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1.
Annabelle Grolleau-Julius Lisa Abernathy Erin Harning Raymond L. Yung 《Cancer immunology, immunotherapy : CII》2009,58(12):1935-1939
Effective cancer immunotherapy depends on the body’s ability to generate tumor antigen-presenting cells and tumor-reactive
effector lymphocytes. As the most potent antigen presenting cells (APCs), dendritic cells (DCs) are capable of sensitizing
T cells to new and recall antigens. Clinical trials of antigen-pulsed autologous DCs have been conducted in patients with
a number of hematological and solid cancers, including malignant melanoma, lymphoma, myeloma, and non-small cell lung cancer.
These studies suggest that antigen-loaded DC vaccination is a potentially safe and effective cancer therapy. However, the
clinical results have been variable. Since the elderly are preferentially affected by diseases targeted by DC-directed immunotherapy,
it is quite striking that few studies to date have focused on the effect of aging on DC function, a key aspect of optimal
immunotherapy design in an aging population. In the present paper, we will discuss the consequences of aging on murine bone
marrow-derived DC function and their use in cancer immunotherapy. 相似文献
2.
Gerty Schreibelt Jurjen Tel Kwinten H. E. W. J. Sliepen Daniel Benitez-Ribas Carl G. Figdor Gosse J. Adema I. Jolanda M. de Vries 《Cancer immunology, immunotherapy : CII》2010,59(10):1573-1582
Dendritic cells (DCs) are central players of the immune response. To date, DC-based immunotherapy is explored worldwide in
clinical vaccination trials with cancer patients, predominantly with ex vivo-cultured monocyte-derived DCs (moDCs). However,
the extensive culture period and compounds required to differentiate them into DCs may negatively affect their immunological
potential. Therefore, it is attractive to consider alternative DC sources, such as blood DCs. Two major types of naturally
occurring DCs circulate in peripheral blood, myeloid DCs (mDCs) and plasmacytoid (pDCs). These DC subsets express different
surface molecules and are suggested to have distinct functions. Besides scavenging pathogens and presenting antigens, DCs
secrete cytokines, all of which is vital for both the acquired and the innate immune system. These immunological functions
relate to Toll-like receptors (TLRs) expressed by DCs. TLRs recognize pathogen-derived products and subsequently provoke DC
maturation, antigen presentation and cytokine secretion. However, not every TLR is expressed on each DC subset nor causes
the same effects when activated. Considering the large amount of clinical trials using DC-based immunotherapy for cancer patients
and the decisive role of TLRs in DC maturation, this review summarizes TLR expression in different DC subsets in relation
to their function. Emphasis will be given to the therapeutic potential of TLR-matured DC subsets for DC-based immunotherapy. 相似文献
3.
Tamir A Basagila E Kagahzian A Jiao L Jensen S Nicholls J Tate P Stamp G Farzaneh F Harrison P Stauss H George AJ Habib N Lechler RI Lombardi G 《Cancer immunology, immunotherapy : CII》2007,56(12):2017-2016
Background Dendritic cells (DCs) are the most effective antigen-presenting cells. In the last decade, the use of DCs for immunotherapy
of cancer patients has been vastly increased. High endocytic capacity together with a unique capability of initiating primary
T-cell responses have made DCs the most potent candidates for this purpose. Although DC vaccination occasionally leads to
tumor regression, clinical efficacy, and immunogenicity of DCs in clinical trials has not been yet clarified. The present
study evaluated the safety and effectiveness of tumor-lysate loaded DC vaccines in advanced colorectal cancer (CRC) patients
with carcinoembryonic antigen (CEA) positive tumors.
Results Six patients HLA-A*0201-positive were vaccinated with autologous DCs loaded with tumor lysates (TL) together with tetanus
toxoid antigen, hepatitis B, and influenza matrix peptides. Two additional patients were injected with DCs that were generated
from their sibling or parent with one haplotype mismatch. All patients received the vaccines every 2 weeks, with a total of
three intra-nodal injections per patient. The results indicated that DC vaccination was safe and well tolerated by the patients.
Specific immune responses were detected and in some patients, transient stabilization or even reduction of CEA levels were
observed. The injection of haplotype mismatched HLA-A*0201-positive DCs resulted in some enhancement of the anti-tumor response
in vitro and led to stabilization/reduction of CEA levels in the serum, compared to the use of autologous DCs.
Conclusion Altogether, these results suggest that TL-pulsed DCs may be an effective vaccine method in CRC patients. Elimination of regulatory
mechanisms as well as adjustment of the vaccination protocol may improve the efficacy of DC vaccination.
An erratum to this article can be found at 相似文献
4.
