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Anti-cancer vaccine therapy for hematologic malignancies: An evolving era.
Feb. 2018 | Nahas, Myrna R; Rosenblatt, Jacalyn; Lazarus, Hillard M; Avigan, David
The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity. PMID 29475779

Progress of dendritic cell-based cancer vaccines for patients with hematological malignancies.
Juni 2016 | Ni, Ming; Hoffmann, Jean-Marc; Schmitt, Michael; Schmitt, Anita
Dendritic cells (DCs) are the most professional antigen-presenting cells eliciting cellular and humoral immune responses against cancer cells by expressing these antigens on MHC class I/II complexes to T cells. Therefore, they have been employed in many clinical trials as cancer vaccines for patients with cancer. This review focuses on the use of DCs in leukemia patients expressing leukemia-associated antigens (LAAs). PMID 27238400

Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.
Apr. 2015 | Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun
Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. PMID 25612920

Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies.
Jan. 2015 | Pyzer, Athalia R; Avigan, David E; Rosenblatt, Jacalyn
The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies. PMID 25625926

Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria.
Mai 2012 | Palma, Marzia; Hansson, Lotta; Choudhury, Aniruddha; Näsman-Glaser, Barbro; Eriksson, Ingrid; Adamson, Lars; Rossmann, Eva; Widén, Karin; Horváth, Rudolf; Kokhaei, Parviz; Vertuani, Simona; Mellstedt, Håkan; Osterborg, Anders
We previously demonstrated that autologous dendritic cells that have endocytosed apoptotic bodies of chronic lymphocytic leukemia (CLL) cells (Apo-DC) can stimulate antileukemic T cell responses in vitro. In this phase I study, we vaccinated 15 asymptomatic CLL patients at five time points with Apo-DC administered intradermally either alone (cohort I), or in combination with subcutaneous granulocyte-macrophage-colony-stimulating-factor (GM-CSF) (cohort II) or with GM-CSF and intravenous low-dose cyclophosphamide (cohort III). Aim of the study was to evaluate the safety and immunogenicity of Apo-DC alone or in combination with GM-CSF and low-dose cyclophosphamide in CLL patients. All patients completed the vaccination schedule without dose-limiting toxicity. No objective clinical responses were seen. Vaccine-induced leukemia-specific immune responses were evaluated by IFN-γ ELISpot and proliferation assays over a 52 weeks observation period and immune response criteria were defined. According to these criteria, 10/15 patients were defined as immune responders. The frequency of immune-responding patients was higher in cohorts II (3/5) and III (5/5) than in cohort I (2/5). In order to further characterize the induced immune response, estimation of secreted cytokines and CD107-degranulation assay were performed. Clustering of T and CLL cells was observed in CD107-degranulation assay and visualized by confocal microscopy. Additionally, assessment of regulatory T cells (T(regs)) revealed their significantly lower frequencies in immune responders versus non-responders (P < 0.0001). Cyclophosphamide did not reduce T(regs) frequency. In conclusion, vaccination with Apo-DC + GM-CSF and cyclophosphamide was safe and elicited anti-CLL immune responses that correlated inversely with T(regs) levels. Lack of clinical responses highlights the necessity to develop more potent vaccine strategies in B cell malignancies. PMID 22086161

Chronic myeloid leukemia lysate-loaded dendritic cells induce T-cell responses towards leukemia progenitor cells.
Apr. 2011 | Westers, Theresia M; van den Ancker, Willemijn; Bontkes, Hetty J; Janssen, Jeroen J W M; van de Loosdrecht, Arjan A; Ossenkoppele, Gert J
Treatment of chronic myeloid leukemia with tyrosine kinase inhibitors, such as imatinib mesylate, dasatinib and nilotinib, results in high rates of cytogenetic and molecular responses. However, in many patients, minimal residual disease is detected by molecular techniques. Since chronic myeloid leukemia cells are particularly good targets for immune surveillance mechanisms, we explored active specific immunotherapy using leukemia lysate-loaded dendritic cells in vitro. Our data show the potency of dendritic cell-based vaccination strategies for the induction of T cell-mediated responses to eradicate minimal residual disease. PMID 21463196

