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1.
Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate 总被引:2,自引:0,他引:2
Salcedo M Bercovici N Taylor R Vereecken P Massicard S Duriau D Vernel-Pauillac F Boyer A Baron-Bodo V Mallard E Bartholeyns J Goxe B Latour N Leroy S Prigent D Martiat P Sales F Laporte M Bruyns C Romet-Lemonne JL Abastado JP Lehmann F Velu T 《Cancer immunology, immunotherapy : CII》2006,55(7):819-829
The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based
on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from
monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen
patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of
both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No
grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate
and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who
received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received
3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen
months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately
10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible
in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens
documented in some treated patients support further investigations to optimize the vaccine formulation.
Margarita Salcedo and Nadège Bercovici both contributed equally to this work 相似文献
2.
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
3.
Redas Trepiakas Annika Berntsen Sine Reker Hadrup Jon Bjørn Poul F. Geertsen Per Thor Straten Mads H. Andersen Anders E. Pedersen Amir Soleimani Torben Lorentzen Julia S. Johansen Inge Marie Svane 《Cytotherapy》2010,12(6):721-734
Background aimsDendritic cells are regarded as the most effective antigen presenting cells and coordinators of the immune response and therefore suitable as vaccine basis. Here we present results from a clinical study in which patients with malignant melanoma (MM) with verified progressive disease received vaccination with autologous monocyte-derived mature dendritic cells (DC) pulsed with p53, survivin and telomerase-derived peptides (HLA-A2+ patients) or with autologous/allogeneic tumor lysate (HLA-A2? patients) in combination with low-dose interleukin (IL)-2 and interferon (IFN)-α2b.ResultsOf 46 patients who initiated treatment, 10 stopped treatment within 1–4 weeks because of rapid disease progression and deterioration. After 8 weeks, 36 patients were evaluable: no patient had an objective response, 11 patients had stable disease (SD); six had continued SD after 4 months, and three patients had prolonged SD for more than 6 months. The mean overall survival time was 9 months, with a significantly longer survival (18.4 months) of patients who attained SD compared with patients with progressive disease (PD) (5 months). Induction of antigen-specific T-cell responses was analyzed by multidimensional encoding of T cells using HLA-A2 major histocompatibility complex (MHC) multimers. Immune responses against five high-affinity vaccine peptides were detectable in the peripheral blood of six out of 10 analyzed HLA-A2+ patients. There was no observed correlation between the induction of immune responses and disease stabilization. A significant lower blood level of regulatory T cells (CD25high CD4 T cells) was demonstrable after six vaccinations in patients with SD compared with PD.ConclusionsVaccination was feasible and safe. Treatment-associated SD was observed in 24% of the patients. SD correlated with prolonged survival suggesting a clinical benefit. Differences in the level of regulatory T cells among SD and PD patients could indicate a significant role of these immune suppressive cells. 相似文献
4.
Nitya G. Chakraborty Jonathan R. Sporn Anne F. Tortora Scott H. Kurtzman Harold Yamase M. T. Ergin Bijay Mukherji 《Cancer immunology, immunotherapy : CII》1998,47(1):58-64
The discoveries of human melanoma-associated antigens in molecular terms have renewed interest in peptide- or peptide- and
antigen-presenting-cell (APC)-based cancer vaccines. Considering the limited scope of immunization using defined peptides,
we have studied an alternative approach of specific immunization with tumor-lysate-loaded autologous APC (adherent peripheral
mononuclear cells cultured in 1000 U granulocyte/macrophage-colony-stimulating factor for 14 days) as a surrogate vaccine.
