and Immunomodulatory xenobiotics)
.For modulation of Th cell responses, peptides offere several advantages over intact Ags as immunogens or tolerogens (either as altered peptide ligands (APLs), competitors, or vaccines). First, peptides require less stringent degradative conditions than native Ags. Second, with a smaller determinant, there is less likelihood of cross-reactivity between the peptide and other self-proteins. And third, peptides offer exquisite specificity over native Ags. Despite these advantages, the use of peptides has remained fairly limited, because they are rapidly cleared from the circulation and poorly taken-up by APCs (by pinocytosis only) : effectiveness of taking up can be increased by coupling peptides to ligands (eg. transferrin (Tf)) specific for cell surface receptors found on APCs (eg. CD71 / TfR).
)
are used for chronic infections and cancers
vaccine : if given within 4 days of exposure to virus, it halts the disease's
advance.
vaccine : intramuscular (2.5 IU
= 1 mL) or intradermic (0.1 mL) injections of at day 0, 3, 7, 14,
28 and 90. Effective for 2-3 years. The treatment
of rabies exposure has come a long way since the time a person had to take
21 shots in the stomach. Today, most people need 5 rabies vaccinations
in the arm spaced out over a 28-day period, as well as a one-time dose
of rabies immune
globulin (RIG).
The WHO recommends 2 economical intradermal regimens for post-exposure
rabies prophylaxis (PEP) :;
purified
chick embryo cell vaccine (PCECV)
and purified
duck embryo vaccine (PDEV).
The other recommended vaccine, purified
vero cell rabies vaccine (PVRV),
has only 0.5 ml per ampoule and it has not been tested with the 8-site
regimen, but if it were used the logical dose would be 0.05 ml per site,
or alternatively 0.1 ml in half the number of sites. (A whole ampoule of
vaccine must be used on day 0 in every case). The 2-site id regimen was
designed for use with PVRV. It requires a dose of 0.1 ml per site for PVRV
and 0.2 ml per site for the other 3 vaccines. Full details
of the economical regimens and practical advice are availableon the
WHO website. The advantages of the 8-site method are a rapid induction
of neutralising antibody, making it the treatment
of choice when no rabies immunoglobulin is available (>95% of post-exposure
treatments in the third world); a wide margin of safety, because if up
to half of the 8 id injections on day 0 are not truly id, the immune response
will still be adequate; and using a wholeampoule on day 0, which avoids
the need to share ampoules of vaccine between patients during the emergency
treatment and eliminates any risk of contamination or wastage of vaccine.
Finally, giving a large antigenic stimulus on day 0 gives the best chance
of survival to patients who are 'low responders' to the vaccine and to
those who fail to return on time for subsequent doses, a common problem
in the rural tropics. The complexity of these treatments demonstrates the
urgent need for animproved, single, simplified regimen that is suitable
for use with all the WHO recommended vaccines. Efforts are being made to
achieve this goal. Meanwhile there is reluctance to use these vaccines
economically. This deprives many patients of excellent treatment and perpetuates
double standards of treatment in the third
world. Under current CDC guidelines, post-exposure prophylaxis for
persons not pre-exposure vaccinated currently consists of a
vaccine : V-1
Immunitor (V1) (Remune©; Immune
Response Corp., Carlsbad, CA, USA, and Trinity Medical Group Co., Ltd.
of Bangkok, Thailand) is a low-cost, polyvalent
therapeutic
mucosal
AIDS
vaccine against core antigens based on the Salk Immunogen, which is derived
from an HIV isolate which has been inactivated by chemical depletion of
gp120 (clade A/G) : it is composed of an HIV-1 isolate (HZ321) from serum
collected from a patient in Zaire in 1976. This virus has been sequenced
and classified as clade A envelope and clade G Gag and grown in the Hut
78 T-cell lineref1,
ref2,
ref3.
It was developed and manufactured in Thailand and has been licensed
by the Thai FDA as a orally available dietary
supplement and investigational R&D drug. It has
shown effectiveness against wasting syndromeref1,
ref2,
ref3.
A phase II double-blind controlled clinical trial using HIV-1 immunogen
was undertaken in Thailand in 1995 in conjunction with phase III approval
in the USA. In most instances, immune response to the virus was induced.