Generation of a dendritic cell-based vaccine in chronic lymphocytic leukaemia using CliniMACS platform for large-scale production.
Mai 2009 | Adamson, L; Palma, M; Choudhury, A; Eriksson, I; Näsman-Glaser, B; Hansson, M; Hansson, L; Kokhaei, P; Osterborg, A; Mellstedt, H
We previously demonstrated that dendritic cells (DC) that have endocytosed apoptotic bodies of autologous leukemic cells (Apo-DC) can boost antileukemic T-cell responses. In this study, we report a description of the production procedure and product specification of the Apo-DC vaccine preparations for clinical use. Enriched populations of CD14+ monocytic precursors and CD19+ leukaemic cells were obtained using CliniMACS technology from a single leukapheresis product. Apoptotic bodies were obtained by irradiating (5 Gy) CD19+ selected B cells. DC were generated ex vivo by culturing monocytes with granulocyte macrophage colony-stimulating factor and interleukin-4. Following coculture with apoptotic bodies, DCs were matured with tumour necrosis factor-alpha. The mean percentage of CD14+ cells in the peripheral blood as well as in the leukapheresis product of the patients (n = 10) was approximately 2% (range, 0.8-3.3). Immunomagnetic selection using the CD14 reagent yielded a CD14+ population that was 91 +/- 2.2% (mean +/- SEM) pure. Immunomagnetic selection of CD19 expressing cells yielded a population that was 100 +/- 0.03% pure. Cell viability immediately after selection was 97% and 98% after 7 days of culture. The Apo-DC cellular vaccine product showed a mature phenotype, with a high rate of endocytosis (84%) of apoptotic leukemic B-cells. In conclusion, despite significant variability in the circulating monocyte frequency of the chronic lymphocytic leukaemia patients, our method permitted the production of a DC vaccine with high reproducibility and conforming with recommended quality standards. PMID 19439014

Vaccine therapy and chronic lymphocytic leukaemia.
Sep. 2008 | Ramsay, Alan G; Gribben, John G
B-cell chronic lymphocytic leukaemia (CLL) should be an ideal target for immune-mediated responses. CLL arises from B cells that can act as antigen-presenting cells (APCs), expresses unique tumour antigens, and has been shown to be a target of the allogeneic T cells which mediate a graft-versus-leukaemia effect. Despite these potential benefits, immune responses against CLL cells have been difficult to elicit. CLL induces immune defects in the host, the tumour cells are inefficient APCs, and therapies given to patients with CLL are themselves immunosuppressive. Successful vaccination approaches in this disease will require steps to overcome these difficulties, including identification of the targets of immune responses in this disease to enable monitoring of the immune response after vaccination, improved presentation of antigens, and steps to improve the immune defects that accompany this disease. PMID 18790447

Development of a dendritic cell-based vaccine for chronic lymphocytic leukemia.
Aug. 2008 | Palma, M; Adamson, L; Hansson, L; Kokhaei, P; Rezvany, R; Mellstedt, H; Osterborg, A; Choudhury, A
Evidence for the existence of CLL-specific antigens recognized by the immune system can be gathered from the observation that many patients display monoclonal or oligoclonal expansions and skewed repertoire of T cells. In vitro functional studies have shown that tumor-specific T-cells are able to lyse the leukemic cells. Antileukemic cellular immunity may be boosted in vivo using dendritic cell-based immunotherapy. Our preclinical studies provide evidence that DC that had endocytosed apoptotic CLL cells (Apo-DC) were superior to fusion hybrids, tumor lysate or RNA in eliciting antileukemic T-cell responses in vitro. We have validated a method for enriching the small number of monocyte precursors present in the peripheral blood of CLL patients and utilize them for generating individualized, Apo-DC cellular vaccines. In most cases, a minimum of 50 x 10(6) Apo-DC could be generated, beginning with immunomagnetically enriched monocytes from a single leukapheresis product containing at least 1% CD14+ cells. Cryopreservation and thawing did not affect the phenotype or the T cell stimulatory function of Apo-DC. A phase I/II, open label clinical trial examining the feasibility, safety and immunogenicity of Apo-DC vaccination has been initiated. CLL patients receive 10(7) Apo-DC for at least five immunizations and monitored clinically and immunologically for 52 weeks. Three cohorts are accrued stepwise. Cohort I receives Apo-DC alone; Cohort II: Apo-DC+ repeated doses of low-dose GM-CSF; Cohort III: low-dose cyclophosphamide followed by Apo-DC + GM-CSF. PMID 18663443

Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia.
Juli 2008 | Lee, Je-Jung; Foon, Kenneth A; Mailliard, Robbie B; Muthuswamy, Ravikumar; Kalinski, Pawel
Induction of active tumor-specific immunity in patients with chronic lymphocytic leukemia (CLL) and other hematologic malignancies is compromised by the deficit of endogenous dendritic cells (DCs). In attempt to develop improved vaccination strategies for patients with CLL and other tumors with poorly identified rejection antigens, we tested the ability of ex vivo-generated DCs to cross-present the antigens expressed by CLL cells and to induce CLL-specific, functional CTL responses. Monocyte-derived DCs from CLL patients were induced to mature using a "standard" cytokine cocktail (in IL-1beta, TNF-alpha, IL-6, and PGE2) or using an alpha-type 1-polarized DC (alphaDC1) cocktail (in IL-1beta, TNF-alpha, IFN-alpha, IFN-gamma, and polyinosinic:polycytidylic acid) and were loaded with gamma-irradiated, autologous CLL cells. alphaDC1 from CLL patients expressed substantially higher levels of multiple costimulatory molecules (CD83, CD86, CD80, CD11c, and CD40) than standard DCs (sDCs) and immature DCs, and their expression of CCR7 showed intermediate level. alphaDC1 secreted substantially higher (10-60 times) levels of IL-12p70 than sDCs. Although alphaDC1 and sDCs showed similar uptake of CLL cells, alphaDC1 induced much higher numbers (range, 2.4-38 times) of functional CD8+ T cells against CLL cells. The current demonstration that autologous tumor-loaded alphaDC1 are potent inducers of CLL-specific T cells helps to develop improved immunotherapies of CLL. PMID 18426971

Dendritic cells and T lymphocyte interactions in patients with lymphoid malignancies.
Juni 2008 | Pytlík, R; Hofman, P; Kideryová, L; Cervinková, P; Obrtlíková, P; Sálková, J; Trnený, M; Klener, P
Dendritic cell (DC) vaccination is an attractive approach to the treatment of patients with lymphoid tumors. To evaluate its feasibility, we have tested the functional properties of DC and T-lymphocytes in patients with treated and untreated chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). Healthy volunteers were used both as controls and as a source of cells for allogeneic mixed leukocyte reaction (MLR). In these reactions, dendritic cells from both untreated and treated patients were comparable to dendritic cells from healthy volunteers. In all the untreated patients studied, autologous dendritic cells promoted the survival and proliferation of both CD4 and CD8 lymphocytes (though the proliferation response was much better in the CD4 subset), whereas only 3 out of 5 treated patients were able to mount this response with CD4 lymphocytes and 4 out of 5 with CD8 lymphocytes. In 3 out of 5 untreated patients, pulsing of DCs with tetanus toxoid promoted a better CD4 response than was achieved with unpulsed DCs, while none of 5 treated patients had an additional response after pulsing with tetanus toxoid. None of patients studied, either treated or untreated, had a better CD8 response to pulsed DCs than to unpulsed ones. During CD4 lymphocyte proliferation, more CD4(+)CD25(hi) lymphocytes were generated in both treated and untreated patients than in healthy controls. Poor proliferation of cytotoxic cells and preferential proliferation of CD4(+)CD25(hi) T-regulatory cells in response to self and/or foreign antigens might be one of the mechanisms responsible for immunosuppression and impaired tumor surveillance in patients with lymphoid malignancies. PMID 17552881