Seventeen patients (11 with active metastatic disease) were intradermally immunized with the vaccine in a phased dose escalation
(105–107 cells/injection) monthly for 4 months. Thirteen patients completed all four immunizations showing no toxicity (3 patients
had to be taken off study because of progressive disease and 1 patient went off study as a result of myocardial infarction
due to multi-vessel coronary artery disease). None has shown any immediate or delayed toxicity attributable to the immunization
and none has shown any evidence of autoimmunity. One patient showed a partial regression of a subcutaneous nodule. Thirteen
patients are alive after 4+ months to 30+ months (17-month median survival for the group). Nine patients showed evidence of
delayed-type hypersensitivity at the vaccine sites. Monitoring of biological response in conventional natural killer or cytolytic
T lymphocyte assays with pre- and post-immune peripheral blood lymphocytes revealed no consistent differences. The vaccine-infiltrating
lymphocytes (VIL) from nine specimens were adequately expanded following in vitro stimulation with the respective autologous-lysate-loaded
APC for phenotypic and functional analyses. Five of the nine ex vivo expanded VIL were predominantly CD8+. Evidence of an antigen-specific CD8+ T cell response (cytotoxicity and/or tumor necrosis factor production) was detected in three of the five CD8+ VIL. These observations suggest that this type of vaccine is feasible, that it has biological activity, and that the approach
may be improved through additional strategic manipulations.
Received: 27 March 1998 / Accepted: 14 May 1998 相似文献
5.
Hersey P Halliday GM Farrelly ML DeSilva C Lett M Menzies SW 《Cancer immunology, immunotherapy : CII》2008,57(7):1039-1051
Background In the present study, we have examined whether treatment of patients with metastatic melanoma with matured dendritic cell
(DC) vaccines with or without low dose IL-2 may improve treatment outcomes.
Methods Sixteen patients received DC vaccines (DCs) sensitized with autologous melanoma lysates and 18 patients received DCs sensitized
with peptides from gp100, MART-1, tyrosinase, MAGE-3.A2, MAGE-A10 and NA17. IL-2 was given subcutaneously (sc) at 1 MU/m2 on the second day after each injection for 5–14 days in half of each group. DCs were given by intranodal injection.
Results There were 2 partial responses (PR) and 3 with stable disease (SD) in the nine patients receiving DCs + peptides + IL-2,
and 1 PR and 1 SD in nine patients treated with DCs + peptides without IL-2. There were only two patients with SD in the group
receiving DCs + autologous lysates and no IL-2. Median overall survival for all patients was very good at 18.5 months but
this was most probably due to selection of a favourable group of patients for the study. There was no significant difference
in survival between the groups by log rank analysis. Treatment was not associated with significant side effects. The quality
and yield of the DCs in the preparations were generally good.
Conclusions We conclude that mature DC preparations may be superior to immature DC preparations for presentation of melanoma peptides
and that IL-2 may increase clinical responses to the DCs plus peptides. However, in our view the low response rates do not
justify the cost and complexity of this treatment approach. 相似文献
6.
Vilella R Benítez D Milà J Lozano M Vilana R Pomes J Tomas X Costa J Vilalta A Malvehy J Puig S Mellado B Martí R Castel T 《Cancer immunology, immunotherapy : CII》2004,53(7):651-658
Eleven AJCC stage IV melanoma patients with progressive disease after treatment with biochemotherapy were treated with autologous dendritic cells pulsed with heterologous tumor cell lysates. The vaccine used mature DCs (CD1a+++, CD40++, CD80++, CD83+, and CD86+++) generated from peripheral blood monocytes in the presence of GM-CSF and IL-4. After 7 days, DCs were matured with a defined cocktail of cytokines (IL-1+IL-6+TNF-+PGE2) and simultaneously pulsed with lysates of heterologous melanoma cell lines, for 2 days. A total of 4×106 DCs was injected monthly under ultrasound control in an inguinal lymph node of normal appearance. The study was closed when all patients died as a consequence of tumor progression. No sign of toxicity was observed during the study. One patient experienced a partial response lasting 5 months, and two patients showed a mixed response which lasted 3 months. The median survival of the whole group was 7.3 months (range 3–14 months). This vaccination program had specific antitumoral activity in highly pretreated and large tumor burden stage IV melanoma patients and was well tolerated. The clinical responses and the median survival of the group of patients, together with the low toxicity of our DC vaccine, suggest that this approach could be applied to earlier AJCC stage IV melanoma patients. 相似文献
7.
