共查询到20条相似文献,搜索用时 406 毫秒
1.
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
2.
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
3.
Cellular immune responses to autologous chronic myelogenous leukaemia cells in vitro 总被引:2,自引:0,他引:2
Graham Pawelec Arnika Rehbein Elke Schlotz Paul da Silva 《Cancer immunology, immunotherapy : CII》1996,42(3):193-199
Using a modification of the autologous mixed lymphocyte/tumour cell culture (MLTC), it is demonstrated here that lymphocytes
from chronic-phase myelogenous leukaemia (CML) patients (n = 58), but not from their HLA-identical siblings, proliferated upon coculture with autologous tumour cells. However, in most
cases, the level of proliferation measured was low (stimulation index <3, n = 37). This was most likely related to the amount of interleukin-10 (IL-10) released into the culture medium by the CML cells,
because addition of neutralizing anti-IL-10 serum to MLTC markedly enhanced proliferative responses. In addition, supplementation
of media with IL-1α further enhanced proliferative responses and a combination of anti-IL-10 serum and IL-1α was more effective
than either agent alone. Only HLA-DR-matched CML cells, but not HLA-DR-mismatched CML cells or matched or mismatched PBMC
restimulated proliferation of IL-2-dependent T cell lines derived from MLTC supplemented with IL-1α and anti-IL-10 serum.
The responding cells under these conditions were predominantly CD4+ and secreted IL-2, and interferon γ; some secreted IL-4, but none secreted IL-10. These data therefore suggest the existence
of an HLA-DR-restricted DTH/Th1-type of tumour-specific immunity in CML patients, which may be down-regulated in vitro by
excessive secretion of IL-10 together with depressed secretion of IL-1.
Received: 9 November 1995 / Accepted: 8 February 1996 相似文献
4.
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
5.
Mahipal A Terai M Berd D Chervoneva I Patel K Mastrangelo MJ Sato T 《Cancer immunology, immunotherapy : CII》2011,60(7):1039-1045
Objectives
Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP). 相似文献6.
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
7.
M. Margaret Prechel Yvonne Lozano Mark A. Wright J. Ihm M. R. I. Young 《Cancer immunology, immunotherapy : CII》1996,42(4):213-220
Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor
cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal
immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow
for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D3 eliminated natural suppressor activity. In mice that were first treated with vitamin D3 and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus
IL-2. In addition, spleen and lymph node cells from vitamin-D3/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon γ (IFNγ), although
IL-2 production was not stimulated. A prominent effect of the combined vitamin-D3/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional
lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity
was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show
that, after treatment of tumor bearers with vitamin D3 to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFNγ production
and cytolysis by regional lymph node cells of autologous tumor.
Received: 15 December 1995 / Accepted: 22 March 1996 相似文献
8.
Rutger L. van Bezooijen H. Goey Gerrit Stoter J. Hermans G. J. Fleuren 《Cancer immunology, immunotherapy : CII》1997,43(5):293-298
Interleukin-2 (IL-2)-based immunotherapy can induce antitumor responses in about 25% of patients with metastatic renal cell
carcinoma (RCC). The limited effect and the severe side-effects of IL-2 have led us to perform a prognostic factor analysis.
Twenty-four patients with metastatic RCC were treated with IL-2. Flow cytometry and immunohistology were used to determine
DNA ploidy, HLA-II expression on tumor cells, and the presence of macrophages in the primary tumor. These variables were examined
in relation to survival. The 4-year overall survival rate was 38%. Forty-six percent of the primary tumors were aneuploid.
All tumors, except one, showed HLA-II expression and macrophage presence. A statistically significant correlation (r = 0.66, P = 0.002) was found between HLA-II expression and macrophage presence. Patients with high HLA-II expression had a lower 4-year
survival (22% compared to 50%), as had patients with high macrophage presence (20% compared to 42%). Of note, patients characterized
by both high HLA-II and high macrophage expression had the worst survival (13% compared to 50%). We concluded that DNA ploidy
was not predictive for survival, whereas HLA-II expression and macrophage presence may represent valuable prognostic factors
related to survival. The present data suggest that more of the patients with no or moderate HLA-II expression and/or no or
moderate macrophage presence in the primary tumor could survive with persistance of their malignant disease after having received
IL-2 immunotherapy, as compared to patients with both high HLA-II and high macrophage expression.
Received: 2 April 1996 / Accepted: 15 October 1996 相似文献
9.