The results from this study led to the extension of further trials over
the following 4 years. At present, the Thai Food and Drug Administration
(FDA) is in the process of reviewing the files on all information to assess
the effectiveness of this therapeutic vaccine as well as reviewing the
proposal to conduct a phase III trial to further confirm previous efficacy
results from the phase II trialsref.
vaccine : the incidence and severity of
herpes zoster and postherpetic neuralgia increase with age in association
with a progressive decline in cell-mediated immunity to VZV. 38,546 adults
> 60 years of age were enrolled in a randomized, double-blind, placebo-controlled
trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster
vaccine"). Herpes zoster was diagnosed according to clinical and laboratory
criteria. The pain and discomfort associated with herpes zoster were measured
repeatedly for 6 months. The primary end point was the burden of illness
due to herpes zoster, a measure affected by the incidence, severity, and
duration of the associated pain and discomfort. The secondary end point
was the incidence of postherpetic neuralgia. > 95% of the subjects continued
in the study to its completion, with a median of 3.12 years of surveillance
for herpes zoster. A total of 957 confirmed cases of herpes zoster (315
among vaccine recipients and 642 among placebo recipients) and 107 cases
of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo
recipients) were included in the efficacy analysis. The use of the zoster
vaccine reduced the burden of illness due to herpes zoster by 61.1%, reduced
the incidence of postherpetic neuralgia by 66.5% (P<0.001), and reduced
the incidence of herpes zoster by 51.3%. Reactions at the injection site
were more frequent among vaccine recipients but were generally mild. The
zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic
neuralgia among older adults.)
: on the basis of the successes of attenuated pathogen vaccines and owing
to the initial lack of defined tumour antigens, the first cancer vaccines
were composed of whole cancer cells removed during surgery, killed by irradiation
and re-administered together with non-specific adjuvants.
(modified tumour cells / transfectoma)
: hapten-treated autologous melanoma cells,
then killed by irradiation and administered intradermallyref
(good responses)ref1,
ref2,
ref3,
ref4
(good responses)ref1,
ref2ref1,
ref2ref
in patients with recurrent prostate
adenocarcinoma.
A single-institution phase I/II trial was done in hormone therapy-naive
patients with PSA relapse following radical prostatectomy and absence of
radiologic metastases. Treatments were administered weekly via intradermal
injections of 1.2 x 108 GM-CSF gene-transduced, irradiated,
cancer cells (6 x 107 LNCaP cells and 6 x 107 PC-3
cells) for 8 weeks. 21 patients were enrolled and treated. Toxicities included
local injection-site reactions, pruritus, and flu-like symptoms. 1 patient
had a partial PSA response of 7-month duration. At 20 weeks post first
treatment, 16 of 21 (76%) patients showed a statistically significant decrease
in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection
site biopsies showed intradermal infiltrates consisting of CD1a+
dendritic cells and CD68+ macrophages, similar to previous clinical
trials using autologous GM-CSF-transduced cancer cells. Posttreatment,
patients developed new oligoclonal antibodies reactive against at least
five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody
response against a 250-kDa antigen expressed on normal prostate epithelial
cells was induced in a patient with partial PSA remission; titers of this
antibody decreased when treatment ended, and subsequent PSA relapse occurredrefref1,
ref2
is an allogeneic melanoma tumor cell lysate combined with the adjuvant
Detox-PC, often in regimens containing pretreatment with low-dose cyclophosphamide
and IFN-a2bref1,
ref2
: phase I and II trials in stage IV patients showed a 10-20% response rate
(clearing of some metastatic sites) and in another 10-20% of patients disease
was stabilized (no progression for various periods of time of tumours that
were growing at the start of the vaccine protocol. It may have its greatest
benefit in a large subset of melanoma patients who express either the HLA-A2
and/or HLA-C3ref.
and colon cancer : irradiated allogeneic cells induce IgG and IgM immune
responses to glycoprotein melanoma-associated antigen (TA90) after surgical
resection, but only the IgM response is correlated with improved survival
: endogenous immune responses to TA90 have also been reportedref.
It is a polyvalent vaccine (PV) containing > 20 tumor antigens. In vitro
cellular immune response to Canvaxin cells directly correlates with survival
after subsequent initiation of immunotherapy for AJCC stage III melanomaref.
Canvaxin is currently undergoing a multi-centre phase III randomized clinical
trials for melanoma and a phase II trial for colorectal
carcinoma.
and colorectal
carcinomas.
as adjuvants would activate DCs to prime immunity to many autoantigens
(otherwise subject to peripheral tolerance) other than the tumor antigens
: the use of whole tumour cells or complex mixtures o tumour-derived material
undermines one unique advantage that immunotherapy has over other forms
of therapy - that is, specificity. Recently, in spite of the availability
of well-defined tumour antigens, development in the cancer-vaccine field
has focused again on the use of whole tumour cells or whole cell lysates
as antigens : the reason being that these complex mixtures will contain
unique
tumour antigens that are expressed only by an individual tumour
that, by analogy to unique antigens of mouse carcinogen-induced tumours
might be more immunogenic and promote a better anti-tumour immune response.