Smithers M O'Connell K MacFadyen S Chambers M Greenwood K Boyce A Abdul-Jabbar I Barker K Grimmett K Walpole E Thomas R 《Cancer immunology, immunotherapy : CII》2003,52(1):41-52
Metastatic melanoma is poorly responsive to treatment, and immunotherapeutic approaches are potentially beneficial. Predictors of clinical response are needed to identify suitable patients. We sought factors associated with melanoma-specific clinical response following intradermal vaccination with autologous melanoma peptide and particulate hepatitis B antigen (HBsAg)-exposed immature monocyte-derived dendritic cells (MDDC). Nineteen patients with metastatic melanoma received a maximum of 8, 2-weekly vaccinations of DC, exposed to HBsAg in addition to autologous melanoma peptides. A further 3 patients received an otherwise identical vaccine that did not include HBsAg. Patients were assessed 1-2 monthly for safety, disease volume, and cellular responses to HBsAg and melanoma peptide. There was no significant toxicity. Of 19 patients receiving HBsAg-exposed DC, 9 primed or boosted a cellular response to HBsAg, and 10 showed no HBsAg response. HBsAg-specific responses were associated with in vitro T cell responses to melanoma peptides and to phytohemagglutinin (PHA). Zero out of 10 non-HBsAg-responding and 4/9 HBsAg-responding patients achieved objective melanoma-specific clinical responses or disease stabilization - 1 complete and 2 partial responses and 1 case of stable disease ( P=0.018). Development of melanoma-specific cellular immunity and T cell responsiveness to mitogen were greater in the group of patients responding to HBsAg. Therefore stimulation of an immune response to nominal particulate antigen was necessary when presented by melanoma peptide-exposed immature DC, to achieve clinical responses in metastatic melanoma. Since general immune competence may be a determinant of treatment response, it should be assessed in future trials on DC immunotherapy. 相似文献
8.
Rogel A Vignard V Bobinet M Labarriere N Lang F 《Cancer immunology, immunotherapy : CII》2011,60(3):327-337
CD4+ T cells contribute importantly to the antitumor T cell response, and thus, long peptides comprising CD4 and CD8 epitopes
may be efficient cancer vaccines. We have previously identified an overexpressed antigen in melanoma, MELOE-1, presenting
a CD8+ T cell epitope, MELOE-136–44, in the HLA-A*0201 context. A T cell repertoire against this epitope is present in HLA-A*0201+ healthy subjects and melanoma
patients and the adjuvant injection of TIL containing MELOE-1 specific CD8+ T cells to melanoma patients was shown to be beneficial. In this study, we looked for CD4+ T cell epitopes in the vicinity of the HLA-A*0201 epitope. Stimulation of PBMC from healthy subjects with MELOE-126–46 revealed CD4 responses in multiple HLA contexts and by cloning responsive CD4+ T cells, we identified one HLA-DRβ1*1101-restricted and one HLA-DQβ1*0603-restricted epitope. We showed that the two epitopes
could be efficiently presented to CD4+ T cells by MELOE-1-loaded dendritic cells but not by MELOE-1+ melanoma cell-lines. Finally, we showed that the long peptide
MELOE-122–46, containing the two optimal class II epitopes and the HLA-A*0201 epitope, was efficiently processed by DC to stimulate CD4+ and CD8+ T cell responses in vitro, making it a potential candidate for melanoma vaccination. 相似文献
9.
Zhou J Yuen NK Zhan Q Velazquez EF Murphy GF Giobbie-Hurder A Hodi FS 《Cancer immunology, immunotherapy : CII》2012,61(5):655-665
Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families.
Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally
relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma,
contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune
responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by
immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein
was utilized to screen cellular responses in stage I–IV patients and healthy controls by ELISPOT. A broad array of CD4+ and CD8+ cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes
were analyzed further for frequency of reactivity. The generation of specific CD4+ and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and
tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in
a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune
responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune
responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis
support the development of ML-IAP as a disease marker and therapeutic target. 相似文献
10.