J. M. Jessup C. M. McBride F. C. Ames L. Guarda D. M. Ota M. M. Romsdahl R. G. Martin 《Cancer immunology, immunotherapy : CII》1986,21(3):233-239
Summary The ability of active specific immunotherapy to enhance immune responses to autologous tumor-associated antigens (TAA) and to prolong the disease-free interval was evaluated in patients with Dukes B2 and C colorectal carcinoma who had undergone potentially curative resections. Patients were sensitized in the early postoperative period with irradiated autologous adenocarcinoma cells mixed with bacillus Calmette-Guérin (BCG) to yield either a low-dose vaccine (3×106 tumor cells) or a high-dose vaccine (1×107 tumor cells). Six of seven patients who received the low-dose vaccine developed delayed-type hypersensitivity (DTH) responses to autologous tumor cells upon completion of the vaccination, whereas all four patients receiving high-dose vaccine displayed a positive DTH response. However, DTH responses to autologous TAA waned within 3 months in all patients receiving the low-dose vaccine; DTH responses persisted for 3 months in three of the four high-dose vaccine patients. In vitro lymphoproliferative responses to TAA correlated with DTH responses to autologous tumor cells. Active specific immunotherapy appeared to induce specific immune responses either in vitro or in vivo to autologous TAA because it did not induce responses to autologous mucosa cells. There were no complications caused by BCG or tumor cells. This series demonstrates that active specific immunotherapy is a nontoxic treatment that augments immunity to autologous TAA.This project was supported by grants from Cutter Laboratories, Inc., the Annual Campaign of the University of Texas System Cancer Center, and the National Cancer Cytology Center 相似文献
10.
Pulaski BA Clements VK Pipeling MR Ostrand-Rosenberg S 《Cancer immunology, immunotherapy : CII》2000,49(1):34-45
Because they are difficult to treat, animal models of widespread, established metastatic cancer are rarely used to test novel
immunotherapies. Two such mouse models are used in this report to demonstrate the therapeutic efficacy and to probe the mechanisms
of a novel combination immunotherapy consisting of the cytokine interleukin-12 (IL-12) combined with a previously described
vaccine based on MHC class II, CD80-expressing cells. BALB/c mice with 3-week established primary 4T1 mammary carcinomas up
to 6 mm in diameter and with extensive, spontaneous lung metastases show a significant reduction in lung metastases following
a 3-week course of immunotherapy consisting of weekly injections of the cell-based vaccine plus injections of IL-12 three
times per week. C57BL/6 mice with 7-day established intravenous B16 melF10 lung metastases show a similar response following
immunotherapy with IL-12 plus a vaccine based on B16 MHC class II, CD80-expressing cells. In both systems the combination
therapy of cells plus IL-12 is more effective than IL-12 or the cellular vaccine alone, although, in the 4T1 system, optimal
activity does not require MHC class II and CD80 expression in the vaccine cells. The cell-based vaccines were originally designed
to activate tumor-specific CD4+ T lymphocytes specifically and thereby provide helper activity to tumor-cytotoxic CD8+ T cells, and IL-12 was added to the therapy to facilitate T helper type 1 lymphocyte (Th1) differentiation. In vivo depletion
experiments for CD4+ and CD8+ T cells and natural killer (NK) cells and tumor challenge experiments in beige/nude/XID immunodeficient mice demonstrate
that the therapeutic effect is not exclusively dependent on a single cell population, suggesting that T and NK cells are acting
together to optimize the response. IL-12 may also be enhancing the immunotherapy via induction of the chemokine Mig (monokine
induced by interferon γ), because reverse PCR experiments demonstrate that Mig is present in the lungs of mice receiving therapy
and is most likely synthesized by the tumor cells. These results demonstrate that the combination therapy of systemic IL-12
and a cell-based vaccine is an effective agent for the treatment of advanced, disseminated metastatic cancers in experimental
mouse models and that multiple effector cell populations and anti-angiostatic factors are likely to mediate the effect.
Received: 15 October 1999 / Accepted: 24 November 1999 相似文献
11.
