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Immunotherapy for the treatment of multiple myeloma.
März 2017 | Jung, Sung-Hoon; Lee, Hyun-Ju; Vo, Manh-Cuong; Kim, Hyeoung-Joon; Lee, Je-Jung
Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade. Genetically engineered T cells, such as chimeric antigen receptor T cells or T cell receptor-engineered T cells, have also shown encouraging results in recent clinical studies of patients with MM. In this paper, we discuss recent progress in immunotherapy for the treatment of MM. PMID 28259300

Targeting the immune niche within the bone marrow microenvironment: The rise of immunotherapy in Multiple Myeloma.
Feb. 2017 | Podar, Klaus; Jäger, D
Multiple Myeloma (MM) cells inhibit the development of an effective anti-MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive pro-inflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance. The usefulness of immunotherapies in MM patients has first been supported by the identification of the graft-versus-myeloma effect in the context of allogeneic bone marrow (BM) transplantation. Subsequently, the inclusion of thalidomide and its derivatives, the Immunomodulatory Drugs (IMiDs) as well as of (immuno) proteasome inhibitors into MM regimens dramatically improved MM patients' outcome during the last 15 years. Despite these unprecedented therapeutic advances MM remains an incurable disease. Novel immunotherapeutic approaches aim to restore the balance within the immunologic niche of the MM BM microenvironment. Indeed, the inclusion of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor-engineered (CAR) T cells, genetically engineered T cells, and vaccination, dendritic cell- based cancer vaccines in particular, into existing regimens is likely to significantly improve MM patient outcome in the near future. PMID 28201977

A phase I clinical study of autologous dendritic cell therapy in patients with relapsed or refractory multiple myeloma.
Jan. 2017 | Jung, Sung-Hoon; Lee, Hyun-Ju; Lee, Youn-Kyung; Yang, Deok-Hwan; Kim, Hyeoung-Joon; Rhee, Joon Haeng; Emmrich, Frank; Lee, Je-Jung
Cellular immunotherapy is emerging as a potential immunotherapeutic modality in multiple myeloma (MM). We have developed potent immunotherapeutic agent (VAX-DC/MM) generated by dendritic cells (DCs) loaded with autologous myeloma cells irradiated with ultraviolet B. In this study, we evaluated the safety and efficacy of VAX-DC/MM in patients with relapsed or refractory MM. This trial enrolled relapsed or refractory MM patients who had received both thalidomide- and bortezomib-based therapies. Patients received the intradermal VAX-DC/MM injection every week for 4 weeks. Patients were treated with 5 × 106 or 10 × 106 cells, with nine patients treated at a higher dose. The median time from diagnosis to VAX-DC/MM therapy was 56.6 months (range, 28.5-130.5). Patients had received a median of five prior treatments, and 75% had received autologous stem cell transplantation. VAX-DC therapy was well-tolerated, and the most frequent adverse events were local reactions at the injection site and infusion-related reactions. In seven of nine patients who received 10×106 cells, an immunological response (77.8%) was observed by interferon-gamma ELISPOT assay or a mixed lymphocyte reaction assay for T-cell proliferation. The clinical benefit rate was 66.7% including one (11.1%) with minor response and five (55.6%) with stable disease; three (33.3%) patients showed disease progression. In conclusion, VAX-DC/MM therapy was well-tolerated, and had disease-stabilizing activity in heavily pretreated MM cases. Further studies are needed to increase the efficacy of VAX-DC/MM in patients with MM. PMID 28088784

Lenalidomide enhances the function of dendritic cells generated from patients with multiple myeloma.
Nov. 2016 | Vo, Manh-Cuong; Anh-NguyenThi, Truc; Lee, Hyun-Ju; Nguyen-Pham, Thanh-Nhan; Jaya Lakshmi, Thangaraj; Jung, Sung-Hoon; Kim, Hyeoung-Joon; Lee, Je-Jung
Lenalidomide (LEN) has been used as an immunomodulatory drug with direct and indirect anti-tumor effects. In this study, we evaluated the effect of LEN on the differentiation, maturation, and function of dendritic cells (DCs) in patients with multiple myeloma in vitro. Various doses of LEN were added after the monocytes had differentiated into immature DCs and were activated into mature DCs. LEN (5 μg/mL) was the optimal concentration to promote differentiation and maturation of DCs. Immature DCs treated with LEN exhibited enhanced endocytic capacity. Mature DCs treated with LEN produced higher levels of interleukin-12p70, possessed stronger allogeneic T-cell stimulation capacity, reduced the number of suppressor cells, and generated antigen-specific cytotoxic T lymphocytes more potently compared with control DCs. These results suggest that LEN enhanced the function of DCs generated from patients with multiple myeloma by stimulating the capacity of allogeneic T cells, inhibiting the generation of immunosuppressive cells, inducing naïve T cells toward Th1 polarization, and generating potent myeloma-specific cytotoxic T lymphocytes. PMID 27889516