Filiberto Belli Flavio Arienti J. Sulé-Suso C. Clemente Luigi Mascheroni Alessandro Cattelan Cristina Santantonio Gian Francesco Gallino Cecilia Melani Stefania Rao Mario P. Colombo Michele Maio Natale Cascinelli G. Parmiani 《Cancer immunology, immunotherapy : CII》1997,44(4):197-203
From January 1994 to July 1996 we immunized metastatic melanoma patients with HLA-A2-compatible, interleukin-2 (IL-2)-secreting,
immunogenic melanoma lines in an attempt to induce a systemic reaction that might also affect distant melanoma lesions. Twelve
patients (6 male and 6 female) aged from 28 to 72 years, affected with visceral and/or subcutaneous (s.c.) melanoma metastases,
were treated. Two different HLA-A2+ melanoma lines were transduced with the human IL-2 gene (14932/IL-2 and 1B6/IL-2) and used as vaccine. Two groups of 4 patients
each were injected s.c. with 5×107 and 15×107 irradiated 14932/IL-2 melanoma cells respectively, whereas a third group received 5×107 cells of the second line (1B6/IL-2). All patients received the vaccine on days 1, 13, 26; if no progression was evident,
further immunizations were administered at monthly intervals. All patients were assessable for clinical response after at
least three injections of the vaccine. In 4 cases a stabilization of disease lasting from 2 to 6 months was observed; in 2
of them a mixed type of response to treatment was noted with simultaneous evidence of regressing and non-responding lesions
in the same patients. No signs of clinical response were found in the remaining patients. Nine patients died of disease between
3 and 24 months after the onset of therapy, whereas 3 were alive 3 months after the end of therapy. The local and systemic
side-effects of treatment were mild. These results indicate that vaccination with cells bearing the appropriate antigens and
releasing IL-2 locally can produce weak clinical responses, but also indicate that better results may be achieved through
modifications of the vaccine, the schedule of immunization and/or a more appropriate selection of patients.
Received: 20 December 1996 / Accepted: 27 February 1997 相似文献
11.
Spontaneous T cell responses to melanoma differentiation antigens from melanoma patients and healthy subjects 总被引:2,自引:0,他引:2
Qiyuan Chen Heather Jackson Peter Gibbs Ian D. Davis Joseph Trapani Jonathan Cebon 《Cancer immunology, immunotherapy : CII》1998,47(4):191-197
The spontaneous cytotoxic T cell responses to melanoma differentiation antigens and influenza matrix peptide were compared
in 20 HLA-A2+ melanoma patients and 17 healthy A2+ individuals. Cytotoxic T lymphocyte (CTL) responses were determined by mixed lymphocyte peptide culture (MLPC) involving
two stimulations of unfractionated peripheral blood lymphocytes (PBLs) with peptide in vitro. CTL responses to Melan-A 9-mer
(amino acids 27–35, AAGIGILTV) peptide were detected in 4 out of 16 normal individuals, but in none of the melanoma patients.
CTL specific for influenza matrix peptide were frequently found in both normal individuals and melanoma patients, suggesting
that generalized immuno-suppression was not responsible for this difference. No significant responses were observed in either
normal individuals or melanoma patients to Melan-A 10-mer (26–35, EAAGIGILTV), two gp100 epitopes (280–288, YLEPGPVTA; 457–466,
LLDGTATLRL) and two tyrosinase epitopes (1–9, MLLAVLYCL; 368–376, YMDGMSQV). Melan-A (27–35)-specific CTL cells generated
by normal individuals and melanoma patients recognized both synthetic peptide-pulsed T2 cells and two HLA-A2+, Melan-A+ melanoma cell lines (ME272, LAR1) in an antigen-specific, MHC class I restricted manner. T cells generated against Melan-A
9-mer were also able to recognize Melan-A 10-mer-pulsed target cells. Spontaneous CTL responses to Melan-A 9-mer from three
known responder normal individuals were further evaluated over a prolonged time course (6–11 months). All 3 subjects demonstrated
specific Melan-A 9-mer responses throughout the study period, although lytic activity fluctuated over time for a given individual.
