-derived
peptides plus cyclophosphamide, one study involves FBP-derived
epitopes given together with GM-CSF and one study is based on
a replication-defective NY-ESO-1-coding canarypox virus combined with GM-CSF and the mammalian target or rapamycin
(mTOR) inhibitor sirolimus (source www.clinicaltrials.gov).
Additional Neoplasms and Mixed Clinical Cohorts
Recombinant TAA-derived peptides and full-length proteins
have been tested in a few additional clinical settings, encompassing oral and urothelial cancer patients208,209 as well as rather heterogeneous cohorts including subjects affected by wide arrays of
solid neoplasms.101,210–219 Thus, oral and urothelial cancer patients
(n = 11 and n = 9, respectively) have been treated with a survivin-derived 9-mer, either as a subcutaneous or as a intratumoral
adjuvanted injection.208,209 In addition, WT1-derived 9-mers,
HER2-derived short epitopes or long peptides complexed with
CHP, and not better indicated peptides recognized by circulating T cells in the periphery have been tested, as adjuvanted
standalone interventions, in cohort of patients affected by not
better specified solid tumors (n = 5, n = 10, n = 9, n = 24 and
n = 14),101,210–212,219 NY-ESO-1-derived peptides have been evaluated in patients bearing metastatic NY-ESO-1-expressing cancers
(n = 12),213 and epitopes corresponding to mutated regions of
RAS, CEA-derived peptides, complex multi-peptide preparations
as well as HSP-complexed antigens have been used to vaccinate
patients affected by distinct types of carcinoma or advanced neoplasms (n = 8, n = 10, n = not available, n = 113 and n = 16).214–218
In general, the administration of purified peptides/proteins to
OncoImmunology
1569
Table 7. Clinical trials testing TAA-derived peptides and/or full length proteins as therapeutic interventions in patients affected by additional tumor
type and in mixed patient cohorts
Tumor type
Trials
Phase
Status
Type
TAAs
Co-therapy
Ref.
Bile duct cancer
1
I
Recruiting
Peptide
URLC10
Combined with gemcitabine
NCT00624182
Head and neck
carcinoma
1
I
Unknown
Peptide
HPV-16 antigens
MAGE-A3
As single AA
NCT00704041
Hepatocellular
carcinoma
1
I
Recruiting
Peptide
VEGFR1/2
As single AA
NCT01266707
HER2+ cancers
1
I
Not yet
recruiting
Virus
HER2
As single AA
NCT01526473
HPV-induced cancers
1
I-II
Recruiting
Peptide
p16INK4a
As single AA
NCT01462838
Recruiting
Peptide
WT1
Combined with GM-CSF
NCT01265433
Mesothelioma
2
II
Not yet
recruiting
Virus
5T4
As single AA
NCT01569919
Metastatic
solid tumors
1
I
Recruiting
Peptide
HER2
As single AA
NCT01376505
NY-ESO-1+ tumors
1
I
Recruiting
FL protein
NY-ESO-1
Combined with CpG ODNs
± cyclophosphamide
NCT00819806
Solid tumors
2
I
Recruiting
Peptide
MUC-1
NCT01556789
As single AA
WT1
Various tumors
1
I
Unknown
FL protein
NY-ESO-1
NCT01621542
Combined with resiquimod
NCT00821652
AA, adjuvanted agent; FL, full-length; GM-CSF, granulocyte macrophage colony-stimulating factor; HPV, human papillomavirus; MAGE-A3, melanomaassociated antigen A3; MUC-1, mucin 1; ODN, oligodeoxynucleotide; TAA, tumor associated antigen; URLC10, upregulated in lung cancer 10; VEGFR,
vascular endothelial growth factor receptor; WT1, Wilms’ tumor 1.*. *started after January, 1st 2008 and not withdrawn, terminated or completed at the
day of submission.
these patients was well tolerated and promoted—in a few cases—
immunological and clinical responses.
Today (September 2012), official sources list 12 recent, ongoing Phase I-II clinical trials investigating the safety and efficacy
of recombinant peptides/proteins in patients affected by various
tumor types encompassing head and neck carcinoma (1 trial),
hepatocellular carcinoma (1 trial), mesothelioma (2 trials), bile
duct cancer (1 trial), as well as in relatively heterogeneous patient
cohorts (7 trials) (Table 7). The vast majority of these studies
involves the administration of TAA-derived peptides, either as
standalone adjuvanted agents or combined with immunostimulatory compounds such as GM-CSF, TLR agonists or low doses
of cyclophosphamide. Two notable exceptions are constituted by
NCT01569919, testing a recombinant modified vaccinia Ankara
viral vector encoding the 5T4 fetal oncoprotein in mesothelioma
patients and NCT01526473, evaluating a non-infective variant of
the Venezuelan equine encephalitis virus encoding the extracellular
domain and transmembrane region of HER2 in patients affected
by not better specific HER2+ neoplasms (www.clinicaltrials.gov).
Concluding Remarks
During the last two decades, the molecular and cellular circuitries whereby malignant cells and the immune system mutually
interact have been the subject of in-depth investigation. Such a
renovated interest, stemming within the conceptual framework
1570
provided by Polly Matzinger’s danger theory, has been paralleled
by the development of multiple strategies for anticancer vaccination. These approaches, involving the use of recombinant proteins, TAA-encoding vectors or DC preparations, have generated
encouraging results in both preclinical and clinical settings.
However, only a few trials assessing the efficacy of TAA-derived
peptides and/or full length proteins have reported consistent
rates of objective, long-term clinical responses.108,129,171,204,220 In
line with this notion, no more than three anticancer vaccines
are currently approved by FDA for use in humans: Provenge®,
employed as a therapeutic intervention in a limited subset of prostate carcinoma patients; Cervarix® and Gardasil®, both given as
prophylactic agents against HPV infection (and hence against
HPV-associated cervical carcinoma). At least in part, this is due
to the fact that the eradication of established malignant lesions
requires a robust tumor-specific, cell-mediated immune response
that is relatively difficult to obtain, owing to multiple reasons
(see above). Moreover, it appears that several TAA-derived peptides and/or full-length protein exhibit (at least some degree of)
clinical activity when administered as adjuvant therapy or to
patients with minimal residual disease, yet fail to provide any
clinical benefit to individuals bearing advanced and/or metastatic lesions.80,108,220–222 We believe that (1) the discovery of novel
bona fide TRAs, (2) the optimization of adjuvant strategies that
potently activate DCs in vivo, (3) the rational combination of
anticancer vaccines with immunomodulatory agents (such as
OncoImmunology
Volume 1 Issue 9
anti-CTLA4 and anti-PD1 antibodies), (4) the precise identification of the subsets of patients that are most likely to respond to
vaccination with robust immune responses and (5) the establishment of standardized protocols to evaluate the nature, breadth
and quality of antigen-specific T-cell responses, an objective
recently proposed by the MIATA (Minimal Information About T
Cell Assays) project,223–225 are the keys toward the development of
new, efficient and (perhaps) clinically useful anticancer vaccines.
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