Role of Immunotherapy in Targeting the Bone Marrow Microenvironment in Multiple Myeloma: An Evolving Therapeutic Strategy.
Nov. 2016 | Chung, Clement
Multiple myeloma (referred to henceforth as myeloma) is a B-cell malignancy characterized by unregulated growth of plasma cells in the bone marrow. The treatment paradigm for myeloma underwent significant evolution in the last decade, with an improved understanding of the pathogenesis of the disease as well as the development of therapeutic agents that target not only the tumor cells but also their microenvironment. Despite these therapeutic advances, the prognosis of patients with relapsed or refractory myeloma remains poor. Accordingly, a need exists for new therapeutic avenues that can overcome resistance to current therapies and improve survival outcomes. In addition, myeloma is associated with progressive immune dysregulation, with defects in T-cell immunity, natural killer cell function, and the antigen-presenting capacity of dendritic cells, resulting in a tumor microenvironment that promotes disease tolerance and progression. Together, the immunosuppressive microenvironment and oncogenic mutations activate signaling networks that promote myeloma cell survival. Immunotherapy incorporates novel treatment options (e.g., monoclonal antibodies, antibody-drug conjugates, chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, bispecific antibodies, and tumor vaccines) either alone or in combination with existing lines of therapies (e.g., immunomodulatory agents, proteasome inhibitors, and histone deacetylase inhibitors) to enhance the host anti myeloma immunity within the bone marrow microenvironment and improve clinical response. Following the U.S. Food and Drug Administration approval of daratumumab and elotuzumab in 2015, more immunotherapeutic agents are expected to be become available as valuable treatment options in the near future. This review provides a basic understanding of the role of immunotherapy in modulating the bone marrow tumor microenvironment and its role in the treatment of myeloma. Clinical efficacy and safety of recently approved therapeutic monoclonal antibodies (daratumumab, elotuzumab) are discussed, along with the therapeutic potential of emerging immunotherapies (antibody-drug conjugates, chimeric antigen receptor T-cell therapy, tumor vaccines, and immune checkpoint inhibitors). PMID 27870103

Efficacy of host-dendritic cell vaccinations with or without minor histocompatibility antigen loading, combined with donor lymphocyte infusion in multiple myeloma patients.
Nov. 2016 | Oostvogels, R; Kneppers, E; Minnema, M C; Doorn, R C; Franssen, L E; Aarts, T; Emmelot, M E; Spierings, E; Slaper-Cortenbach, I; Westinga, K; Goulmy, E; Lokhorst, H M; Mutis, T
Donor lymphocyte infusions (DLI) can induce durable remissions in multiple myeloma (MM) patients, but this occurs rather infrequently. As the graft-versus-tumor (GvT) effect of DLI depends on the presence of host-dendritic cells (DCs), we tested in a phase I/II trial whether the efficacy of DLI could be improved by simultaneous vaccination with host-DCs. We also analyzed the possibility of further improving the GvT effect by loading the DCs with peptides of mismatched hematopoietic cell-specific minor histocompatibility antigens (mHags). Fifteen MM patients not responding to a first DLI were included. Eleven patients could be treated with a second equivalent dose DLI combined with DC vaccinations, generated from host monocytes (moDC). For four patients, the DC products did not meet the quality criteria. In four of the treated patients the DCs were loaded with host mHag peptides. Toxicity was limited and no acute GvHD occurred. Most patients developed objective anti-host T-cell responses and in one patient a distinct mHag-specific T-cell response accompanied a temporary clinical response. These findings confirm that DLI combined with host-DC vaccination, either unloaded or loaded with mHag peptides, is feasible, safe and capable of inducing host-specific T-cell responses. The limited clinical effects may be improved by developing more immunogenic DC products or by combining this therapy with immune potentiating modalities like checkpoint inhibitors. PMID 27841858

Vaccination of multiple myeloma: Current strategies and future prospects.
Okt. 2015 | Allegra, Alessandro; Penna, Giuseppa; Innao, Vanessa; Greve, Bruna; Maisano, Valerio; Russo, Sabina; Musolino, Caterina
Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of dendritic cell/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs may synergize with immunotherapies. The task ahead is to evaluate these approaches in appropriate clinical settings, and to couple them with strategies to overcome mechanisms of immunoparesis as a means to induce more robust clinically significant immune responses. PMID 26123319

Lenalidomide Synergistically Enhances the Effect of Dendritic Cell Vaccination in a Model of Murine Multiple Myeloma.
Sep. 2015 | Nguyen-Pham, Thanh-Nhan; Jung, Sung-Hoon; Vo, Manh-Cuong; Thanh-Tran, Huong-Thi; Lee, Youn-Kyung; Lee, Hyun-Ju; Choi, Nu-Ri; Hoang, My-Dung; Kim, Hyeoung-Joon; Lee, Je-Jung
We investigated the efficacy of lenalidomide (LEN) in combination with dendritic cell (DC) vaccination in the MOPC-315 murine myeloma model. After tumor growth, LEN was injected intraperitoneally for 4 consecutive days in combination with DC vaccination. The combination of LEN and vaccination efficiently inhibited tumor growth compared with the single agents alone. A cytotoxic assay revealed that the anticancer effects of DC vaccination plus LEN involved not only generation of antigen-specific cytotoxic T lymphocytes but also NK cells. Vaccinated mice had reduced numbers of suppressor cells, including both myeloid-derived suppressor cells and regulatory T cells, in the spleen. The proportions of CD4 and CD8 T cells increased in the spleen, and a Th1 cytokine (interferon-γ) rather than a Th2 cytokine (interleukin-10) was synthesized in response to tumor antigens. LEN enhanced the innate immune response by modulating NK cell numbers and function. In addition, LEN reduced the production levels of angiogenesis-inducing factors in tumor-bearing mice. Together, these results suggest that a combination of LEN and DC vaccination may synergistically enhance anticancer immunity in the murine myeloma model, by inhibiting immunosuppressor cells and stimulating effector cells, as well as effectively polarizing the Th1/Th2 balance in favor of a Th1-specific immune response. PMID 26325377