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response.
Mai 2008 | Hus, I; Schmitt, M; Tabarkiewicz, J; Radej, S; Wojas, K; Bojarska-Junak, A; Schmitt, A; Giannopoulos, K; Dmoszyńska, A; Roliński, J
Recently, we described that vaccination with allogeneic dendritic cells (DCs) pulsed with tumor cell lysate generated specific CD8+ T cell response in patients with B-cell chronic lymphocytic leukemia (B-CLL). In the present study, the potential of autologous DCs pulsed ex vivo with tumor cell lysates to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated. Twelve patients at clinical stage 0-2 as per Rai were vaccinated intradermally up to eight times with a mean number of 7.4 x 10(6) DCs pulsed with B-CLL cell lysate. We observed a decrease of peripheral blood leukocytes and CD19+/CD5+ leukemic cells in five patients, three patients showed a stable disease and four patients progressed despite DC vaccination. A significant increase of specific cytotoxic CD8+ T lymphocytes against the leukemia-associated antigens RHAMM or fibromodulin was detected in four patients after DC vaccination. In patients with a clinical response, an increase of interleukin 12 (IL-12) serum levels and a decrease of the frequency of CD4+CD25(+)FOXP3+ T regulatory cells were observed. Taken together, the study demonstrated that vaccination with autologous DC in CLL patients is feasible and safe. Immunological and to some extend hematological responses could be noted, justifying further investigation on this immunotherapeutical approach. PMID 18323802

Vaccination with autologous non-irradiated dendritic cells in patients with bcr/abl+ chronic myeloid leukaemia.
Apr. 2007 | Westermann, Jörg; Kopp, Joachim; van Lessen, Antje; Hecker, Ann-Christine; Baskaynak, Gökben; le Coutre, Philipp; Döhner, Konstanze; Döhner, Hartmut; Dörken, Bernd; Pezzutto, Antonio
In chronic myeloid leukaemia (CML), dendritic cells (DC) and leukaemic cells share a common progeny, leading to constitutive expression of putative tumour antigens, such as bcr/abl, in DC. In this phase-I/II study, autologous DC were used as a vaccine in patients with chronic phase bcr/abl+ CML, who had not achieved an adequate cytogenetic response after treatment with alpha-interferon or imatinib. Ten patients were enrolled, DC were generated from peripheral blood monocytes and vaccination consisted of four subcutaneous injections of increasing numbers of DC (1-50 x 10(6) cells per injection) on days 1, 2, 8 and 21. Vaccination was feasible and safe. Improvement of the cytogenetic/molecular response, as detected by fluorescence in situ hybridization of peripheral blood mononuclear cells (PBMC), was possibly related to vaccination in four of 10 patients. In three of these patients, T cells recognizing leukaemia-associated antigens became detectable. The proliferative capacity of PBMC in response to autologous DC increased after vaccination in all evaluable patients. We conclude that vaccination with autologous, non-irradiated 'leukaemic' DC is feasible, safe and induces anti-leukaemic T-cell responses in some CML patients. DC vaccination might be useful in CML as postremission therapy, i.e. after treatment with tyrosine kinase inhibitors. PMID 17408402

Dendritic cell vaccines for leukemia patients.
März 2007 | Schmitt, Anita; Hus, Iwona; Schmitt, Michael
Dendritic cells are the most professional antigen-presenting cells to elicit T-cellular responses toward microbial agents and cancer cells. The graft-versus-leukemia effect observed after allogeneic stem cell transplantation strongly suggests that T lymphocytes play a major role in the rejection of leukemic cells. This graft-versus-leukemia effect might be enhanced through dendritic cell vaccination. The characterization of leukemia-specific antigens eliciting immune responses in the autologous host has prompted researchers and clinicians to broaden the spectrum of dendritic cell vaccines to hematological malignancies. Recently, the focus is on acute myeloid leukemia and chronic lymphocytic leukemia. This review summarizes data on the administration of autologous and allogeneic dendritic cells to leukemia patients as an interesting approach in cellular therapy of leukemias. PMID 17338648