We found the MLPC assay to be reliable and easy to perform for monitoring T cell responses, although it may still not be sufficiently
sensitive to detect low numbers of precursor T cells.
Received: 21 May 1998 / Accepted: 23 July 1998 相似文献
12.
Jacobus J. Bosch Uzoma K. Iheagwara Sarah Reid Minu K. Srivastava Julie Wolf Michal Lotem Bruce R. Ksander Suzanne Ostrand-Rosenberg 《Cancer immunology, immunotherapy : CII》2010,59(1):103-112
We are exploring cell-based vaccines as a treatment for the 50% of patients with large primary uveal melanomas who develop
lethal metastatic disease. MHC II uveal melanoma vaccines are MHC class I+ uveal melanoma cells transduced with CD80 genes and MHC II genes syngeneic to the recipient. Previous studies demonstrated
that the vaccines activate tumor-specific CD4+ T cells from patients with metastatic uveal melanoma. We have hypothesized that vaccine potency is due to the absence of
the MHC II-associated invariant chain (Ii). In the absence of Ii, newly synthesized MHC II molecules traffic intracellularly
via a non-traditional pathway where they encounter and bind novel tumor peptides. Using confocal microscopy, we now confirm
this hypothesis and demonstrate that MHC II molecules are present in both the endosomal and secretory pathways in vaccine
cells. We also demonstrate that uveal melanoma MHC II vaccines activate uveal melanoma-specific, cytolytic CD8+ T cells that do not lyse normal fibroblasts or other tumor cells. Surprisingly, the CD8+ T cells are cytolytic for HLA-A syngeneic and MHC I-mismatched uveal melanomas. Collectively, these studies demonstrate that
MHC II uveal melanoma vaccines are potent activators of tumor-specific CD4+ and CD8+ T cells and suggest that the non-conventional intracellular trafficking pattern of MHC II may contribute to their enhanced
immunogenicity. Since MHC I compatibility is unnecessary for the activation of cytolytic CD8+ T cells, the vaccines could be used in uveal melanoma patients without regard to MHC I genotype. 相似文献
13.
Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine 总被引:3,自引:0,他引:3
O'Rourke MG Johnson M Lanagan C See J Yang J Bell JR Slater GJ Kerr BM Crowe B Purdie DM Elliott SL Ellem KA Schmidt CW 《Cancer immunology, immunotherapy : CII》2003,52(6):387-395
Advanced metastatic melanoma is incurable by standard treatments, but occasionally responds to immunotherapy. Recent trials using dendritic cells (DC) as a cellular adjuvant have concentrated on defined peptides as the source of antigens, and rely on foreign proteins as a source of help to generate a cell-mediated immune response. This approach limits patient accrual, because currently defined, non-mutated epitopes are restricted by a small number of human leucocyte antigens. It also fails to take advantage of mutated epitopes peculiar to the patient's own tumour, and of CD4+ T lymphocytes as potential effectors of anti-tumour immunity. We therefore sought to determine whether a fully autologous DC vaccine is feasible, and of therapeutic benefit. Patients with American Joint Cancer Committee stage IV melanoma were treated with a fully autologous immunotherapy consisting of monocyte-derived DC, matured after culture with irradiated tumour cells. Of 19 patients enrolled into the trial, sufficient tumour was available to make treatments for 17. Of these, 12 received a complete priming phase of six cycles of either 0.9x10(6) or 5x10(6) DC/intradermal injection, at 2-weekly intervals. Where possible, treatment continued with the lower dose at 6-weekly intervals. The remaining five patients could not complete priming, due to progressive disease. Three of the 12 patients who completed priming have durable complete responses (average duration 35 months+), three had partial responses, and the remaining six had progressive disease (WHO criteria). Disease regression was not correlated with dose or with the development of delayed type hypersensitivity responses to intradermal challenge with irradiated, autologous tumour. However, plasma S-100B levels prior to the commencement of treatment correlated with objective clinical response ( P=0.05) and survival (log rank P<0.001). The treatment had minimal side-effects and was well tolerated by all patients. Mature, monocyte-derived DC preparations exposed to appropriate tumour antigen sources can be reliably produced for patients with advanced metastatic melanoma, and in a subset of those patients with lower volume disease their repeated administration results in durable complete responses. 相似文献
14.