Dendritic Cell-Based Cancer Immunotherapy against Multiple Myeloma: From Bench to Clinic.
Apr. 2015 | Hoang, My-Dung; Jung, Sung-Hoon; Lee, Hyun-Ju; Lee, Youn-Kyung; Nguyen-Pham, Thanh-Nhan; Choi, Nu-Ri; Vo, Manh-Cuong; Lee, Seung-Shin; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon; Lee, Je-Jung
Although the introduction of stem cell transplantation and novel agents has improved survival, multiple myeloma (MM) is still difficult to cure. Alternative approaches are clearly needed to prolong the survival of patients with MM. Dendritic cell (DC) therapy is a very promising tool immunologically in MM. We developed a method to generate potent DCs with increased Th1 polarization and migration ability for inducing strong myeloma-specific cytotoxic T lymphocytes. In this review, we discuss how the efficacy of cancer immunotherapy using DCs can be improved in MM. PMID 25914874

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 cell-tumor fusion cells in multiple myeloma patients: a promising strategy?
Okt. 2013 | Garcia-Marquez, Maria A; Shimabukuro-Vornhagen, Alexander; Theurich, Sebastian; von Bergwelt-Baildon, Michael
Evaluation of: Rosenblatt J, Avivi I, Vasir B et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin. Cancer Res. 19(13), 3640-3648 (2013). Recently, dendritic cell (DC)-tumor fusion vaccines have been explored as a promising therapeutic approach for the treatment of cancer. Fusion vaccines offer several advantages that distinguish them from other DC-based vaccines. In this Phase II clinical trial, Rosenblatt et al. demonstrate that repeated immunization with a DC-tumor fusion vaccine after autologous stem cell transplantation induces myeloma-specific immunity and improves clinical response. They showed that generation of an autologous fusion vaccine with dendritic and myeloma cells was feasible and that vaccination was well tolerated without grade 3-4 toxicities. The results of this study suggest that the time after autologous stem cell transplantation represents a unique setting for cancer vaccination and that combining autologous stem cell transplantation with post-transplant vaccination increases the immunogenicity. PMID 24088074

Immunogenicity of dendritic cells pulsed with MAGE3, Survivin and B-cell maturation antigen mRNA for vaccination of multiple myeloma patients.
Juli 2013 | Hobo, Willemijn; Strobbe, Leonie; Maas, Frans; Fredrix, Hanny; Greupink-Draaisma, Annelies; Esendam, Ben; de Witte, Theo; Preijers, Frank; Levenga, Henriëtte; van Rees, Bas; Raymakers, Reinier; Schaap, Nicolaas; Dolstra, Harry
The introduction of autologous stem cell transplantation (SCT) and novel drugs has improved overall survival in multiple myeloma (MM) patients. However, minimal residual disease (MRD) remains and most patients eventually relapse. Myeloma plasma cells express tumor-associated antigens (TAA), which are interesting targets for immunotherapy. In this phase 1 study, we investigated the safety and immunological effects of TAA-mRNA-loaded dendritic cell (DC) vaccination for treatment for MRD in MM after SCT. Mature monocyte-derived DCs were pulsed with keyhole limpet hemocyanin (KLH) and electroporated with MAGE3, Survivin or B-cell maturation antigen (BCMA) mRNA. Twelve patients were vaccinated three times with intravenous (5-22 × 10(6) DCs) and intradermal vaccines (4-11 × 10(6) DCs), at biweekly intervals. Immunological responses were monitored in blood and delayed-type hypersensitivity (DTH) biopsies. All patients developed strong anti-KLH T-cell responses, but not KLH antibodies. In 2 patients, vaccine-specific T cells were detected in DTH biopsies. In one patient, we found MAGE3-specific CD4(+) and CD8(+) T cells, and CD3(+) T cells reactive against BCMA and Survivin. In the other patient, we detected low numbers of MAGE3 and BCMA-reactive CD8(+) T cells. Vaccination was well tolerated with limited toxicity. These findings illustrate that TAA-mRNA-electroporated mature DCs are capable of inducing TAA-T-cell responses in MM patients after SCT. PMID 23728352

Optimizing dendritic cell vaccine for immunotherapy in multiple myeloma: tumour lysates are more potent tumour antigens than idiotype protein to promote anti-tumour immunity.
Okt. 2012 | Hong, S; Li, H; Qian, J; Yang, J; Lu, Y; Yi, Q
Dendritic cells (DCs) are the most potent antigen-presenting cells and are the mediators of T cell immunity. Many investigators have explored the potential of using DCs as a vaccine for tumour-derived antigens in immunotherapy of B cell malignancies, and the results have been disappointing. To search for better tumour antigens to improve the efficacy of DC-based immunotherapy in myeloma, we evaluated and compared the efficacy of the vaccination of DCs pulsed with idiotype (Id) or tumour lysate in the 5TGM1 myeloma mouse model. Our results showed that Id- or tumour lysate-pulsed DC vaccines protected mice efficiently against developing myeloma, retarded tumour growth, induced tumour regression against established tumour and protected surviving mice from tumour rechallenge. The therapeutic responses were associated with an induction of strong humoral immune responses, including anti-Id or anti-lysate antibodies, and cellular immune responses including myeloma-specific CD8(+) cytotoxic T lymphocytes, CD4(+) type 1 T helper cells and memory T cells in mice receiving Id- or tumour lysate-pulsed DC vaccines. In addition, our studies showed that tumour lysate-pulsed DCs were more potent vaccines than the Id-pulsed DC vaccines to promote anti-tumour immunity in the model. This information will be important for improving the strategies of DC-based immunotherapy for patients with myeloma and other B cell tumours. PMID 23039887