But experiments carried out in mice transgenic for shared
tumour antigenshave shown that these antigens can elicit equally
strong antitumour immunity and tumour rejection.
vaccine : conventional envelope-based antibody-inducing vaccines
do not appear to hold promise, and broadly-neutralizing antibodies are
now being searched as an alternative to the failed approach with subunit
vaccines. The current consensus is that cellular immune responses, especially
those mediated by CD8+ CTL and CD4+ Th
lymphocytes, are needed to control HIV. Vaccines capable of inducing cell-mediated
responses are, therefore, considered critical for controlling the spread
of HIV. DNA-based vaccines triggering CTL reaction are currently thought
to be an answer, but will they fulfill the promise?
vaccine : P. insidiosum-antigen
(PIA) 100-200 ml of PIA (2.0 mg/ml), at a 14-day
intervalref1,
ref2,
ref3-antigen
therapeutic vaccines (see also immunooncology). |
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has developed as a powerful technique to select ligands to essentially
any chosen target from diverse repertoires of peptides, proteins, or Abs
displayed on the surface of a phage particle. Previous application has
mainly focused on Ab libraries and constrained or linear peptide libraries.
This technology has also been used to identify immunogenic targets or epitopes
recognized by Abs; for example, selection of peptide libraries on mAbs
and complex sera of patients with disease has led to the isolation of immunoreactive
peptide epitopes. Although mapping sera with peptide phage libraries has
had some success with small viral genomes such as HBV,
the selection of peptide repertoires appears not to be a suitable approach
when profiling the complexity of the immune response in the context of
the human genome. One of the drawbacks is that often predominantly Ag
mimotopes are recovered, for which further complicated analysis is
required to recover the original Ag that elicited the immune response.
A more successful approach is to display cDNA expression libraries on filamentous
phage. In contrast to the use of peptide display repertoires, there have
been significantly fewer reports on cDNA display due to technical challenges
in their construction and expression. For example, due to stop codons inherent
to cDNA, cDNA display libraries cannot be fused to the N terminus of the
popular phage anchor protein pIII. As such, anchoring of the cDNA product
on the phage coat has to be performed via indirect linkage to pIII or by
direct fusion to the C terminus of another phage coat protein, pVI. In
the case of low titer IgG response that predominate in immunosuppressed
conditions such as cancer, early studies using autologous selection of
phage-displayed primary tumor cDNA repertoires were unsuccessful, although
selections with both mAbs and polyclonal rabbit sera did recover specific
ligands. Selections performed with immobilized autologous cancer patient
IgG using and anti-human IgG capture Ab resulted in the preferential recovery
of only IgG transcripts that were present due to tumor-infiltrating B cells.-associated
tumors provide target Ags for immunotherapy,
lung,
bladder,
ovarian
carcinomas,
hepatocellular
carcinoma (HCC)
(MAGE-1, SSX-1, CTp11 and HCA587 => polyvalent vaccinationsref),
breast
carcinomas
and multiple myeloma.
T-cell immune responses to CGAg have been identified in patients with solid
tumors and multiple myelomaref.
They do not belong to the immunological self because they are expressed
only in immunoprivileged
sites.
Since germ line cells do not carry HLA molecules on their surface they
cannot present antigens to T cells. Their immunogenicity can be enhanced
if they are expressed (together with both allogeneic and (transfected)
syngeneic and MHC determinants) by highly antigenic (e.g. non-self)
cells after DNA transfection.
Supporting the role of DNA methylation in generating the intratumor heterogeneity
of CTA, the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-dCyd)
invariably induced their expression in all CTA-negative clones of human
cutaneous melanomaref)
: a MAGE-3 antigen presented by HLA-A1 has been used in several vaccination
trials on metastatic melanoma patients. Only a small minority of patients
have shown evidence of tumor regression. Attempts to correlate the tumor
rejections with the cytotoxic T lymphocyte (CTL) response against the vaccine
have been hampered by the low level of these responses. In noncancerous
individuals, the frequency of the T cell precursors against antigen MAGE-3.A1
is approximately 4 x 10-7 CD8 T cells. The diversity of the
TcR repertoire of these anti-MAGE-3.A1 precursors was analyzed in one individual.