Haanen JB Baars A Gomez R Weder P Smits M de Gruijl TD von Blomberg BM Bloemena E Scheper RJ van Ham SM Pinedo HM van den Eertwegh AJ 《Cancer immunology, immunotherapy : CII》2006,55(4):451-458
Purpose: To study the effect of autologous tumor cell vaccinations on the presence and numbers of circulating CD8+ T cells specific for tumor-associated antigens (TAA) in metastatic melanoma patients. To investigate the correlation between
the presence of tumor-infiltrating lymphocytes (TIL) and circulating TAA-specific CD8+ T cells before and after autologous tumor cell vaccination with overall survival. Experimental design: Twenty-five stage III and resected stage IV metastatic melanoma patients were adjuvantly treated with a series of intracutaneously
injected autologous tumor cell vaccinations, of which the first two contained BCG as an immunostimulatory adjuvant. Tumor
samples and blood samples obtained before and after vaccination of these patients were studied for the presence of TAA-specific
T cells using HLA-tetramers and results were correlated with survival. Results: In 5 of 17 (29%) melanoma patients, circulating TAA-specific T cells were detectable prior to immunizations. No significant
changes in the frequency and specificity were found during the treatment period in all patients. Presence of circulating TAA-specific
T cells was not correlated with survival (log rank, P=0.215). Inside melanoma tissue, TAA-specific TIL could be detected in 75% of 16 available tumor samples. In case of detectable
TAA-specific TIL, median survival was 22.5 months compared to median survival of 4.5 months in case of absence of TAA-specific
T cells (log rank, P=0.0094). In none of the patients, TAA-specific T cells were found both in tumor tissue and blood at the same time. Conclusions: These data suggest that the presence of TAA-specific TILs forms a prognostic factor, predicting improved survival in advanced-stage
melanoma patients. The absence of TAA-specific T cells in the circulation suggests that homing of the tumor-specific T cell
population to the tumor site contributes to the effectiveness of antitumor immunity.
J.B.A.G. Haanen and A. Baars contributed equally to this work. 相似文献
15.
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
16.
Yinin Hu Gina R. Petroni Walter C. Olson Andrea Czarkowski Mark E. Smolkin William W. Grosh Kimberly A. Chianese-Bullock Craig L. Slingluff Jr. 《Cancer immunology, immunotherapy : CII》2014,63(8):779-786
Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4+ T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8+ T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund’s adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4+ and CD8+ T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-γ ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4+ T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE-A3281–295 (49 %) and tyrosinase386–406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8+ T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4+ and CD8+ T cell responses against melanoma antigens. CD4+ T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8+ T cell responses suggests epitope spreading and systemic activity mediated at the tumor site. 相似文献
17.
Schuler-Thurner B Dieckmann D Keikavoussi P Bender A Maczek C Jonuleit H Röder C Haendle I Leisgang W Dunbar R Cerundolo V von Den Driesch P Knop J Bröcker EB Enk A Kämpgen E Schuler G 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(6):3492-3496
Dendritic cell (DC) vaccination, albeit still in an early stage, is a promising strategy to induce immunity to cancer. We explored whether DC can expand Ag-specific CD8+ T cells even in far-advanced stage IV melanoma patients. We found that three to five biweekly vaccinations of mature, monocyte-derived DC (three vaccinations of 6 x 106 s.c. followed by two i.v. ones of 6 and 12 x 106, respectively) pulsed with Mage-3A2.1 tumor and influenza matrix A2. 1-positive control peptides as well as the recall Ag tetanus toxoid (in three of eight patients) generated in all eight patients Ag-specific effector CD8+ T cells that were detectable in blood directly ex vivo. This is the first time that active, melanoma peptide-specific, IFN-gamma-producing, effector CD8+ T cells have been reliably observed in patients vaccinated with melanoma Ags. Therefore, our DC vaccination strategy performs an adjuvant role and encourages further optimization of this new immunization approach. 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.