Immunotherapy using dendritic cells against multiple myeloma: how to improve?
Apr. 2012 | Nguyen-Pham, Thanh-Nhan; Lee, Yoon-Kyung; Kim, Hyeoung-Joon; Lee, Je-Jung
Multiple myeloma (MM) is a good target disease in which one can apply cellular immunotherapy, which is based on the graft-versus-myeloma effect. This role of immune effector cells provides the framework for the development of immune-based therapeutic options that use antigen-presenting cells (APCs) with increased potency, such as dendritic cells (DCs), in MM. Current isolated idiotype (Id), myeloma cell lysates, myeloma dying cells, DC-myeloma hybrids, or DC transfected with tumor-derived RNA has been used for immunotherapy with DCs. Immunological inhibitory cytokines, such as TGF-β, IL-10, IL-6 and VEGF, which are produced from myeloma cells, can modulate antitumor host immune response, including the abrogation of DC function, by constitutive activation of STAT3. Therefore, even the immune responses have been observed in clinical trials, the clinical response was rarely improved following DC vaccinations in MM patients. We are going to discuss how to improve the efficacy of DC vaccination in MM. PMID 22481968

Cellular immunotherapy using dendritic cells against multiple myeloma.
Apr. 2012 | Nguyen-Pham, Thanh-Nhan; Lee, Youn-Kyung; Lee, Hyun-Ju; Kim, Mi-Hyun; Yang, Deok-Hwan; Kim, Hyeoung-Joon; Lee, Je-Jung
Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic tool to treat multiple myeloma (MM). DC-based idiotype vaccination was recently suggested to induce idiotype-specific immune responses in MM patients. However, the clinical results so far have been largely disappointing, and the clinical effectiveness of such vaccinations in MM still needs to be demonstrated. DC-based therapies against MM may need to be boosted with other sources of tumor-associated antigens, and potent DCs should be recruited to increase the effectiveness of treatment. DCs with both high migratory capacity and high cytokine production are very important for effective DC-based cancer vaccination in order to induce high numbers of Th1-type CD4(+) T cells and CD8(+) cytotoxic T lymphocytes. The tumor microenvironment is also important in the regulation of tumor cell growth, proliferation, and the development of therapeutic resistance after treatment. In this review, we discuss how the efficacy of DC vaccination in MM can be improved. In addition, novel treatment strategies that target not only myeloma cells but also the tumor microenvironment are urgently needed to improve treatment outcomes. PMID 22479274

Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma.
Jan. 2011 | Rosenblatt, Jacalyn; Vasir, Baldev; Uhl, Lynne; Blotta, Simona; Macnamara, Claire; Somaiya, Poorvi; Wu, Zekui; Joyce, Robin; Levine, James D; Dombagoda, Dilani; Yuan, Yan Emily; Francoeur, Karen; Fitzgerald, Donna; Richardson, Paul; Weller, Edie; Anderson, Kenneth; Kufe, Donald; Munshi, Nikhil; Avigan, David
We have developed a tumor vaccine in which patient-derived myeloma cells are chemically fused with autologous dendritic cells (DCs) such that a broad spectrum of myeloma-associated antigens are presented in the context of DC-mediated costimulation. We have completed a phase 1 study in which patients with multiple myeloma underwent serial vaccination with the DC/multiple myeloma fusions in conjunction with granulocyte-macrophage colony-stimulating factor. DCs were generated from adherent mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α and fused with myeloma cells obtained from marrow aspirates. Vaccine generation was successful in 17 of 18 patients. Successive cohorts were treated with 1 × 10(6), 2 × 10(6), and 4 × 10(6) fusion cells, respectively, with 10 patients treated at the highest dose level. Vaccination was well tolerated, without evidence of dose-limiting toxicity. Vaccination resulted in the expansion of circulating CD4 and CD8 lymphocytes reactive with autologous myeloma cells in 11 of 15 evaluable patients. Humoral responses were documented by SEREX (Serologic Analysis of Recombinant cDNA Expression Libraries) analysis. A majority of patients with advanced disease demonstrated disease stabilization, with 3 patients showing ongoing stable disease at 12, 25, and 41 months, respectively. Vaccination with DC/multiple myeloma fusions was feasible and well tolerated and resulted in antitumor immune responses and disease stabilization in a majority of patients. PMID 21030562

Induction of cellular immune responses in patients with stage-I multiple myeloma after vaccination with autologous idiotype-pulsed dendritic cells.
Dez. 2010 | Röllig, Christoph; Schmidt, Christian; Bornhäuser, Martin; Ehninger, Gerhard; Schmitz, Marc; Auffermann-Gretzinger, Susanne
Idiotype vaccines have shown both biological efficacy and clinical benefit in lymphoma. Circulating idiotype proteins (Id) in multiple myeloma patients offer a suitable target for immunotherapy. So far, specific immune responses after vaccination with Ids have been evaluated mostly in advanced myeloma. We explored the potential of dendritic-cell (DC)-based immunotherapy in 9 patients with stage-I disease. Mature monocyte-derived Id-pulsed DCs and keyhole limpet hemocyanin (KLH) were administered at dose levels between 2 and 20×10⁶ cells. Patients received 5 immunizations every 4 weeks. A median number of 6.8×10⁶ DCs were administered per vaccination. Five out of 9 patients (56%) developed Id-specific T cells as showed in proliferation assays and 8 out of 9 patients (89%) showed specific T-cell-mediated cytokine release after Id stimulation. The cytokine-secretion did not show a distinct Th1-type or Th2-type pattern. The M protein dropped slightly in 3 out of 9 patients. We could show that DC-based Id vaccination is a feasible way of inducing specific T-cell responses in stage-I myeloma patients. Further trials are needed to increase the rate of responses and to define the role of DC-based vaccination in the era of new pharmacologic therapies. PMID 21150718

Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T-cell immune responses in patients.
Aug. 2010 | Yi, Qing; Szmania, Susann; Freeman, John; Qian, Jianfei; Rosen, Nancy A; Viswamitra, Sanjaya; Cottler-Fox, Michele; Barlogie, Bart; Tricot, Guido; van Rhee, Frits
Vaccination with idiotype (Id) protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id- and keyhole limpet haemocyanin (KLH)-pulsed, CD40 ligand-matured DCs administered intranodally. Nine patients with smouldering or stable myeloma without treatment were enrolled and DC vaccines were administered at weekly intervals for a total of four doses. Following vaccination, all patients mounted Id-specific gamma-interferon T-cell response. Interleukin-4 response was elicited in two, and skin delayed-type hypersensitivity reaction occurred in seven patients. More importantly, Id-specific cytotoxic T-cell responses were also detected in five patients. Most if not all patients mounted a positive T-cell response to KLH following vaccination. At 1-year follow-up, six of the nine patients had stable disease, while three patients had slowly progressive disease even during the vaccination period. At 5-year follow-up, four of the six patients continued with stable disease. No major side effects were noted. In summary, intranodal administration of Id-pulsed CD40 ligand-matured DCs was able to induce Id-specific T and B-cell responses in patients. Current efforts are geared towards breaking tumour-mediated immune suppression and improving clinical efficacy of this immunotherapy. PMID 20618329

Generation of myeloma-specific T cells using dendritic cells loaded with MUC1- and hTERT- drived nonapeptides or myeloma cell apoptotic bodies.
Juni 2010 | Ocadlikova, D; Kryukov, F; Mollova, K; Kovarova, L; Buresdova, I; Matejkova, E; Penka, M; Buchler, T; Hajek, R; Michalek, J
Dendritic cells are able to induce anti-tumor immune responses by presenting tumor-specific antigens to T-lymphocytes. Various tumor-associated antigens have been studied in multiple myeloma in an effort to find a strong antigen capable of generating clinically meaningful responses in vaccinated patients. The aim of our study was to generate myeloma-specific cytotoxic T lymphocytes in vitro using dendritic cells loaded with peptide antigens or apoptotic bodies. Peripheral blood mononuclear cells from HLA-A2+ healthy donors were used for isolation and culture of dendritic cells (DCs) and T lymphocytes. DCs were loaded with hTERT- and MUC1-derived nonapeptides or apoptotic bodies from myeloma cells. Repeated stimulation of T lymphocytes led to their activation characterized by interferon-gamma production. Activated T lymphocytes were separated immunomagnetically and expanded in vitro. Specific cytotoxicity of the expanded T lymphocytes was tested against a myeloma cell line. There was evidence of cytotoxicity for all three types of antigens used for T lymphocyte priming and expansion. No statistically significant differences were observed in T lymphocyte cytotoxicity for any of the antigens. We present a method for the priming and expansion of myeloma-specific T lymphocytes using dendritic cells loaded with different types of tumor antigens. Cytotoxic T lymphocytes and/or activated dendritic cells generated by the described methods can be applied for cellular immunotherapy against multiple myeloma and other malignancies. PMID 20568900

Partial T cell-depleted allogeneic stem cell transplantation following reduced-intensity conditioning creates a platform for immunotherapy with donor lymphocyte infusion and recipient dendritic cell vaccination in multiple myeloma.
Feb. 2010 | Levenga, Henriëtte; Schaap, Nicolaas; Maas, Frans; Esendam, Bennie; Fredrix, Hanny; Greupink-Draaisma, Annelies; de Witte, Theo; Dolstra, Harry; Raymakers, Reinier
Allogeneic stem cell transplantation (SCT) in multiple myeloma (MM) may induce a curative graft-versus-myeloma (GVM) effect. Major drawback in unmanipulated reduced-intensity conditioning (RIC) SCT is the risk of severe and longstanding graft-versus-host-disease (GVHD). This study demonstrates that transplantation with a partial T cell-depleted graft creates a platform for boosting GVM immunity by preemptive donor lymphocyte infusion (DLI) and recipient dendritic cell (DC) vaccination, with limited GVHD. All 20MM patients engrafted successfully. Chimerism analysis in 19 patients evaluable at 3 months revealed that 7 patients were complete donor, whereas 12 patients were mixed chimeric. Grade II acute GVHD (aGVHD) occurred in 7 patients (35%) and only 4 patients (21%) developed chronic GVHD (cGVHD). Fourteen patients received posttransplantation immunotherapy, 8 preemptive DLI, 5 patients both DLI and DC vaccination, and 1 patient DC vaccination only. DC vaccination was associated with limited toxicity, and none of these patients developed GVHD. Importantly, overall treatment-related mortality (TRM) at 1 year was low (10%). Moreover, the overall survival (OS) is 84% with median follow-up of 27 months, and none of the patients died from progressive disease. These findings illustrate that this novel approach is associated with limited GVHD and mortality, thus creating an ideal platform for adjuvant immunotherapy. PMID 19835972