The results indicate that it is very likely that the repertoire comprises
>100 clonotypes. On this basis, it is possible to use not only the frequency
of CTL precursors in the blood but also the presence of dominant clonotypes
to ascertain in patients the existence of anti-MAGE-3.A1 responses as low
as 10-6 of CD8. With this approach, we observed a correlation
between tumor regression and anti-MAGE-3.A1 CTL responses in patients vaccinated
with a recombinant virus encoding the antigen and also in patients vaccinated
with peptide-pulsed dendritic cells. In contrast, for patients showing
tumor regression after vaccination with peptide alone, CTL responses were
almost never observed. It is possible that even those CTL responses that
are below our present detection level can trigger a sequence of events
that leads to tumor regressionref.
MAGE-A3 peptides presented by HLA class I molecules have been identified
using CD8 lymphocytes stimulated with cells that either expressed gene
MAGE-A3 or were pulsed with candidate peptides. One antigen identified
with the latter method is peptide MAGE-A3195-203 IMPKAGLLI,
presented by HLA-A24 molecules. It has been used to vaccinate advanced
cancer patients. HLA/peptide tetramers were used to detect T cells recognizing
this peptide. Their frequency was estimated to be 2 x 10-8 of
the blood CD8 cells in non-cancerous HLA-A24+ individuals, which
is 10-fold lower than the reported frequencies of T cells against other
MAGE peptides. In the blood of a patient vaccinated with MAGE-A3, the estimated
frequency was 5 x 10-7. Anti-MAGE-3.A24 cytolytic T cell clones
were derived, that lysed peptide-pulsed cells with half-maximal effect
at the low concentration of 500 pM. However, these CTL did not recognize
a panel of HLA-A24+ tumor cells that expressed MAGE-A3 at levels
similar to those found in HLA-A1+ tumor cells recognized by
anti-MAGE-3.A1 CTLs. Furthermore, 293-EBNA cells transfected with MAGE-A3
and HLA-A24 constructs were hardly recognized by the anti-MAGE-3.A24 CTL
clones. These results suggest that peptide MAGE-A3195-203 is
poorly processed and is not an appropriate target for cancer immunotherapyref.,
lung,
bladder,
and head and neck
cancers)
: the peptide NYKRCFPVI, which corresponds to amino acids 143 to151 of
the MAGE-4 protein, can be presented by HLA-A24 molecules, which are widely
expressed in different ethnic groups. A cytolytic T cell clone that recognized
the MAGE-4 peptide was isolated from the blood cells of a donor without
cancer and lysed specifically A24 carcinoma cells expressing MAGE-4. The
antigenic peptide is processed more efficiently in tumor cells pre-treated
with IFN-gref.
respectively. Both CT antigens were more frequently expressed in squamous
cell carcinoma (SCC) than in adenocarcinoma. An inverse correlation was
found between MAGE-A4 expression and patient survival in advanced stage
cancers. Combined infiltration of both CD4+ and CD8+ T cells into tumor
nest predicted better survival. There was no correlation, however, between
lymphocyte infiltration and antigen expression in the tumor. MAGE-A4 expression
in advanced group and T cell infiltration may provide prognostic information.
Lastly, these CT antigens, especially MAGE-A4, may represent potential
targets for cancer immunotherapy in patients with NSCLCref.
and acute myeloid
leukemias)ref)
is a highly immunogenic protein and the observation that > 90% of vasectomized
males develop immunity against Sp17 suggests the opportunity and safety
of Sp17 for tumor vaccines. Although Sp17 transcripts could be detected
by RT-PCR in some normal tissues, the levels of expression were <2%
of those in normal testis. In contrast, Sp17+ myeloma cells
expressed 3-18% of normal testis levels of Sp17 transcript. IHC using 2
Sp17 murine mAbs, each directed at a non-overlapping B-cell epitope, showed
Sp17 protein to be expressed only in testis and not any other normal tissues.
Specificity of binding of the antibodies to testis was also confirmed in
competitive binding assaysref.
Recent works by other workers suggest a low level of expression of Sp17
in some normal tissues, and investigators have questioned whether Sp17
is in fact a suitable target for immunotherapyref.
Sp17-specific HLA class I-restricted CTL generation was successful in all
4 patients, irrespective of the Sp17 status of their tumors : most importantly,
the CTLs were able to lyse autologous tumor cells that expressed Sp17ref.
Sp17-specific HLA class I-restricted CTLs can also be easily generated
from the peripheral blood of healthy donor. Because CTLs are able to kill
HLA-matched fresh myeloma cells, it may be possible to generate and administer
myeloma-specific donor T cells to MM patients following allogeneic stem
cell transplantation to enhance graft-versus-myeloma (GVM) without inducing
graft-versus-host disease (GVHD)ref1,
ref2.