The generation of anti-tumoral cells using dentritic cells from the peripheral bloood of patients with malignant brain tumors 总被引:3,自引:0,他引:3
Yoshida S Morii K Watanabe M Saito T Yamamoto K Tanaka R 《Cancer immunology, immunotherapy : CII》2001,50(6):321-327
Dendritic cells (DCs) can be the principal initiators of antigen-specific immune responses. We analyzed the in vitro-responses
against brain tumor cells using DCs from the peripheral blood of patients with brain tumors. Peripheral blood mononuclear
cells (PBMC) were obtained from 19 patients with malignant brain tumors: 12 metastatic brain tumors of lung adenocarcinoma,
7 high-grade astrocytomas. PBMC were cultured with 100 ng/ml of GM-CSF and 10 ng/ml of IL-4 for 5–7 days in order to produce
mature DCs. The autologous tumor lysate (5 mg/ml, containing 1 × 106 cells) was then added to the cultured DCs. Using the DCs generated by these treatments, we assessed the changes that occurred
in their immune responses against brain tumor via 51Cr-release and lymphocyte proliferation assays. We found that the matured DCs displayed the typical surface phenotype of CD3+, CD45+, CD80+ and CD86+. After the pulsation treatment with tumor lysate, DCs were found to have strong cytotoxic T lymphocyte activity, showing
42.5 ± 12.7% killing of autologous tumor cells. We also found an enhancement of allogeneic T cell proliferation after pulsing
the DC with tumor lysate. These data support the efficacy of DC-based immunotherapy for patients with malignant brain tumors.
Received: 2 October 2000 / Accepted: 26 April 2001 相似文献
12.
Jacobs JF Aarntzen EH Sibelt LA Blokx WA Boullart AC Gerritsen MJ Hoogerbrugge PM Figdor CG Adema GJ Punt CJ de Vries IJ 《Cancer immunology, immunotherapy : CII》2009,58(1):145-151
The occurrence of vitiligo in patients with melanoma is especially reported for patients undergoing immunotherapy. While vitiligo
in these patients is thought to be related to an immune response directed against melanoma cells, solid evidence is lacking.
Here we report local cytotoxic T cell reactivity in three melanoma patients who developed vitiligo, after experimental immunotherapy
using dendritic cell vaccinations. Tetramer analysis showed that vaccine-induced T cells recognizing gp100 and tyrosinase
are present at the vitiligo lesions. These T cells secrete IFN-γ and IL-2 upon peptide specific stimulation as well as upon
recognition of the autologous tumor. We show that functional CD8+ T cells specific for melanoma differentiation antigens used in a melanoma immunotherapy trial, do not only invade the tumor,
but also the vitiligo lesions. This directly links vitiligo to the immuno-therapeutic intervention and supports the hypothesis
that vitiligo is a marker of immunity against melanoma cells.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
13.
Activation markers on T cells infiltrating melanoma metastases after therapy with dinitrophenyl-conjugated vaccine 总被引:1,自引:0,他引:1
David Berd Henry C. Maguire Jr. Michael J. Mastrangelo George Murphy 《Cancer immunology, immunotherapy : CII》1994,39(3):141-147
Treatment of metastatic melanoma patients with an autologous vaccine modified by the hapten, dinitrophenyl (DNP), produces a striking immunological effect: the induction of clinically evident inflammatory responses in metastatic tumors. Histological examination shows these tumors to be infiltrated with T lymphocytes. We studied the expression of activation markers on those cells and compared them with matched peripheral blood lymphocytes (PBL) and with lymphocytes extracted from metastases before treatment with DNP-conjugated vaccine. The median fraction of cells that were T cells in post-vaccine tumors was 41%, as compared with 9% in pre-treatment tumors, and those T cells were predominantly CD8+ (mean CD8/CD4 ratio=5.0). A high proportion of both pre- and posttreatment infiltrating T cells expressed HLA-DR (mean±SE=48%±4%), CD69 (56%±7%), and ganglioside GD3 (68%±5%). This distinguished them from matched PBL in which expression of those markers was significantly lower (HLA-DR=10%±2%; CD69=2%±0.4%; GD3=49%±4%). These changes were not accompanied by increased cell-surface expression of interleukin-2 (IL-2) receptors, either CD25 or p75, which were expressed by 1%–2% and 12% of tumor-infiltrating lymphocytes (TIL), respectively. The pattern of activation marker expression that we identified appears to be characteristic of tissue T cells with the memory phenotype. The low expression of IL-2 receptors could indicate functional impairment of TIL in situ, perhaps because of inhibitory molecules produced by melanoma cells.This work was supported by NIH grants CA 39248, CA 40358, and AR 39674 from the National Institutes of Health and by funds from the Nat Pincus Trust 相似文献
14.