[Dendritic cell-based immunotherapy for multiple myeloma -- review].
Juni 2009 | Zhu, Xue-Jun; He, Long; Sun, Xue-Mei
Patients with multiple myeloma (MM) have increased constantly in recent years, but treatment for patients with MM is currently unsatisfactory and it is necessary to develop new complementary therapies. Dendritic cells (DCs) are specialized antigen-presenting cells capable of initiating and regulating immune responses. Vaccination with tumor antigen-pulsed DCs has shown to be safe and possesses therapeutic effect against many tumors. In this review, the various types of MM-associated antigens and clinical trials on DC-based immunotherapy in MM are summarized, the development of DC immunotherapy for MM patients in future trials is discussed. PMID 19549416

[The preparation of anticancer vaccine for patients with multiple myeloma on the base of monoclonal immunoglobulin loaded dendritic cells].
Juni 2009 | Ocadlíková, D; Zahradová, L; Kovárová, L; Smejkalová, J; Pour, L; Vidláková, P; Kyjovská, D; Moravcová, J; Rycová, M; Novotná, H; Jelínková, I; Penka, M; Michálek, J; Hájek, R
On June 2006, phase II clinical trial focused on anticancer vaccination of multiple myeloma patients, was started. On September 2007, the immune and clinical response evaluation of first four patients was finished.The anticancer vaccine contained dendritic cells loaded with monoclonal immunoglobulin produced by myeloma cells. PMID 19522376

Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma.
Jan. 2009 | Cohen, Sharon; Haimovich, Joseph; Hollander, Nurit
Multiple myeloma is an incurable plasma cell malignancy. Immunotherapy in myeloma patients had limited success to date. We have previously demonstrated that dendritic cells (DCs) pulsed with autologous Ig Id induced Id-reactive CD8(+) T cells and protection against a myeloma tumor challenge. In this work, we studied the therapeutic efficacy of chemotherapy combined with different formulations of DC-based vaccines in mice bearing large plasma cell tumors. The comparative study demonstrated that s.c. injection of DCs loaded with Id coupled to keyhole limpet hemocyanin, s.c. injection of DCs loaded with irradiated tumor cells, and intratumoral injection of naive DCs were similarly effective in mediating tumor regression and long-term survival. However, whereas the Id-keyhole limpet hemocyanin-DC vaccine was inefficient against myeloma cells that lost expression of the Ig H chain, intratumoral injection of naive DCs and s.c. injection of DCs loaded with irradiated tumor cells were highly effective against cells producing L chains only. This may be of particular importance for patients with L chain myeloma. Given that T cells respond primarily to peptides derived from H chain CDRs, attempts to treat L chain disease with myeloma protein-pulsed DCs may be futile. Vaccination with tumor cell-loaded DCs may, however, induce an effective antitumor response. PMID 19155516

Immunotherapy of hematological malignancies using dendritic cells.
Apr. 2008 | Van de Velde, Ann L R; Berneman, Zwi N; Van Tendeloo, Viggo F I
The arsenal of therapeutic weapons against hematological malignancies is constantly growing. Unravelling the secrets of tumor immunobiology has allowed researchers to manipulate the immune system in order to stimulate tumor immunity or to bypass tumor-induced immunosuppression. An area of great interest is active specific immunotherapy where dendritic cell (DC)-based therapeutic vaccines for cancer have definitely grabbed the spotlight. DC are intensively investigated as cellular adjuvants to harness the immune system to fight off cancer by augmenting the number and effector functions of tumor-specific CD8+ cytotoxic T lymphocytes. In the present review we present a comprehensive synopsis and an update of the use of DC in hematological malignancies. In the future, more basic research as well as more clinical trials are warranted to fully establish the value of DC vaccination as an adjuvant therapy for modern hematological oncology. PMID 18390412

Phase I/II clinical trial of sequential subcutaneous and intravenous delivery of dendritic cell vaccination for refractory multiple myeloma using patient-specific tumour idiotype protein or idiotype (VDJ)-derived class I-restricted peptides.
Okt. 2007 | Curti, Antonio; Tosi, Patrizia; Comoli, Patrizia; Terragna, Carolina; Ferri, Elisa; Cellini, Claudia; Massaia, Massimo; D'Addio, Alessandra; Giudice, Valeria; Di Bello, Cristiana; Cavo, Michele; Conte, Roberto; Gugliotta, Gabriele; Baccarani, Michele; Lemoli, Roberto M
Fifteen multiple myeloma (MM) patients who had failed maintenance therapy after tandem autologous stem cell transplantation underwent anti-idiotype (Id) vaccination with dendritic cells (DCs). CD14(+)-derived DCs were loaded with the autologous Id as whole protein (=6) or Id-derived class I-restricted peptides (=9) and keyhole limpet hemocyanin (KLH). Vaccination consisted of three subcutaneous (sc) and two intravenous injections of increasing DC doses at 2 weeks interval. DC therapy was well tolerated. Most patients developed both humoral and T-cell responses to KLH, suggesting immunocompetence. Eight of 15 patients developed an Id-specific T-cell proliferative response, 8/15 increased interferon-gamma-secreting T cells and 4/15 showed an Id-positive delayed-type hypersensitivity test. Anti-Id cytotoxic T-lymphocyte precursors increased after DC vaccination in 2/2 evaluable patients. A more robust T-cell response was observed after sc DC injections and increased Id-specific T-cell proliferation was found up to 1 year after vaccination. VDJ-derived peptides were as effective as the whole protein in stimulating T-cell responses. Clinically, 7/15 patients have stable disease after a median follow-up of 26 months, one patient achieved durable partial remission after 40 months, and seven patients progressed. In conclusion, sc injections of cryopreserved Id-pulsed DCs were safe and, in contrast with intravenous administrations, induced anti-MM T-cell responses. PMID 17910631

