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1.
Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes 总被引:4,自引:0,他引:4
Marjorie J. Arca John C. Krauss Scott E. Strome Mark J. Cameron A. E. Chang 《Cancer immunology, immunotherapy : CII》1996,42(4):237-245
We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete
interleukin-2 (IL-2), IL-4, interferon γ (IFNγ) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters
were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells
derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFNγ and IL-4
partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be
achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the
growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting
tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy.
Neither IL-2 nor IFNγ secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found
to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not
lead to enhanced induction of immune T cells. GM-CSF secretion was found to up-regulate B7-1 expression in TDLN, consistent
with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by
cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability
of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T
cell immune reactivity to the poorly immunogenic BL6 tumor.
Received: 30 January 1996 / Accepted: 22 March 1996 相似文献
2.
Dendritic cells presenting tumor antigen 总被引:13,自引:0,他引:13
Michael R. Shurin 《Cancer immunology, immunotherapy : CII》1996,43(3):158-164
Since the first identification of dendritic cells by Steinman and Cohn in 1973, progress in understanding their biology has
included the development of novel methods of cell culture, recognition of critical aspects of migration and maturation, and
appreciation of their major role as antigen-presenting cells (APC), and how this activity is regulated by cytokines and expression
of accessory molecules. Dendritic cells are the major APC involved in the initiation of the immune response and the development
of tolerance. There is considerable evidence that they can acquire antigen in the peripheral tissues and process, transport,
and present it to T cells in secondary lymphoid tissue. A number of studies show that, in vitro or in vivo, antigen-pulsed
dendritic cells can directly sensitize T cells and stimulate the development of antigen-specific immune responses, including
both protective and therapeutic antitumor responses. In this paper, several important aspects of dendritic cell biology are
discussed and a number of studies confirming the role of these professional APC in antitumor immunity are reviewed.
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
3.
M. K. Gjersten Ingvil Sæterdal Klaus Beiske Gustav Gaudernack 《Cancer immunology, immunotherapy : CII》1997,43(5):262-268
Mesothelial cells obtained from ascites fluid of a Ras-peptide vaccinated pancreatic adenocarcinoma patient were cultured
in vitro. Fresh isolated cells expressed HLA class II molecules, which were lost upon culture, but could be up-regulated after
coculture with human recombinant interferon-γ. The antigen-presenting capacity of these mesothelial cells was tested with
allogeneic peripheral blood mononuclear cells (PBMC) in a mixed lymphocyte mesothelial cell culture and by stimulating autologous
PBMC with purified protein derivative of Mycobacterium tuberculosis. Cloned T cells from the same patient allowed us to test the ability of mesothelial cells to present a mutant Ras-derived
peptide to specific T cells in a DLA-DR-restricted manner. Mesothelial cells effectively stimulated allogeneic resting T lymphocytes
to proliferate and presented soluble protein antigen or a mutant Ras-derived peptide to specific T cells, indicating that
they display processing and presenting capabilities. Since mesothelial cells are in close anatomical relationship with intraabdominal
malignancies, they may contribute to stimulation of specific T cells by endocytosing tumour-specific antigens and presenting
them to T lymphocytes. This could be a possible mechanism in which mesothelial cells participate in maintaining local specific
immunity in patients already primed.
Received: 17 July 1996 / Accepted: 15 October 1996 相似文献
4.