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
15.
H. Belfrage Mikael Dohlsten Gunnar Hedlund Terje Kalland 《Cancer immunology, immunotherapy : CII》1997,44(2):77-82
Injection of the superantigen staphylococcal enterotoxin A (SEA) activates both CD4+ and CD8+ T cells expressing certain families of T cell receptor (TCR) variable-region β (Vβ) chain. T cells respond with profound cytokine production and induction of cytotoxicity. Repeated injections, however, cause
deletion and anergy of both CD4+ and CD8+ T cells, resulting in reduced frequency of SEA-responsive cells TCR-Vβ11+ as well as reduced cytokine levels in serum upon challenge with SEA. Exogenous interleukin-2 (IL-2) in vivo rescued SEA-responsive
CD4+ and CD8+ cells from SEA-induced deletion and/or increase expansion of SEA-primed cells as well as preventing down-regulation of endogenous
IL-2 production in vivo. Combined treatment with SEA and IL-2 also superinduced production of important cytokines for the
cytotoxic function of T cells, tumour necrosis factor α, interferon γ and IL-6, on a cellular level. These studies show that
continuous stimulation with IL-2 in vivo could be useful for superantigen-based immunotherapy by induction of excessive T
cell activation and by prevention of the development of T cell deletion and anergy.
Received: 29 August 1996 / Accepted: 16 January 1997 相似文献
16.
Toshihiro Fujimoto Michael A. O’Donnell Akos Szilvasi H. Yang R. B. Duda 《Cancer immunology, immunotherapy : CII》1996,42(5):280-284
Although immunotherapy with bacillus Calmette Guérin (BCG) is an established adjuvant treatment for malignant melanoma, the
mechanism of its role in this process is unclear. To investigate the possible contribution of tumor-inhibitory cytokines induced
by BCG, B16F10 melanoma cell growth in culture was assessed in response to purified cytokines and conditioned media of BCG-stimulated
splenocytes. Interferon-γ (IFNγ) was the most potent single agent (IC50≈50 pg/ml). Tumor necrosis factor α was substantially weaker (IC50>10 ng/ml) but provided synergy with IFNγ. None of the other
cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12, or granulocyte/macrophage-colony-stimulating factor had
direct antitumor activity against B16F10 melanoma cells. However, when IL-2 and/or GM-CSF were combined with BCG either by
exogenous addition or through endogenous production by novel cytokine-secreting recombinant BCG (rBCG), a substantial increase
in INFγ production by splenocytes was observed. Antitumor activity of this conditioned medium directly correlated with IFNγ
concentration and was completely blocked by neutralizing antibody to IFNγ. These results suggest that BCG may exert part of
its antitumor action on melanoma through the induction of IFNγ, which can be greatly enhanced through the concomitant addition
of IL-2 and/or GM-CSF. Furthermore, by utilizing rBCG that secrete these cytokines, it may be possible to potentiate the antitumor
effect of BCG directly at the site of BCG inoculation.
Received: 29 January 1996 / Accepted: 9 April 1996 相似文献
17.
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
18.
Synergy between interleukin-2 and prothymosin α for the increased generation of cytotoxic T lymphocytes against autologous human carcinomas 总被引:3,自引:0,他引:3
Voutsas IF Baxevanis CN Gritzapis AD Missitzis I Stathopoulos GP Archodakis G Banis C Voelter W Papamichail M 《Cancer immunology, immunotherapy : CII》2000,49(8):449-458
Peripheral blood mononuclear cells (PBMC) from cancer patients were cultured in vitro with irradiated autologous tumor cells
isolated from malignant effusions (mixed lymphocyte tumor cultures, MLTC) and low-dose (50 IU/ml) recombinant interleukin-2
(IL-2). The combination of IL-2 and prothymosin α (ProTα) resulted in a greater PBMC-induced response to the autologous tumor
than that brought about by IL-2 alone. In particular, ProTα specifically enhanced the CD4+ T-cell-mediated proliferation against the autologous tumor. CD4+ T cells seemed to recognize tumor antigens presented by HLA-DR molecules expressed on the autologous monocytes, since preincubation
of the latter with an anti-HLA-DR monoclonal antibody (mAb) abrogated the response. In addition, MLTC set up with IL-2 and
ProTα also generated more MHC-class-I-restricted cytotoxic T lymphocytes (CTL) against the autologous tumor than did MLTC
set up with IL-2 alone. The MLTC-induced CTL contained high levels of cytoplasmic perforin and their development was strictly
dependent on the presence of both autologous CD4+ T cells and monocytes. In the absence of either population there was a strong impairment of both proliferative and cytotoxic
responses which was not restored by the presence of ProTα. In contrast, when both cell populations were present, ProTα exerted
optimal enhancement of CD4+ T cell proliferation, which was associated with potentiated CTL responses. Our data emphasize the role of ProTα for the enhancement
of IL-2-induced CTL responses against autologous tumor cells. Such responses require collaborative interactions between CD4+, CD8+ T cells and monocytes as antigen-presenting cells. Our data are relevant for adoptive immunotherapeutic settings utilizing
IL-2 and ProTα-induced autologous-tumor-specific CTL.