Dendritic cells (DCs) are the most potent antigen presenting cells in the human organism. Ever since the discovery of their function in the self/nonself discrimination, DCs have been seen as potential candidates for therapy in malignant tumors. With the exception of differentiated thyroid cancer, endocrine malignancies are rare tumors and apart from surgical intervention there is no truly established method for their treatment. Therefore, the prognosis of many endocrine carcinomas is still poor and new therapeutic options are needed. In the last decade, different immunotherapeutic approaches have shown promising results in other solid tumors. In recent studies, immunotherapy using DCs has been proven to be safe and effective to induce antitumor immune responses leading to tumor regression and even rejection of cancer in some cases. This review will summarize the latest progress in DCs based immunotherapy with special focus on the limited experience in endocrine malignancies. With regard to these tumors, it is of special interest which antigens could serve as potential target antigens for future trials. We also discuss what steps have to be taken to develop a better immunotherapy in endocrine tumors. 相似文献
5.
Linkage of foreign carrier protein to a self-tumor antigen enhances the immunogenicity of a pulsed dendritic cell vaccine 总被引:19,自引:0,他引:19
The unique Ag-presenting capabilities of dendritic cells (DCs) make them attractive vehicles for the delivery of therapeutic cancer vaccines. While tumor Ag-pulsed DC vaccination has shown promising results in a variety of murine tumor models and early clinical trials, the optimal form of tumor Ag for use in DC pulsing has not been determined. We have studied DC vaccination using alternative forms of a soluble protein tumor Ag, the tumor-specific Ig idiotype (Id) expressed by a murine B cell lymphoma. Vaccination of mice with Id-pulsed DCs was able to induce anti-Id Abs only when the Id was modified to constitute a hapten-carrier system. DCs pulsed with Id proteins modified to include foreign constant regions, foreign constant regions plus GM-CSF, or linkage to keyhole limpet hemocyanin (KLH) carrier protein were increasingly potent in their ability to elicit anti-Id Abs. Vaccination with Id-KLH-pulsed DCs induced tumor-protective immunity superior to that obtained with Id-KLH plus a chemical adjuvant, and protection was not dependent upon effector T cells. Rather, protection was associated with the induction of high titers of anti-Id Abs of the IgG2a subclass, characteristic of a Th1 response. These findings have implications for the design of therapeutic Ag-pulsed DC vaccines for cancer immunotherapy in humans. 相似文献
6.
The long-held belief that breast cancer is a weakly immunogenic tumor and a poor candidate for immunotherapy should be reappraised. There is ample evidence for the existence of an immune response, which is, however, attenuated by multiple inhibitory factors. Many tumor-associated antigens (TAA) have been identified in breast cancer, some of which appear to play a critical role in tumorigenesis and may be attractive targets for immunotherapy. There is evidence for DC recruitment and activation within breast cancers, and the presence of intratumoral activated DCs impacts favorably upon survival. Furthermore, there is a striking paucity of activated DCs within the primary draining or sentinel lymph nodes of breast cancers. Tumor infiltrating lymphocytes (TIL) are often documented, however, their function is impaired by inhibitory cytokines, increased regulatory T lymphocyte activity, tumor cell MHC molecule alterations, and aberrant Fas ligand expression, amongst others. DCs are recognized as one of the critical interfaces between a cancer and the immune system, and have emerged as a promising platform for cancer vaccination via ex vivo immunomodulation. Clinical evaluation of DC vaccination in breast cancer is still relatively limited, although evolving. This article details evidence for the immune response in breast cancer and its many failings, and reviews the clinical trials and significant preclinical data which, taken together, validate the concept of DC vaccination in breast cancer. 相似文献
7.
Engell-Noerregaard L Hansen TH Andersen MH Thor Straten P Svane IM 《Cancer immunology, immunotherapy : CII》2009,58(1):1-14
During the past years numerous clinical trials have been carried out to assess the ability of dendritic cell (DC) based immunotherapy
to induce clinically relevant immune responses in patients with malignant diseases. A broad range of cancer types have been
targeted including malignant melanoma which in the disseminated stage have a very poor prognosis and only limited treatment
options with moderate effectiveness. Herein we describe the results of a focused search of recently published clinical studies
on dendritic cell vaccination in melanoma and review different vaccine parameters which are frequently claimed to have a possible
influence on clinical response. These parameters include performance status, type of antigen, DC maturation status, route
of vaccine administration, use of adjuvant, and vaccine induced immune response. In total, 38 articles found through Medline
search, have been included for analysis covering a total of 626 patients with malignant melanoma treated with DC based therapy.