T. D. Nguyen Melanie J. Smith Peter Hersey 《Cancer immunology, immunotherapy : CII》1997,43(6):345-354
Determinants of T cell responses to tumor cells remain largely unknown. In the present study we have used long-term cultures
of human melanoma cells and autologous peripheral blood lymphocytes to examine the influence of cytokines with T cell growth
activity on the phenotype and cytotoxic and proliferative response of T cells to melanoma. It was found that addition of interleukin-4
(IL-4) inhibited the response of CD8+ T cells and promoted the response of the CD4 subset. IL-2 or IL-7 was effective in increasing melanoma-specific cytotoxic
T lymphocyte (CTL) activity in cultures where CD8 T cells were predominant, whereas IL-4 followed by IL-2 was most effective
in cultures where CD4 T cells predominated. IL-10 or IL-12 inhibited proliferation and CTL activity against melanoma in long-term
cultures. The effects of IL-12 were reproduced in long-term cultures of T cells stimulated with mAb against CD3 and were shown
to depend on prior exposure of T cells to IL-12 before IL-2. As yet unidentified factors, such as co-factor expression on
melanoma, appear to be as important as exogenous cytokines in determining the nature of T cell responses to melanoma. These
results suggest that analysis of responses in long-term culture may assist in defining the role of key cytokines and other
determinants of immune responses to melanoma.
Received: 4 June 1996 / Accepted: 12 November 1996 相似文献
5.
Waltraud Böhm Reinhold Schirmbeck J. Reimann 《Cancer immunology, immunotherapy : CII》1997,44(4):230-238
We demonstrate in a murine model that targeting an anti-viral T cell response to a growing tumor facilitates priming of a
tumor-associated antigen (TAA)-specific, rejecting T cell response. Murine P815 mastocytoma cells grow aggressively in a syngeneic
host. Transfected P815/S cells (expressing the hepatitis B surface antigen, HBsAg) also grow as subcutaneous tumors, but occasional
‘spontaneous’ rejections after transient growth are observed. Growth of P815/S tumors (but not of P815 tumors) is efficiently
suppressed by a CD8+ cytotoxic T lymphocyte (CTL)-dependent immune mechanism in mice primed to HBsAg by DNA–immunization. In hosts immunized against
HBsAg by DNA vaccination, HBsAg-specific CTL are generated. This specific CTL reactivity was targeted to s.c.-growing P815
tumors by intra tumor injections of either HBsAg-encoding plasmid DNA or viable P815/S cells; this treatment led to tumor
rejection in 70–80% of the tumor-bearing animals. All rejecting animals showed a CD8+ CTL-dependent resistance to subsequent challenges by native, non-transfected P815 tumors. Targeting an established anti-viral
(‘strong’) CTL response to a growing tumor hence is an efficient strategy to facilitate priming of a rejecting CTL response
against (‘weak’) TAA in this system.
Received: 18 December 1996 / Accepted: 6 February 1997 相似文献
6.
Alexei F. Kirkin P. thor Straten J. Zeuthen 《Cancer immunology, immunotherapy : CII》1996,42(4):203-212
Human melanoma is a highly immunogenic tumor capable of inducing a specific immune response. A number of melanoma-associated
antigens have been characterized during the past several years and can be classified into two groups: differentiation antigens
– present also in normal melanocytes – and tumor-specific antigens, which, with the exception of testis, are present only
in tumor cells. In a previous publication [Kirkin A. F., Petersen T. R., Olsen A. C., Li L., thor Straten P., Zeuthen J. (1995)
Cancer Immunol Immunother 41:71] we have described the production of clones of cytotoxic T lymphocytes (CTL) against the highly
immunogenic human melanoma cell line FM3. Using these clones we have defined four previously unknown melanoma-associated antigens,
which could be subdivided into differentiation and progression antigens. In the experiments reported in this paper, we have
further compared CTL clones from different groups and shown that the sensitivity of melanoma cells to CTL that recognize differentiation
or progression antigens is differentially modulated during tumor progression as well as by the lymphokines interferon γ (IFNγ)
and interleukin-10 (IL-10). The interaction of CTL clones recognizing progression antigens was strongly increased after treatment
of melanoma cells with IFNγ, while the recognition by CTL clones specific for differentiation antigens either was unchanged
or significantly decreased. IL-10 treatment of melanoma cells induced up-regulation with respect to recognition by CTL clones
specific for differentiation antigens without affecting the recognition of melanoma cells by CTL clones specific for progression
antigens. Using cellular systems at different stages of tumor progression, we demonstrated that the progressed state of melanoma
cells is associated with increased sensitivity to recognition by CTL clones detecting progression antigens, and with decreased
sensitivity to CTL clones recognizing differentiation antigens. Mimicking tumor progression, treatment with IFN-γ induced
apparent down-regulation of differentiation antigens. A hypothesis is suggested in which IFN-γ plays different roles in the
immune response against poorly immunogenic and highly immunogenic melanoma cells, increasing the progression of poorly immunogenic
tumor cells or promoting a strong immune response and regression of highly immunogenic melanoma cells.