Current status of immunotherapy in B cell malignancies.
Okt. 2006 | Kofler, D M; Mayr, C; Wendtner, C-M
Conventional treatment of hematologic malignancies mainly consists of chemotherapeutic agents or a combination of both, chemotherapy and monoclonal antibodies. Despite recent advances, chemotherapeutic treatments often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore the evaluation of novel therapeutic options is of great interest. B cell malignancies, in particularly follicular lymphomas, chronic lymphocytic leukemia and multiple myeloma, represent the most immune-responsive types of all human cancer. Several immunotherapeutic strategies are presently employed to combat these B-cell malignancies. Active immunotherapies include vaccination strategies with dendritic cells (DCs) and genetically-modified tumor cell preparations as well as DNA and protein vaccination. Most of these vaccines target the tumor-specific immunoglobulin idiotype and have already demonstrated some anti-lymphoma activity in early phase clinical trials while their definitive impact is evaluated in ongoing phase III randomized trials. In contrast to these active immunizations, T cells transduced with chimeric antigen receptors and donor leukocyte infusions (DLI) represent adoptive (passive) immunotherapies. Recent advances of gene transduction technologies enabled improvement of immunotherapeutic strategies based on genetic modification of malignant cells or adoptive T cells. Current early phase clinical trials are investigating the potential of these innovative approaches. At the moment it remains unclear if the novel immunotherapeutic strategies will be able to play a similar role in the treatment of B cell malignancies than the already established antibody-based immunotherapy. PMID 17073599

Generation of DC-based vaccine for therapy of B-CLL patients. Comparison of two methods for enriching monocytic precursors.
Aug. 2006 | Kokhaei, P; Adamson, L; Palma, M; Osterborg, A; Pisa, P; Choudhury, A; Mellstedt, H
The generation of Ag-loaded DC under good manufacturing practice (GMP) conditions is logistically challenging and further compounded when the starting precursors need to be purified from B-CLL patients who have overwhelming numbers of circulating B-CLL cells and decreased numbers of monocytes. PMID 16923607

Circulating myeloid dendritic cell directly isolated from patients with chronic myelogenous leukemia are functional and carry the bcr-abl translocation.
Juni 2006 | Orsini, Enrica; Calabrese, Elisabetta; Maggio, Roberta; Pasquale, Alessia; Nanni, Mauro; Trasarti, Stefania; Tafuri, Agostino; Guarini, Anna; Foa, Robert
Leukemic bcr-abl positive dendritic cells (DCs) are likely to be present in vivo in chronic myelogenous leukemia (CML) patients, but no data are available on their functional qualities. We analyzed the circulating BDCA-1+ myeloid DC compartment in 15 chronic phase CML patients. Phenotypic features of CML DCs were comparable with that of normal DCs, except for the CD80 and CD40 antigens, significantly under-represented in CML patients. Nonetheless, no differences were found between normal samples and leukemic DCs in the allostimulatory ability, as well as in the production of cytokines and polarization of T cell responses. CML DCs were analyzed by fluorescence in situ hybridization (FISH) and found positive for the bcr-abl translocation. However, when bcr-abl+ DCs were tested for their ability to stimulate an autologous T-cell response in vitro, we could not detect a specific recognition. We conclude that an apparently normal circulating DC compartment carrying the Ph+ chromosome can be identified in CML patients; however, these cells appear unable to trigger a protective anti-leukemic immune response in autologous T cells. PMID 16527350

Autologous dendritic cells pulsed with eluted peptide as immunotherapy for advanced B-cell malignancies.
Mai 2006 | Ritchie, David; Hermans, Ian; Yang, Jianping; Walton, Julie; Matthews, Kate; Carter, John; Findlay, Michael; Dady, Peter; Rawson, Pisana; Ronchese, Franca
We have studied the feasibility, safety and efficacy of vaccination with autologous dendritic cells pulsed with eluted peptide in patients with advanced low-grade B-cell malignancies. This study demonstrates that autologous dendritic cell vaccines can be successfully produced from patients with advanced disease and be delivered without significant toxicity. Furthermore, we have demonstrated immunological and clinical responses in two of ten patients treated. These results provide further evidence for the use of immunotherapy in the management of B-cell malignancies, but also suggest that sustained responses may only be possible in patients with low bulk disease early in the disease course. PMID 16690526