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

Production of myeloid dendritic cells (DC) pulsed with tumor-specific idiotype protein for vaccination of patients with multiple myeloma.
Juni 2006 | Guardino, A E; Rajapaksa, R; Ong, K H; Sheehan, K; Levy, R
Immunotherapy of cancer with DC vaccines has produced encouraging results in clinical trials. Antigen (Ag)-pulsed DC have elicited CD4+ and CD8+ T-cell immunity and tumor regression in humans. However, there is no standard method of DC production. The DC phenotype, number and Ag-loading process used in these studies have varied, making comparisons between trials difficult. PMID 16793736

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

Combined vaccination with idiotype-pulsed allogeneic dendritic cells and soluble protein idiotype for multiple myeloma patients relapsing after reduced-intensity conditioning allogeneic stem cell transplantation.
Dez. 2005 | Bendandi, Maurizio; Rodríguez-Calvillo, Mercedes; Inogés, Susana; López-Díaz de Cerio, Ascensión; Pérez-Simón, José Antonio; Rodríguez-Caballero, Arancha; García-Montero, Andres; Almeida, Julia; Zabalegui, Natalia; Giraldo, Pilar; San Miguel, Jesús; Orfao, Alberto
To combine the use of idiotype-pulsed allogeneic dendritic cells (alloDC) and soluble protein Id conjugated with KLH (Id-KLH) in a vaccine strategy for multiple myeloma (MM). PMID 16321824

Dendritic cells in clinical trials for multiple myeloma.
Dez. 2004 | Reichardt, Volker L; Brossart, Peter
Due to the existence of the truly specific tumor antigen idiotype in multiple myeloma and based on encouraging data from dendritic cell vaccinated B-cell non-Hodgkin's lymphoma (NHL) patients, dendritic cell-based vaccination was first initiated in myeloma patients in 1995. This overview will summarize published and ongoing clinical trials in patients with multiple myeloma who are treated with idiotype-based dendritic cell (Id/DC) vaccination. All groups of investigators have found that Id/DC vaccination of multiple-myeloma patients is feasible and that myeloma-specific immunity can be induced in heavily pretreated individuals. In future trials, new dendritic cell-based immunization strategies will be investigated based on techniques like RNA transfection of DC. PMID 15585918

Generation of dendritic cells from positively selected CD14+ monocytes for anti-tumor immunotherapy.
Sep. 2004 | Curti, Antonio; Isidori, Alessandro; Ferri, Elisa; Terragna, Carolina; Neyroz, Paolo; Cellini, Claudia; Ratta, Marina; Baccarani, Michele; Lemoli, Roberto M
Peripheral blood CD14+ monocytes from multiple myeloma (MM) patients can be induced to differentiate into fully functional, mature, CD83+ dendritic cells (DCs) which are highly efficient in priming autologous T lymphocytes in response to the patient-specific tumor idiotype (Id). We have recently scaled up our manufacturing protocol for application in a phase I-II clinical trial of anti-Id vaccination with DCs in MM patients. Elegible patients received a series of by-monthly immunizations consisting of three subcutaneous and two intravenous injections of Id-keyhole limpet hemocyanin (KLH)-pulsed DCs (5 x -, 10 x -, 50 x 10(6) cells and 10 x -, 50 x 10(6) cells, respectively). To generate DCs, monocytes were labeled with clinical grade anti-CD14 conjugates and positively selected by immunomagnetic separation. Cells were then cultured, according to Good Manufacturing Practice guidelines, in FCS-free medium in cell culture bags, and differentiated to DCs with GM-CSF plus IL-4 followed by TNF-alpha or, more recently, by a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. Before maturation, Mo-DCs were pulsed with the autologous Id as whole protein or Id (VDJ)-derived HLA class I restricted peptides. Ten MM patients, who had been treated with two courses of high-dose chemotherapy with peripheral blood stem cell support, entered into the clinical study. CD14+ monocytes were enriched from 16.1+/-5.7% to 95.5+/-3.2% (recovery 67.9+/-15%, viability > 97%). After cell culture, phenotypic analysis showed that 89.6+/-6.6% of the cells were mature DCs. We obtained 2.89+/-1 x 10(8) DCs/leukapheresis which represented 24.5+/-9% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (31+/-10.9 of initial CD14+ cells) of DCs than TNF-alpha alone, secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic and autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of pre-loaded DCs. The recovery of thawed, viable DCs, was 78+/-10%. Thus, positive selection of CD14+ monocytes allows the generation of a uniform population of mature pre-loaded DCs which can be cryopreserved with no effects on phenotype and function and are suitable for clinical trials. Based on these results, a DCs-based phase II trial of anti-Id vaccination with VDJ-derived HLA class I-restricted peptides and KLH is underway for lymphoma patients. PMID 15359643