Received: 23 November 1995 / Accepted: 7 March 1996 相似文献
7.
Chungwen Wei Eugene Storozynsky A. J. McAdam Kun-Yun Yeh Brian R. Tilton Richard A. Willis Richard K. Barth R. John Looney Edith M. Lord J. G. Frelinger 《Cancer immunology, immunotherapy : CII》1996,42(6):362-368
Human prostate-specific antigen (PSA) has a highly restricted tissue distribution. Its expression is essentially limited
to the epithelial cells of the prostate gland. Moreover, it continues to be synthesized by prostate carcinoma cells. This
makes PSA an attractive candidate for use as a target antigen in the immunotherapy of prostate cancer. As a first step in
characterizing the specific immune response to PSA and its potential use as a tumor-rejection antigen, we have incorporated
PSA into a well-established mouse tumor model. Line 1, a mouse lung carcinoma, and P815, a mouse mastocytoma, have been transfected
with the cDNA for human PSA. Immunization with a PSA-expressing tumor cell line demonstrated a memory response to PSA which
protected against subsequent challenge with PSA-expressing, but not wild-type, tumors. Tumor-infiltrating lymphocytes could
be isolated from PSA-expressing tumors grown in naive hosts and were specifically cytotoxic against a syngeneic cell line
that expressed PSA. Immunization with tumor cells resulted in the generation of primary and memory cytotoxic T lymphocytes
(CTL) specific for PSA. The isolation of PSA-specific CTL clones from immunized animals further demonstrated that PSA can
serve as a target antigen for antitumor CTL. The immunogenicity studies carried out in this mouse tumor model provide a rationale
for the design of methods to elicit PSA-specific cell-mediated immunity in humans.
Received: 4 April 1996 / Accepted: 31 May 1996 相似文献
8.
Effects of interleukin-12 on in vitro culture with interleukin-2 of regional lymph node lymphocytes from lung cancer patients 总被引:2,自引:0,他引:2
T. Hanagiri Mitsuhiro Takenoyama Takashi Yoshimatsu Chikashi Hirashima Ichiro Yoshino Kozo Nakanishi Akira Nagashima Kikuo Nomoto Kosei Yasumoto 《Cancer immunology, immunotherapy : CII》1996,43(2):87-93
In the present study, we carried out a functional analysis of regional lymph node lymphocytes (RLNL) from patients with lung
cancer after in vitro activation by interleukin-2 (IL-2) and interleukin-12 (IL-12). IL-12 (100 U/ml) enhanced both the proliferation
and cytotoxic activity of RLNL in a culture with low doses of IL-2 (5 – 10 JRU/ml). After comparing an RLNL culture with a
low dose of IL-2 alone, a higher proportion of CD8+ cells and CD56+ cells and a lower proportion of CD4+ cells were found in the culture with both IL-12 and a low dose of IL-2. Such a combination of the cytokines effectively activated
RLNL in terms of the expression of IL-2 receptors. In the culture condition of IL-12 and a low dose of IL-2, a synergistic
effect was observed in the production of such cytokines as interferon γ, tumor necrosis factor α (TNFα), and TNFβ, as well
as in tumor cytotoxicity. However, the addition of IL-12 inhibited the cytotoxicity of RLNL in the culture with a high dose
of IL-2 (100 JRU/ml). This inhibition is considered to be partially due to the endogenous production of TNFα by lymphocytes,
because the neutralization of TNFα bioactivity partially restored the cytotoxic activities of RLNL. Furthermore, in the presence
of hydrocortisone, IL-12 synergistically enhanced the cytotoxic activity of RLNL cultured with a high dose of IL-2. These
results provide useful information about the improvement of adoptive immunotherapy against cancer using RLNL.