Imatinib mesylate minimally affects bcr-abl+ and normal monocyte-derived dendritic cells but strongly inhibits T cell expansion despite reciprocal dendritic cell-T cell activation.
Apr. 2006 | Boissel, Nicolas; Rousselot, Philippe; Raffoux, Emmanuel; Cayuela, Jean-Michel; Soulier, Jean; Mooney, Nuala; Charron, Dominique; Dombret, Hervé; Toubert, Antoine; Rea, Delphine
In chronic myeloid leukemia, bcr-abl+ monocytes provide a unique opportunity to generate dendritic cells (DC) expressing a broad spectrum of leukemic antigens, and bcr-abl+ DC vaccines may allow immunological eradication of leukemic cells persisting under treatment with the tyrosine kinase inhibitor imatinib. However, the efficiency of bcr-abl+ DC vaccines will critically depend on the absence of deleterious effects of bcr-abl and of imatinib on DC functions. We show that bcr-abl+ monocytes, devoid of contamination of CD14low granulocytic precursors, differentiate into DC with typical immunophenotypical and functional features, and bcr-abl transcription decreases simultaneously. During differentiation, imatinib induces a slight increase of DC apoptosis and prevents CD1a up-regulation in a dose-dependent manner in bcr-abl+ and normal monocyte-derived DC, but at most, 25% of DC fail to acquire CD1a. When DC maturation is induced in the presence of imatinib, bcr-abl+ and normal monocyte-derived DC up-regulate major histocompatibility complex and costimulatory molecules, CC chemokine receptor 7 and CD83. However, secretion of interleukin-12p70 is decreased in a dose-dependent manner. Imatinib exposure of bcr-abl+ and normal monocyte-derived DC during differentiation and maturation is not detrimental to T cell immunostimulatory functions of DC. In sharp contrast, imatinib, when added to DC-T cell cultures, profoundly suppresses DC-mediated T cell proliferation, despite reciprocal DC-T cell activation attested by up-regulation of CD25 on T cells and of CD86 on DC. Our findings demonstrate that T cells, not normal or bcr-abl+ monocyte-derived DC, are major targets for imatinib immunomodulatory effects. It can be envisioned already that imatinib-free windows will be required to enable vaccination-induced, leukemia-specific T cell expansion. PMID 16461746

Vaccine strategies to treat lymphoproliferative disorders.
Dez. 2005 | Radford, Kristen J; Vari, Frank; Hart, Derek N J
Lymphoproliferative disorders, including follicular lymphoma (FL), multiple myeloma (MM) and chronic lymphatic leukaemia (CLL), are slowly progressive malignancies which remain incurable despite advances in therapy. Harnessing the immune system to recognise and destroy tumours is a promising new approach to treating these diseases. Dendritic cells (DC) are unique antigen-presenting cells that play a central role in the initiation and direction of immune responses. DC loaded ex vivo with tumour-associated antigens and administered as a vaccine have already shown promise in early clinical trials for a number of lymphoproliferative disorders, but the need for improvement is widely agreed. Recent advances in the understanding of basic DC biology and lessons from early clinical trials have provided exciting new insights into the generation of anti-tumour immune responses and the design of vaccine strategies. In this review we provide an overview of our current understanding of DC biology and their function in patients with lymphoproliferative disorders. We discuss the current status of clinical trials and new approaches to exploit the antigen presenting capacity of DC to design vaccines of the future. PMID 16373232

Generation of in vitro B-CLL specific HLA class I restricted CTL responses using autologous dendritic cells pulsed with necrotic tumor lysate.
Dez. 2005 | Suresh, Kalathil; Fraser, Graeme; Scheid, Elizabeth; Leber, Brian; Gauldie, Jack; Foley, Ronan
New approaches in the treatment of chronic B lymphocytic leukemia (B-CLL) have led to improved clinical response rates. In this setting there is a need to evaluate novel therapeutic approaches that aim to eradicate minimal residual B-CLL cells following an initial favorable response. The use of tumor lysate-pulsed dendritic cells (DC) represents a potentially important development in the field of cancer vaccination. B-CLL is ideally suited for DC-based vaccination since tumor cells are readily available (peripheral blood) and both known (tumor idiotype) and unknown antigens can be exploited to stimulate immune responses. In the current study we have evaluated the ability to stimulate in vitro autologous immune reactivity against target B-CLL cells using autologous DCs pulsed with B-CLL tumor lysate. Enhanced specific T cell IFN-gamma expression was detected in 9 of 14 patients evaluated. These responses were specific with increased levels of IFN-gamma mRNA measurable in T-cells stimulated with NC-DCs and not unpulsed DCs or DCs pulsed with normal B cell lysate. CTLs demonstrating increased levels of IFN-gamma mRNA also lysed autologous B-CLL targets cells in an MHC class 1-restricted manner by (51)chromium release assay. Priming target leukemic cells with CD40 ligand and IL-4 enhanced CTL killing. The effector CTL displayed negligible toxicity against NK susceptible target cells K-562 and spared CD19(+)CD5(-) normal B cells in cytotoxicity assays. The specificity of the CTL response was confirmed by blocking HLA class I molecules and cold target inhibition assays. PMID 16321861

Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia.
Aug. 2005 | Hus, I; Roliński, J; Tabarkiewicz, J; Wojas, K; Bojarska-Junak, A; Greiner, J; Giannopoulos, K; Dmoszyńska, A; Schmitt, M
Recently, immunotherapies with allogeneic dendritic cells (DCs) pulsed with tumor antigens to generate specific T-cell responses have been tested in clinical trials for patients with solid tumors. This is the first report on a clinical vaccination study with DCs for patients with B-cell chronic lymphocytic leukemia (B-CLL). The potential of allogeneic DCs pulsed ex vivo with tumor cell lysates or apoptotic bodies to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated. Monocyte-derived DCs were obtained from unrelated healthy donors. Nine patients (clinical stage 0 and 1 according to Rai) were vaccinated five times with a mean number of 32 x 10(6) stimulated DCs administered intradermally once every 2-3 weeks. No signs of autoimmunity were detected, and only mild local skin reactions were noted. During the treatment period, we observed a decrease of peripheral blood leukocytes and CD19+/CD5+ leukemic cells. In one patient, a significant increase of specific cytotoxic T lymphocytes against RHAMM/CD168, a recently characterized leukemia-associated antigen, could be detected after DC vaccination. Taken together, the study demonstrated that DC vaccination in CLL patients is feasible and safe. Immunological and to some extent hematological responses could be noted, justifying further investigation on this immuno-therapeutical approach. PMID 15990861

Current status of vaccination therapy for leukemias.
Dez. 2004 | Reichardt, Volker L; Brossart, Peter
Therapeutic vaccination has challenged immunologists and hematologists for more than two decades and has developed from early animal studies to phase III trials in some human malignancies. Acute and chronic leukemias are common diseases in the clinical practice but few vaccination protocols have found their way to phase I trials in leukemias. Therapeutic vaccination protocols share the goal of inducing or augmenting leukemia-specific immune responses in the tumor-bearing host in order to potentially achieve therapeutical benefit in these otherwise fatal diseases. Major interest has been drawn to the use of dendritic cell (DC-based immunotherapy protocols relying on the unique properties of these most powerful antigen-presenting cells. With the bcr-abl oncogene a target of specific immunotherapy has been determined in chronic myelogenous leukemia (CML), while there is a limited information on leukemia-specific tumor antigens in acute myelogenous and lymphoblastic leukemias. This review will focus on immunotherapy development in acute and chronic leukemias and will discuss published clinical trials in acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and CML. PMID 15610663

Dendritic cell-based immunotherapy for the treatment of hematological malignancies.
Mai 2003 | Büchler, Tomas; Michalek, Jaroslav; Kovarova, Lucie; Musilova, Romana; Hajek, Roman
Dendritic cells (DCs) are professional antigen-presenting cells and are frequently used in current immunotherapy protocols. The administration of DCs loaded with tumor-associated proteins or peptides results in the induction of immune responses against different types of malignant cells. Methods for large-scale generation of DCs in a sufficient quality and quantity have permitted their use in clinical experiments. DC-based vaccines have already shown promise in follicular non-Hodgkin's lymphoma, and to some extent, in other hematological malignancies. Several strategies have been developed to boost their potency as a new and relatively non-toxic treatment modality. Our review focuses on clinical trials using DCs in the treatment of hematologic malignancies and on recent studies of the immunophenotype, development, and maturation of DCs may have an important impact on designing DC-based antitumor vaccines. PMID 12745659