Claudia Durán-Aniotz Gabriela Segal Lorena Salazar Cristián Pereda Cristián Falcón Fabián Tempio Raquel Aguilera Rodrigo González Claudio Pérez Andrés Tittarelli Diego Catalán Bruno Nervi Milton Larrondo Flavio Salazar-Onfray Mercedes N. López 《Cancer immunology, immunotherapy : CII》2013,62(4):761-772
Introduction
Immunization with autologous dendritic cells (DCs) loaded with a heat shock-conditioned allogeneic melanoma cell lysate caused lysate-specific delayed type hypersensitivity (DTH) reactions in a number of patients. These responses correlated with a threefold prolonged long-term survival of DTH+ with respect to DTH? unresponsive patients. Herein, we investigated whether the immunological reactions associated with prolonged survival were related to dissimilar cellular and cytokine responses in blood.Materials and methods
Healthy donors and melanoma patient’s lymphocytes obtained from blood before and after vaccinations and from DTH biopsies were analyzed for T cell population distribution and cytokine release.Results/discussion
Peripheral blood lymphocytes from melanoma patients have an increased proportion of Th3 (CD4+ TGF-β+) regulatory T lymphocytes compared with healthy donors. Notably, DTH+ patients showed a threefold reduction of Th3 cells compared with DTH? patients after DCs vaccine treatment. Furthermore, DCs vaccination resulted in a threefold augment of the proportion of IFN-γ releasing Th1 cells and in a twofold increase of the IL-17-producing Th17 population in DTH+ with respect to DTH? patients. Increased Th1 and Th17 cell populations in both blood and DTH-derived tissues suggest that these profiles may be related to a more effective anti-melanoma response.Conclusions
Our results indicate that increased proinflammatory cytokine profiles are related to detectable immunological responses in vivo (DTH) and to prolonged patient survival. Our study contributes to the understanding of immunological responses produced by DCs vaccines and to the identification of follow-up markers for patient outcome that may allow a closer individual monitoring of patients. 相似文献20.
Purpose: A human monoclonal antibody (L612 HuMAb) that binds to ganglioside GM3 has been developed in our laboratory. L612 HuMAb is a 100% human IgM protein. L612 HuMAb binds to cell surface of melanoma and can kill the cells in the presence of complement. The primary objective of this study was to test the toxicity and pharmacokinetics associated with administration of L612 HuMAb to melanoma patients whose tumor cells expressed GM3. Experimental design: Nine patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered in the study. Eight had failed previous treatments that included chemotherapy, radiation therapy, melanoma cell vaccine, and/or biological therapy. All patients received a 48-h continuous infusion of L612 HuMAb at a dose of 960 mg, 1,440 mg, or 1,920 mg. Five of these patients received a second infusion and one patient received a third infusion, all with the previous dose. Results: Toxicity was limited to transient and mild pruritus and skin rash. One patient complained of pain at the site of subcutaneous metastases. Serum antibody levels peaked 24 to 48 h after starting the infusion. Two patients, one receiving a single course of 960 mg (612 mg/m2) and the second receiving two courses of 1,440 mg (911 mg/m2) followed by surgical therapy, are without evidence of disease >5 years after antibody infusion. Conclusions: The human IgM monoclonal antibody, L612 HuMAb, was well tolerated. Infusion of L612 HuMAb appears to produce significant antitumor activity in melanoma patients.Dr. Ollila is currently affiliated with the University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.Supported by grant CA 30647 from the National Institutes of Health, National Cancer Institute. 相似文献