Received: 2 February 1996 / Accepted: 30 July 1996 相似文献
9.
Gene-modified tumor cells as cellular vaccine 总被引:5,自引:0,他引:5
Sivasubramanian Baskar 《Cancer immunology, immunotherapy : CII》1996,43(3):165-173
The identification and characterization of many tumor antigens and the parallel explosion of knowledge of the cellular and
molecular mechanisms of antigen recognition by the immune system have given renewed hopes that immunogenetherapy could be
a promising modality to treat certain tumors. Many different novel strategies have been developed to derive genetically modified
tumor cells and use them as cellular vaccines to induce useful antitumor immunity in a variety of animal tumor models. This
review discusses induction of tumor immunity by injecting tumor cells that are genetically engineered to secrete various cytokines
and to express major histocompatibility complex molecules and/or costimulatory molecules. While there has been a great success
in inducing excellent antitumor immunity in a variety of tumor models, there are some difficulties and limitations in the
application of these gene-modified tumor cells for the treatment of preexisting tumors. A number of improvements and modifications
are already underway to overcome some of these problems.
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
10.
Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies 总被引:4,自引:0,他引:4
A new type of cancer vaccine for therapeutic application in cancer patients is described. It consists of three components.
(1) autologous tumor cells, (2) Newcastle Disease Virus (NDV), to be used for infection and (3) bispecific antibodies (bsAb)
which attach to the viral hemagglutinin neuraminidase (HN) molecule on the infected tumor cells. A standardized procedure
has been developed for generating virus infected human autologous tumor cell vaccines (ATV-NDV) which includes cell dissociation,
removal of leukocytes and cell debris, gamma-irradiation and cryopreservation. Infection with the non-virulent strain NDV
Ulster is performed within 30 min of co-incubation. While virus infection already increased immunogenicity of the tumor vaccine,
further augmentation of T cell stimulatory capacity is achieved by attachment of specially designed bi-specific antibodies
(bs HN × CD28 or bs HN × CD3).
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
11.
Keith R. Jerome Allan D. Kirk Gabriele Pecher Wayne W. Ferguson O. J. Finn 《Cancer immunology, immunotherapy : CII》1997,43(6):355-360
The human mucin, MUC-1, is a transmembrane glycoprotein that is produced by both normal an malignant epithelium. The MUC-1
produced by malignant epithelium is underglycosylated, which leads to the expression by tumors of novel T and B cell epitopes
on the mucin polypeptide core. Similar underglycosylation occurs in the lactating breast. In this report, we describe a long-term
survivor of breast cancer whose tumor strongly expressed the T- and B-cell-stimulatory epitopes. Five years after presenting
with the tumor, the patient had her first pregnancy, at which time she developed fulminant lymphocytic mastitis. We demonstrate
that the lactating breast produced mucin expressing the same “tumor-specific” epitopes as the original cancer. The patient
had circulating anti-mucin antibodies of both the IgM and IgG isotypes (these are not found in normal controls), and mucin-specific
cytotoxic T lymphocytes in the peripheral blood. Limiting – dilution analysis for mucin – specific cytotoxic T lymphocytes
in three different experiments yielded frequencies of 1 in 3086, 1 in 673, and 1 in 583, compared to approximately 1 in 106 in normal controls. The patient remains clinically free of carcinoma after 5 additional years of follow-up. We propose that
the original tumor primed the patient’s immune response against the mucin epitopes, and that the re-expression of these epitopes
on the lactating breast evoked a secondary immune response. It is tempting to speculate that the vigor of her anti-mucin immunity
may have helped protect this patient against recurrent tumor.
Received: 12 February 1996 / Accepted: 5 November 1996 相似文献
12.