Clinical response (CR, PR and SD) were found to be significantly correlated with the use of peptide antigens (p = 0.03), the use of any helper antigen/adjuvant (p = 0.002), and induction of antigen specific T cells (p = 0.0004). No significant correlations between objective response (CR and PR) and the tested parameters were found. However,
a few non-significant trends were demonstrated; these included an association between objective response and use of immature
DCs (p = 0.08), use of adjuvant (p = 0.09), and use of autologous antigen preparation (p = 0.12). The categorisation of SD in the response group is debatable. Nevertheless, when the SD group were analysed separately
we found that SD was significantly associated with use of peptide antigens (p = 0.0004), use of adjuvant (p = 0.01), and induction of antigen specific T cells (p = 0.0003). No specific route of vaccine administration showed superiority. Important lessons can be learned from previous
studies, interpretation of these findings should, however, be done with reservation for the many minor deviations in the different
treatment schedules among the published studies, which were not considered in order to be able to process and group the data. 相似文献
8.
《Cytotherapy》2014,16(4):427-439
Tumor growth is controlled by natural antitumor immune responses alone or by augmented immune reactivity resulting from different forms of immunotherapy, which has demonstrated clinical benefit in numerous studies, although the overall percentage of patients with durable clinical responses remains limited. This is attributed to the heterogeneity of the disease, the inclusion of late-stage patients with no other treatment options and advanced tumor-associated immunosuppression, which may be consolidated by certain types of chemotherapy. Despite variable responsiveness to distinct types of immunotherapy, therapeutic cancer vaccination has shown meaningful efficacy for a variety of cancers. A key step during cancer vaccination involves the appropriate modeling of the functional state of dendritic cells (DCs) capable of co-delivering four critical signals for proper instruction of tumor antigen–specific T cells. However, the education of DCs, either directly in situ, or ex vivo by various complex procedures, lacks standardization. Also, it is questioned whether ex vivo–prepared DC vaccines are superior to in situ–administered adjuvant-guided vaccines, although both approaches have shown success. Evaluation of these variables is further complicated by a lack of consensus in evaluating vaccination clinical study end points. We discuss the role of signals needed for the preparation of classic in situ and modern ex vivo DC vaccines capable of proper reprogramming of antitumor immune responses in patients with cancer. 相似文献
9.
Dendritic cells (DCs) are bone marrow–derived immune cells that play a crucial role in inducing the adaptive immunity and supporting the innate immune response independently from T cells. In the last decade, DCs have become a hopeful instrument for cancer vaccines that aims at re-educating the immune system, leading to a potent anti-cancer immune response able to overcome the immunosuppressive tumor microenvironment (TME). Although several studies have indicated that DC-based vaccines are feasible and safe, the clinical advantages of DC vaccination as monotherapy for most of the neoplasms remain a distant target. Recently, many reports and clinical trials have widely used innovative combinatorial therapeutic strategies to normalize the immune function in the TME and synergistically enhance DC function. This review will describe the most relevant and updated evidence of the anti-cancer combinatorial approaches to boost the clinical potency of DC-based vaccines. 相似文献
10.
Immunotherapy of cancer with dendritic-cell-based vaccines 总被引:32,自引:0,他引:32
Animal studies have shown that vaccination with genetically modified tumor cells or with dendritic cells (DC) pulsed with
tumor antigens are potent strategies to elicit protective immunity in tumor-bearing animals, more potent than “conventional”
strategies that have been tested in clinical settings with limited success. While both vaccination strategies are forms of
cell therapy requiring complex and costly ex vivo manipulations of the patient’s cells, current protocols using dendritic
cells are considerably simpler and would be more widely available. Vaccination with defined tumor antigens presented by DC
has obvious appeal. However, in view of the expected emergence of antigen-loss variants as well as natural immunovariation,
effective vaccine formulations must contain mixtures of commonly, if not universally, expressed tumor antigens. When, or even
if, such common tumor antigens will be identified cannot be, predicted, however. Thus, for the foreseeable future, vaccination
with total-tumor-derived material as source of tumor antigens may be preferable to using defined tumor antigens. Vaccination
with undefined tumor-derived antigens will be limited, however, by the availability of sufficient tumor tissue for antigen
preparation. Because the mRNA content of single cells can be amplified, tumor mRNA, or corresponding cDNA libraries, offer
an unlimited source of tumor antigens. DC transfected with tumor RNA were shown to engender potent antitumor immunity in animal
studies. Thus, immunotherapy using autologous DC loaded with unfractionated tumor-derived antigens in the form of RNA emerges
as a potentially powerful and broadly useful vaccination strategy for cancer patients.
Received: 10 October 1997 / Accepted: 12 January 1998 相似文献