Received: 2 March 2000 / Accepted: 1 June 2000 相似文献
19.
Powell DJ Dudley ME Hogan KA Wunderlich JR Rosenberg SA 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(9):6527-6539
Cancer vaccines can induce the in vivo generation of tumor Ag-specific T cells in patients with metastatic melanoma yet seldom elicit objective clinical responses. Alternatively, adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL) can mediate tumor regression in 50% of lymphodepleted patients, but are logistically and technically difficult to generate. In this study, we evaluated the capability of vaccine-induced PBMC to mediate tumor regression after transfer to patients receiving the same chemotherapy-induced lymphodepletion used for TIL transfer therapy. Autologous PBMC from nine gp100-vaccinated patients with metastatic melanoma were stimulated ex vivo with the gp100:209-217(210M) peptide and transferred in combination with high-dose IL-2 and cancer vaccine. Transferred PBMC contained highly avid, gp100:209-217 peptide-reactive CD8(+) T cells. One week after transfer, lymphocyte counts peaked (median of 14.3 x 10(3) cells//microl; range of 0.9-59.7 x 10(3) cells/microl), with 56% of patients experiencing a lymphocytosis. gp100:209-217 peptide-specific CD8(+) T cells persisted at high levels in the blood of all patients and demonstrated significant tumor-specific IFN-gamma secretion in vitro. Melanocyte-directed autoimmunity was noted in two patients; however, no patient experienced an objective clinical response. These studies demonstrate the feasibility and safety of using vaccine-induced PBMC for cell transfer, but suggests that they are not as effective as TIL in adoptive immunotherapy even when transferred into lymphodepleted hosts. 相似文献
20.
Stanley P. L. Leong Yuan-Ming Zhou Michael E. Granberry Ti-Fen Wang Thomas M. Grogan Catherine Spier Ruby White Abhay Mehta Augustine Y. Lin 《Cancer immunology, immunotherapy : CII》1995,40(6):397-409
Metastatic or tumor-draining lymph nodes from six of nine melanoma patients undergoing lymph node dissection for metastatic melanoma generated cytotoxic T cells against autologous melanoma when these lymph node cells were treated by in vitro sensitization and recombinant interleukin-2 (IL-2). During the initial lymphocyte culture (2–6 weeks), cross-reactivity with autologous tumor cells, K562 and Daudi cells was usually noted. Cold-target inhibition assay with K562 and Daudi showed K562/Daudi-associated antigens on melanoma cells. During the later phase of lymphocyte culture with repeated in vitro sensitization (over 6–10 weeks), cytotoxicity was noted against autologous and allogeneic melanoma cells but not against K562, Daudi cells or autologous fibroblasts. Repeated in vitro sensitization resulted in the selection of specific cytotoxic lymphocytes against melanoma. Cold-target inhibition assay with autologous and allogeneic melanoma cells revealed shared and individual antigens. Using blocking monoclonal antibodies, MHC-restricted killing was noted in the autologous system. Further, both the autologous and allogeneic systems could be mediated through adhesion molecules such as ICAM-1 and LFA-3 on melanoma cells and LFA-1 on T cells. This study suggests that a constellation of cytotoxic effector cells and melanoma-associated antigens may be pivotal in tumor killing. Thus, future adoptive immunotherapy should modulate and enhance this complex interaction.This work was supported by an Elsa, U. Pardee Foundation grant, the Arizona Chronic Disease Research Commission grant and partly by grant CA23074 from the National Institutes of Health, Bethesda, MD, 20892 相似文献