C. Renner Gerhard Held Sascha Ohnesorge Stefan Bauer Klaus Gerlach Jan-Peter Pfitzenmeier Michael Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,44(2):70-76
Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes,
induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis
contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation,
FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin’s cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for
perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity
in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative
state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance
of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells
in bi-mAb-mediated apoptosis and necrosis of tumor cells.
Received: 5 December 1996 / Accepted: 16 January 1997 相似文献
13.
M. R. L. Krul Edwin J. Tijhaar John A. F. W. Kleijne Anton M. Van Loon Mirjam G. Nievers Hans Schipper Liesbeth Geerse M. Van der Kolk Peter A. Steerenberg Frits R. Mooi Willem Den Otter 《Cancer immunology, immunotherapy : CII》1996,43(1):44-48
Human papillomaviruses (HPV) are present in approximately 95% of all cervical carcinomas and the HPV E6 and E7 genes are
continuously expressed in these lesions. There is also circumstantial evidence that often natural immunity against HPV is
generated and that this is of influence on HPV-induced lesions. Stimulation of the immune system by proper presentation of
relevant HPV antigens might, therefore, lead to a prophylactic or therapeutic immunological intervention for HPV-induced lesions.
For this purpose we have expressed the E6 and E7 protein of HPV 16 in an attenuated strain of Salmonella typhimurium (SL3261, aroA mutation), which has been used extensively as a live vector. Live recombinant Salmonella vaccines have the ability to elicit humoral, secretory and cell-mediated immune responses, including cytotoxic T cells, against
the heterologous antigens they express. This report describes the construction of recombinant Salmonella strains expressing the HPV 16 E6 and E7 proteins, and the induction of an HPV-16-specific immune response in mice after immunization
with these live vectors.
Received: 25 June 1996 / Accepted: 6 August 1996 相似文献
14.
Govindaswami Ragupathi 《Cancer immunology, immunotherapy : CII》1996,43(3):152-157
Carbohydrate antigens such as GM2, GD2 and GD3 (gangliosides), Lewisy and globo-H (neutral glycolipids and glycoproteins), and Tn, TF and sTn (glycoproteins) are overexpressed in a variety of
cancers. Antibodies against several of these carbohydrate antigens have been detected in sera from patients treated with cancer
vaccines, and have been associated with a more favorable prognosis. Clinical responses have been reported after treatment
with monoclonal antibodies against some of these antigens. Hence cell-surface carbohydrate antigens have been identified as
suitable targets for immune attack by both active and passive immunotherapies. Different approaches have been adopted to induce
immune responses against these carbohydrate antigens. These includes vaccination with whole or lysed tumor cells, purified
or synthetic carbohydrates, immunogenic carbohydrate derivatives, or carbohydrates conjugated with immunogenic carriers and
administered with immunological adjuvants. In the case of gangliosides, immunization with either whole tumor cells or cell
lysates has only occasionally induced responses against carbohydrate antigens, and the antibodies were generally IgM antibodies
of low titer. Compared with other methods of vaccination, conjugate vaccines have consistently induced the highest titer of
IgM and IgG antibodies against gangliosides and other carbohydrate antigens. Preclinical and clinical studies with conjugate
carbohydrate vaccines have induced IgM and IgG antibody responses capable of inducing complement-mediated cytotoxicity of
tumor cells in vitro and associated with prolonged disease-free and overall survival in patients.
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
15.
Lola Weiss Samir Nusair Shoshana Reich Haim Sidi S. Slavin 《Cancer immunology, immunotherapy : CII》1996,43(2):103-108
The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone
marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/lymphoma. Allogeneic cell therapy,
induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic
activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing
mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes
with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained
from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic
lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved
after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can
be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by
allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal
residual disease provided that graft versus host disease can be prevented or adequately controlled.
Received: 14 May 1996 / Accepted: 6 August 1996 相似文献
16.