Sp17 was found to be expressed in the primary tumor cells from 70% of the
patients with ovarian
carcinoma.
HLA class I-restricted Sp17 specific CTLs were generated successfully from
the peripheral blood of 3 patients with ovarian carcinoma at the time of
disease presentation. These CTLs were able to lyse autologous EBV-transformed
lymphoblastoid cells in a Sp17-dependent manner. Target lysis was HLA class
I-dependent and could be blocked by antibodies against monomorphic HLA
class I but not HLA class II molecules. The CTLs also lysed Sp17+
autologous tumor cells, suggesting that Sp17 is processed and presented
in association with the HLA class I molecules in Sp17+ tumor
cells in a concentration and configuration that could be recognized by
recombinant protein-primed CTLs. Tumor cell killing by the CTLs appeared
to be mediated through the perforin pathwayref,
3 of 11 chronic
lymphocytic leukemia (CLL),
4 of 14 chronic
myeloid leukemia,
and 6 of 17 multiple myeloma.
In contrast, they were not detected in corresponding specimens from any
healthy donors. SLLP1 exhibited a very restricted normal tissue expression,
being found only in testis/spermatozoa. SLLP1 was expressed in some tumor
cells at a level of >25%. High titer IgG antibodies against SLLP1 were
also detected in the sera of some of these patients. CONCLUSIONS: SLLP1
is a novel cancer-testis antigen in hematologic malignancies and is capable
of eliciting B-cell immune responses in vivo in cancer-bearing individualsref
and other hematologic malignancies such as chronic
lymphocytic leukemia (CLL),
chronic
myeloid leukemia,
and acute myeloid
leukemia.
It is not expressed in any normal tissue except testis. High-titer IgG3
and IgG2 against SPAN-Xb were detectable in the sera of
these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected
in any of the healthy donors. There was a good correlation between SPAN-Xb
gene expression and B-cell immune responses. These results suggest the
in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer
IgG responses suggests that the B-cell responses are likely to have been
generated with CD4 T-cell cognitive helpref)ref
have antibody responses to SCP-1, but not to other cancer testis antigens
(GAGE, LAGE-1a,-1b, CT-7, NY-ESO-1, SSX-1-5). Antibody response correlated
with the expression of SCP-1 in the primary tumor of the respective patient
as shown by RT-PCR, IHC and Western blot. In contrast, no serological response
to CTAgs was observed in healthy donors. The humoral immune response against
SCP-1 was associated with the size of tumor, but not with other clinico-pathological
parameters such as histology, stage, presence of lymph node metastases,
grading, age, gender or gemcitabine treatmentref
is highly expressed in 80% of hepatocellular
carcinoma (HCC)ref1,
ref2,
ref3,
ref4,
ref5,
but AFP immunization alone still resulted in lower levels of specific response
and poorly reproducible protective immunityref1,
ref2,
ref3,
ref4,
ref5
: the immunogenicity of AFP could be improved by presenting to APCs through
HSP70 moleculesref1,
ref2,
ref3,
ref4,
ref5.
Sequential immunization by i.m. injection of a recombinant DNA plasmid
vaccine encoding AFP and HSP70 fragments could generate effective AFP-specific
T cell responses and induce definite antitumor effects on AFP-producing
tumors, which may be suitable for some clinical testing as a vaccine for
HCCref.
The recombinant expression vectors PEGF-N3/AFP1 and PEGF-N3/AFP2 with or
without signal peptide were constructed successfully. AFP2/DCs can specifically
activate T lymphocytes in vitro and effectively induce antitumor
immune responseref.
: C57BL/6 and BALB/c mice were immunized with 2 different plasmids (p91023B
and pKCEA66) encoding different forms of the TAA CEA. The wild type form
of CEA (p91023B), which is expressed at the cell surface, induces stronger
anti-CEA IgG response after DNA-plasmid immunizations than the modified
intracellular form of CEA (pKCEA66), which was designed to mount strong
cellular responses. Boosting with recombinant CEA (rCEA) increased the
anti-CEA IgG response significantly. In the tumor protection model used,
where SCID mice are challenged with human tumor cells mixed with splenocytes
from immunized mice, both innate and specific immune responses are responsible
for the protective effectref.