N. Jacobs Roland Greimers Alessandra Mazzoni Mohamed Trebak Nicole Schaaf-Lafontaine Jacques Boniver Michel P. Moutschen 《Cancer immunology, immunotherapy : CII》1996,42(6):369-375
In this study we have specifically investigated the participation of T cells in the cytotoxic activity of peripheral blood
lymphocytes (PBL) activated by interleukin-2 (IL-2, 50 U/ml) alone or in combination with an anti-CD3 mAb (BMA030, 10 ng/ml,
IgG2a). Purified CD3+ T cells, incubated in the presence of the anti-CD3 mAb for 4 days, mediated a cytotoxic activity against HL60 and U937 tumor
cell lines. Several findings suggested the involvement of a redirected-cytotoxicity phenomenon, since the lytic process was
restricted to target cell lines bearing the high-affinity Fcγ receptor (FcγRI) and T lymphocytes stimulated by IL-2 alone
did not lyse these cell lines. Furthermore, anti-CD3 mAb F(ab′)2, anti-CD3 IgG1 (UCHT1), phytohemagglutinin or staphylococcal enterotoxin A did not induce a similar cytotoxic activity in
T lymphocytes. The cytotoxic process occurred in the presence of a very low level of anti-CD3 antibodies (in the nanomolar
range). The cytotoxic activity of T cells stimulated by IL-2 or by IL-2 + BMA030, against OVCAR-3 cells (MOv18+ ovarian tumor cell line), was also compared in the presence of a bispecific antibody (OC/TR, anti-CD3 × MOv18). The stimulation
by IL-2 + BMA030 induced approximately a twofold higher cytotoxic activity than IL-2-activated T cells. This could be related
to the state of activation of effector cells stimulated by IL-2 + BMA030, since the phenotypic analysis showed an increased
proportion of T cells expressing several activation/differentiation markers (CD25, HLA-DR, CD45R0, adhesion molecules). These
findings could be applied to the design of therapeutic protocols using anti-CD3 ×antitumoral bispecific antibodies.
Received: 6 December 1995 / Accepted: 4 June 1996 相似文献
17.
Sonja Fischer Armin Scheffler D. Kabelitz 《Cancer immunology, immunotherapy : CII》1997,44(3):150-156
Mistletoe (Viscum album) extracts are widely used in adjuvant cancer therapy. We have investigated the in vitro responsiveness of T cells from mistletoe-treated
cancer patients and untreated healthy donors to various preparations of mistletoe extracts. Proliferation of peripheral blood
mononuclear cells from treated but not from untreated patients was observed in response to therapeutically used mistletoe
extracts prepared from apple (mali) or pine (pini) host trees. The strongest proliferation was induced by a vesicle preparation of mali extract. Activation was strongly inhibited by interleukin-10. Using a newly developed flow-cytometry assay, we determined
that cell growth was restricted to CD4 T cells. Analysis with a panel of monoclonal antibodies against the variable region
of the T cell receptor β chain (Vβ) revealed an oligoclonal pattern of CD4 T cell activation. These results indicate that
therapeutic administration of mistletoe extracts sensitizes a restricted set of CD4 T lymphocytes in mistletoe-treated patients.
Received: 25 May 1996 / Accepted: 9 January 1997 相似文献
18.
K. A. O. Ellem Michael G. E. O’Rourke Gregory R. Johnson Gordon Parry Ihor S. Misko Christopher W. Schmidt Peter G. Parsons Scott R. Burrows Simone Cross Andrew Fell Chung-Leung Li John R. Bell Philip J. Dubois Denis J. Moss Michael F. Good Anne Kelso Lawrence K. Cohen Glenn Dranoff Richard C. Mulligan 《Cancer immunology, immunotherapy : CII》1997,44(1):10-20
The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells
as a therapeutic vaccine in a patient with rapidly progressive, widely disseminated malignant melanoma resulted in the generation
of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction
to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing
magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH
sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the
histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma
cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture
without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein
was observed, as was a systemic eosinophilia. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation
of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system
metastases; however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune
response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted
in rapid deterioration and death of the patient.
Received: 20 September 1996 / Accepted: 5 December 1996 相似文献
19.
Takami Sato 《Cancer immunology, immunotherapy : CII》1996,43(3):174-179
We have developed a novel approach to cancer immunotherapy – an autologous whole-cell vaccine modified with the hapten dinitrophenyl
(DNP). This approach elicits significant inflammatory responses in metastatic sites and some objective tumor responses. Post-surgical
adjuvant immunotherapy with DNP-modified melanoma vaccine in a setting of micrometastatic disease produces significant survival
prolongation in stage III melanoma patients. Histologically, the inflammatory responses of the tumor consist of infiltration
by lymphocytes, the majority of which are CD8+, HLA-DR+ T cells. T cells from these lesions tend to have mRNA for interferon γ. T cell receptor analysis suggests that the tumor-infiltrating
T cells are clonally expanded. DNP-modified vaccine also induces T cells in the peripheral blood, which respond to DNP-modified
autologous cells in a hapten-specific, MHC-restricted manner. Moreover, a T cell line generated from these lymphocytes responded
to only a single HPLC fraction of MHC-associated, DNP-modified tumor peptides. Since inflammatory responses in metastases
were not consistently associated with dramatic tumor regression, we considered the possibility of immunosuppression at the
tumor site. We found that mRNA for the anti-inflammatory cytokine, interleukin-10 (IL-10) is expressed in most metastatic
melanoma tissues and subsequently demonstrated that IL-10 protein is produced by melanoma cells. Thus the efficacy of DNP
vaccine could be further enhanced by inhibition of IL-10 production or binding. Finally, we expect these results obtained
with melanoma to be applicable to other human cancers.
Received: 6 August 1996 / Accepted: 20 September 1996 相似文献
20.
M. J. Micallef Kenshi Yoshida Sachiko Kawai Toshiharu Hanaya Keizo Kohno Shigeyuki Arai Tadao Tanimoto Kakuji Torigoe Mitsukiyo Fujii Masao Ikeda Masashi Kurimoto 《Cancer immunology, immunotherapy : CII》1997,43(6):361-367
Interferon-γ-inducing factor/interleukin-18 is a novel cytokine that reportedly augments natural killer (NK) activity in
human and mouse peripheral blood mononuclear cell cultures in vitro and has recently been designated IL-18. In this study,
IL-18 exhibited significant antitumor effects in BALB/c mice challenged intraperitoneally (i.p.) with syngeneic Meth A sarcoma
when administered i.p. on days 1, 2 and 3 after challenge. Intravenous (i.v.) administration also induced antitumor effects
in the tumor-bearing mice; however, subcutaneous (s.c.) administration did not. When mice were twice pretreated with 1 μg
IL-18 3 days and 6 h before tumor challenge, all mice survived whereas control mice died within 3 weeks of challenge. Inhibitory
effects on Meth A cell growth in vitro were not observed with either IL-18 or interferon γ. The effects of IL-18 pretreatment
were abrogated by abolition of NK activity after mice had been injected with anti-asialo GM1 antibody 48 h before and, 24
h and 72 h after tumor challenge. Mice pretreated with IL-18 and surviving tumor challenge resisted rechallenge with Meth
A cells but could not reject Ehrlich ascites carcinoma, and spleen cells from the resistant mice, but not control mice, exhibited
cytotoxic activity against Meth A cells in vitro after restimulation with mitomycin C-treated Meth A cells for 5 days. The
effector cells in the spleen cell preparations from resistant mice appear to be CD4+ cells because cytolytic activity was significantly inhibited after depletion of this subset by monoclonal antibodies and
complement. In conclusion, IL-18 exhibits in vivo immunologically (primarily NK) mediated antitumor effects in mice challenged
with syngeneic Meth A sarcoma and induces immunological memory and the generation of cytotoxic CD4+ cells.
Received: 17 September 1996 / Accepted: 8 November 1996 相似文献