Exosomes from heat-stressed CEA+ tumor cells (CEA+/HS-Exo)
contained CEA and more HSP70 and MHC-I and significantly induced dendritic
cell maturation. Immunization of HLA-A2.1/K(b) transgenic mice with CEA+/HS-Exo
was more efficient in priming a CEA-specific CTL, and the CTL showed antitumor
effect when adoptively transferred to SW480-bearing nude mice. Moreover,
in
vitro incubation of lymphocytes from HLA-A*0201+ healthy
donors and HLA-A*0201+CEA+ cancer patients with CEA+/HS-Exo-pulsed
autologous dendritic cells induces HLA-A*0201-restricted and CEA-specific
CTL response. CEA+/HS-Exo has superior immunogenicity than CEA+/Exo
in inducing CEA-specific CTL responseref.
CEA, the most widely used human tumor marker, is a heavily glycosylated
protein over-expressed by a wide range of tumors. It has been indicated
that CEA might be a useful target for human anti-tumor immunotherapy. CEA
assay for research as well as clinical trials demands a continuous source
of CEA protein preparations. In a multi-purpose research program to provide
a reliable source for large production of CEA, the membrane-bound carcinoembryonic
antigen was converted into a secretory protein by site-specific mutagenesis.
The secretory CEA protein was made by introducing a new stop codon at 99
bp upstream of the original stop codon in CEA cDNA by PCR-based mutagenesis.
The glycosylation of recombinant CEA proteins, especially those destined
for administration to human trials is crucially important. To produce CEA
with the same glycosylation pattern and immunogenicity as the native CEA
expressed by human tumors in vivo, the truncated CEA cDNA which
does not encode the last C-terminal 33-amino acid hydrophobic domain was
transfected into HT29, a human colon carcinoma cell line by the calcium
phosphate method. Stable transfectants were selected and pooled. CEA secretion
from the cells was verified by analysis of the transfectant culture supernatant
for CEA protein. As determined by ELISA, 16 mg/L
of recombinant CEA was secreted per 106 transfectants within
48 hrs, an increase over 40 times relative to the untransfected cells.
The size of the recombinant CEA secreted by HT29 transfectants in our experiment
is identical to that of reference CEA secreted from tumors and is fully
antigenic. It seems that the C-terminal truncation does not affect CEA
glycosylation in HT29 cells. It is predicted that human cancer immunotherapy
using recombinant CEA expressed in this system would be more effective
than the commercial protein which is usually prepared from bacterial or
other heterologous expression systemsref.
The existence of a murine model transgenic for human CEA allows CEA vaccination
efficacy to be studied in a physiologically tolerant context. Immunization
of CEA-transgenic mice with an adenoviral vector coding for CEA induced
a significant CD8+ T-cell response specific to CEA but failed
to induce CEA-specific CD4+ T cells and antibodies. To overcome
CD4+ T-cell tolerance, the effect of adjuvants inducing in
vivo DC maturation were explored. 2 different TLR ligands, monophosphoryl
lipid A (MPL) and CpG motif-containing oligodeoxynucleotides (CpG-ODN),
were tested. CD4+-mediated IFN-g
production was induced in the CEA-transgenic mice only when the genetic
immunization was performed in the presence of these adjuvants. Moreover,
CpG-ODN had a greater effect than MPL in inducing CD4+ T-cell
response and enabling anti-CEA antibody productionref.
in juvenile
myelomonocytic leukemia
are, again, unfolded. Characteristically, expression follows the same tissue
presentation as during embryogenesis. Clinical paternal disomies, i.e.
trophoblastic
diseases,
and their maternal counterpart, i.e. ovarian
teratomas,
are associated with apparent relaxation of imprinting once they turn malignant.
Paediatric neoplasms, like Wilms'
tumor (WT)
and rhabdomyosarcoma,
often express IGF2 and H19. Recently H19 expression has been found in invasive
urothelial cancer. Evidently, imprinted genes display an oncodevelopmental
mode of expression, very much like the classical oncofetal proteins AFP
and CEA.
for adenocarcinomas (certain breast
carcinomas,
...) is overexpressed and modified by tumor cells in > 50% of all cancer
cases. Animal data show that it can be a target for immune-mediated tumor
rejection, and finally, preliminary clinical results show that vaccine-based
immunotherapy with MUC1 does have an impact on the therapy of cancerref.
BLP25
liposome (L-BLP25®) vaccine (source : Biomira)
is a cancer vaccine that targets the exposed core peptide of the MUC1 tumor-associated
antigen. Studies in advanced-stage NSCLC
demonstrate that L-BLP25 vaccine has the potential to extend the survival
of patients with Stage IIIB locoregional NSCLC and maintain quality of
life for longer : it is now undergoing phase III clinical trial. L-BLP25
vaccine also shows promise for prostate
cancer
patients, having the potential to prolong PSA doubling time in men with
biochemical failure post prostatectomy. These clinically meaningful results
with a relatively nontoxic therapeutic vaccine are very encouraging and
suggest potential for L-BLP25 to fulfill an unmet medical needref.
patients received Tn(c)-KLH vaccine containing either 3, 7, or 15
mg
of Tn(c) per vaccination. 10 patients received 100 mg
of Tn(c)-palmitic acid (PAM). QS21 was included in all vaccines. 5 vaccinations
were administered subcutaneously during 26 weeks with an additional booster
vaccine at week 50. Tn(c), when given with the carrier molecule KLH and
QS21, stimulated the production of high-titer IgM and IgG antibodies. Inferior
antibody responses were seen with T(c)-PAM. There was no evidence of enhanced
immunogenicity with increasing doses of vaccine. An antitumor effect in
the form of a decline in posttreatment versus pretreatment PSA slopes was
also observed. A safe synthetic conjugate vaccine in a trimer formation
was developed that can break immunologic tolerance by inducing specific
humoral responses. It seemed to affect the biochemical progression of the
disease as determined by a change in PSA log sloperef.
and MUC-1 (pNGVL-hFLex-MUC-1) is able to induce antigen-specific CTL immunity
in vivo, resulting in a potent anti-tumour response, and the Flt-3L
component is essential to the efficacy of the DNA vaccine. Moreover, the
route of immunization is critical in determining the type of immune response
generated; intramuscular (i.m.) immunization with pNGVL-hFLex-MUC-1 conferred
tumour protection in contrast to poor response with hydrodynamic-based
intravenous delivery. Post-i.m. immunization, a massive infiltration of
mononuclear cells to the injection site was observed, comprised predominantly
of CD11c+/CD8a- DC. Flt-3L
acts as an adjuvant to recruit DC, thereby priming the anti-tumour response.
However, systemic expansion of DC prior to immunization did not enhance
the specific cellular response, suggesting that it is in situ recruitment
or expansion of DC that is critical for pNGVL-hFLex-MUC-1 potencyrefref1,
ref2
(expressed in > 85% of human cancers) : the main risk of targeting dominant
TERT epitopes is induction of autoimmunity in activated B cells. Immunity
against low-affinity epitopes is induced with heteroclitical variants.
The CTL repertoire against high-affinity epitopes of murine TERT (mTERT)
is partially tolerized, while that against low-affinity epitopes is composed
of frequent CTLs with high avidity. The high-affinity p797 and p545 mTERT
epitopes are not able to protect mice from a lethal challenge with the
mTERT-expressing EL4-HHD tumor. In contrast, mice developing CTL responses
against the p572 and p988 low-affinity epitopes exhibit potent antitumor
immunity and no sign of autoimmune reactivity against TERT-expressing normal
tissuesref.
Endogenous in vivo priming of T cells against hTERT is a rare event
in multiple myeloma
patients. These results suggest that strategies targeting hTERT may have
to utilize techniques to induce T cell responses from a naive precursor
frequencyref.
In an attempt to develop an effective vaccine against most human cancers,
a chemotactic-hTERT vaccine has been constructed. 2 hTERT fragments encoding
multiple cytotoxic T lymphocyte and T helper cell epitopes were fused as
a tumor antigen (named Te). The plasmid based DNA vaccine (pCCL21-Te-Fc)
was constructed by linking human CCL21 and IgG Fc gene sequences to each
end of Te. In poorly immunogenic B16F10 mouse melanoma model, DNA (pCCL21-Te-Fc)
vaccination significantly inhibited tumor growth and all of the mice were
dead by day 52. The immunization with pCCL21-Te-Fc-modified tumor cells
(B16/CCL21-Te-Fc) resulted in a higher antitumor effect than DNA vaccination
and 25% of tumor-bearing mice achieved long-term survival (>120 days).
The combined therapy of B16/CCL21-Te-Fc plus anti-4-1BB MAbs further enhanced
the immune response, resulting in 75% of tumor-bearing mice achieved long-term
survival (>120 days) in subcutaneous model and few lung nodules in pulmonary
metastasis model. Rechallenge experiment showed that a persistent memory
response was successfully induced by the combined therapy. In vivo depletion
of lymphocytes indicated that CD8+ T cells were essential in
the antitumor activity induced by B16/CCL21-Te-Fc + anti-4-1BB MAbs, whereas
NK cells and CD4+ T cells played substantial roles. The CTL
activity induced by pCCL21-Te-Fc-transfected PBMCs specifically lysed a
variety of HLA-matched and hTERT-positive human tumor cells, suggesting
pCCL21-Te-Fc could serve as a vaccine against most human cancersref.
HLA-B*0702-restricted peptides from hTERT were selected by using a method
of epitope prediction and tested for their immunogenicity in human (in
vitro) and HLA-B*0702 transgenic mice (in vivo). All the 6 hTERT
peptides that were predicted to bind to HLA-B*0702 molecule were found
to induce primary human CTL responses in vitro. The peptide-specific CD8+
CTL lines were tested against various hTERT+tumor cells. Although
differences were observed according to the tumor origin, only 3 CTL lines
specific for p277, p342, and p351 peptides exhibited cytotoxicity against
tumor cells in a HLA-B*0702-restricted manner. In addition, this cytotoxicity
was inhibited by the addition of peptide-loaded cold target cells and indicated
that these epitopes are naturally processed and presented on the tumor
cells. Further, in vivo studies using humanized HLA-B*0702 transgenic
mice showed that all the candidate peptides were able to induce CTL responses
after peptide immunization. Furthermore, vaccination with a plasmid DNA
encoding full-length hTERT elicited peptide-specific CTL responses, indicating
that these epitopes are efficiently processed in vivo. Together
with previously reported hTERT epitopes, the identification of new CTL
epitopes presented by HLA-B*0702 increases the applicability of hTERT-based
immunotherapy to treating cancerref
: mutations leading to functional inactivation of the p53 tumour suppressor
protein occurs in ~50% of human cancers. Subsequent accumulation of mutant
p53 in nuclei and cytopasm is associated with high-level presentation of
p53-derived peptides by MHC class I molecules on malignant cells. Due to
the diversity of p53 mutations in different tumours, peptides representative
of wild type, as opposed to mutant p53 sequences, were proposed to serve
as a universal TAA for a CTL-based immunotherapy of cancer. Increased susceptibility
of malignant cells to lysis by wt p53-specific CTLs has been demonstrated
to be linked rather to a high turnover rate than to a high steady-state
level of p53 expression. A major barrier to the design of broad-spectrum
p53-specific immunotherapeutics, however, has been the observation that
low-level expression of wt p53 peptides by non-transformed tissues and
cells results in self-tolerance of T lymphocytes with high avidity for
self-MHC class I/self-p53-peptide complex. Although the peripheral T cell
repertoire is mostly devoid of such high-avidity wt p53 epitope-specific
CTLs due to self-tolerance, this does not necessarily preclude the possibility
of developing wt p53-directed vaccination strategies. Low-avidity and even
residual high-avidity CTLs have been demonstrated to partially escape the
induction of wt p53-specific self-tolerance : these can be primed and amplified
in
vivo.
for breast
carcinomas
and oral carcinomas.
HER-2 gene is highly overexpressed in approximately 25% to 30% of invasive
breast carcinomasref1,
ref2,
and in comparison to normal breast epithelial cells, tumor cells may have
up to a 100-fold greater expression of HER-2ref,
with both dominant-negative and a gain-of-function properties, display
early aggressive and metastasizing parotid
tumors.
Multiple acinar and ductal hyperplasia foci overexpressing the HER-2/neu
gene product are evident at wk 5 and progress to poorly differentiated
carcinoma by wk 7. Mice die before wk 18 with invasive carcinomas and multiple
metastases that no longer express HER-2/neu. A combination of repeated
electroporations of plasmids coding for the extracellular and transmembrane
domains of the rat HER-2/neu receptor with systemic IL-12 administrations
started when the parotids that present diffuse hyperplasia protected all
female and 50% of the male mice until the close of the experiment at wk
40. This combined treatment began when multifocal in situ carcinomas
that were already present cured 33% of the females and 25% of the males.
The most prominent immunologic features associated with the antitumor protection
were the production of high titers of anti-HER-2/neu Abs and the nonappearance
of cell-mediated cytotoxic reactivity. In conclusion, anti-HER-2/neu vaccination
combined with systemic IL-12 control parotid carcinomas as far as p53 mutation
makes their growth independent of HER-2/neu expressionref.
and melanoma
in humans, and it was useful as a novel tumor marker. The preimmunization
of BALB/c mice with dendritic cells pulsed with the H-2Kd-restricted
mouse GPC3298-306 (EYILSLEEL) peptide prevented the growth of
tumor-expressing mouse GPC3. Because of similarities in the peptide binding
motifs between H