Accomplishments and perspectives of immunological interventions in lymphoproliferative disorders.
Mai 2004 | Milosević, D B
The purpose of this review is to consider evidences accumulated in the last few years which might lead to a new therapeutic strategy for lymphoproliferative disorders. Tumor-targeted and immunologically designed therapy has already started. Clinical effectiveness also includes the primary and secondary prevention of these malignancies. The fortifying of body's defense through vaccination as primary prevention with tumor-specific cell surface antigen, has been seen over the past few years, and will lead to health patient's improvement. Data collected from clinical trials and in vitro analysis indicated that the immune system of patients could recognize and eliminate neoplastic cells while sparing normal cells. In B-cell lymphomas and myelomas, the tumor-idiotype (Id) produced by a single B-cell clone, has been used for vaccination. Therapeutic Id vaccination used two types of antigen-presenting cells as natural adjuvants for the induction of antigen-specific T cell response. Dendritic cells (DCs)--based vaccines are under active investigation and are entering clinical evaluation. Current research focuses on optimization of DCs source, choice and loading of antigen, mode of injection, as well as immune monitoring. Some preliminary results were obtained and no significant side effects of dendritic cells vaccination of lymphoma and myeloma patients have so far been reported. The over-estimation of clinical effectiveness, at this moment, is still limited by the small number of patients included in this kind of treatment. The challenge for the future will be to extend these early results to reproducible vaccination strategy according to current standards of good clinical practice (GCP). PMID 15149145

Tumour cell/dendritic cell fusions as a vaccination strategy for multiple myeloma.
Apr. 2004 | Raje, Noopur; Hideshima, Teru; Davies, Faith E; Chauhan, Dharminder; Treon, Steven P; Young, Gloria; Tai, Yu-Tzu; Avigan, David; Gong, Jianlin; Schlossman, Robert L; Richardson, Paul; Kufe, Donald W; Anderson, Kenneth C
Multiple myeloma (MM) cells express certain tumour-associated antigens (TAAs) that could serve as targets for active-specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0-007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow-cytometry and dual immunofluorescence microscopy. These FCs induced MM-specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC-primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex-restricted MM-specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway. PMID 15086415

DC-based immunotherapy of B-cell malignancies.
Feb. 2004 | Reichardt, V L; Brossart, Peter
B-cell malignancies are a group of diseases for which vaccination protocols have been thoroughly studied over the last few years. All different vaccination protocols share the goal of inducing or augmenting tumor-specific immune responses in the tumor-bearing host, in order to potentially achieve therapeutic benefit in these otherwise ultimately fatal diseases. Attention has been drawn to the use of DC-based immunotherapy protocols relying on the unique properties of these powerful APCs. This review focuses on DC-based immunotherapy experience gained so far in B-cell malignancies, and discusses published and on-going clinical trials in follicular NHL and multiple myeloma, and preclinical results in CLL and Waldenström's macroglobulinemia. This will form the basis for a discussion of perspectives of DC vaccination in this group of human malignancies. PMID 14985168

Dendritic cell-based immunotherapy in multiple myeloma.
Feb. 2004 | Yi, Qing
Most patients with multiple myeloma (MM) cannot be cured with currently available therapies. Although complete remission could be achieved in about 50% of newly diagnosed patients with high-dose chemotherapy and tandem transplantation, relapses of the underlying disease occur frequently. To realize long-term disease-free survival, it will be necessary to develop complementary therapies that are non-cross-resistant with chemotherapy. To this end, immunotherapy aimed at inducing or enhancing tumor-specific immunity that may control or eradicate remaining tumor cells may be an appealing method. Dendritic cells (DCs) are professional antigen-presenting cells and considered the best natural adjuvants for immunotherapy in malignancies. Vaccination with tumor antigen-pulsed DCs has been shown to be protective and therapeutic in animal tumor models, and induced a strong tumor-specific immunity and durable tumor regression in human solid tumors and B-cell lymphoma. As a result, clinical trials in various human malignancies have been initiated. This review will focus on DC-based immunotherapy in MM. I will discuss myeloma antigens and antigen-specific immune responses, the capacity of DCs to present myeloma antigens and induce cytotoxic T-cell responses, and clinical experience of DC vaccination in myeloma patients. PMID 14959845

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

Dendritic cell vaccines in the treatment of multiple myeloma: advances and limitations.
Jan. 2003 | Büchler, Tomas; Hajek, Roman
Dendritic cells (DCs) are antigen-presenting cells that play a key role in the induction of cytotoxic T-lymphocytes. Adjuvant immunotherapy with antigen-loaded DCs represents an attractive anticancer strategy for multiple myeloma (MM). Autologous DCs loaded with idiotypic protein or other myeloma-associated antigen have been used in several clinical trials. Preclinical and first clinical experience have provided valuable insights in the mechanisms of cellular immunity, but few, if any, patients with MM benefited from such vaccination. Taken together, the data suggest that antitumor T-cell responses fail in MM because of a deregulated cytokine network, downregulation of costimulatory surface receptor expression, and changes in T-cell repertoire, enabling tumor cells to escape immune effectors by preventing the antitumor immune response. We discuss current clinical protocols for DC-based immunotherapy in MM and review some strategies that may increase the efficacy of DC vaccines. PMID 12512914

Idiotypic vaccination for B-cell malignancies as a model for therapeutic cancer vaccines: from prototype protein to second generation vaccines.
Sep. 2002 | Ruffini, Pier Adelchi; Neelapu, Sattva S; Kwak, Larry W; Biragyn, Arya
Cancer vaccines are aimed at inducing tumor-specific immunity by immunizing patients with tumor cells or their antigenic components, known as tumor-associated antigens (TAA). Antigens which are either mutated or selectively or abundantly expressed in malignant, but not in normal, cells are considered as TAA. Each patient's B-cell malignancy is usually derived from a single expanded B-cell clone, which expresses an immunoglobulin (Ig) with a unique idiotype (Id, variable regions of Ig). Therefore, Id can be regarded as a TAA and a potential target in clinical vaccination approaches. Although use of tumor-derived Id as an immunogen to elicit antitumor immunity against B-cell malignancies is an attractive idea, the broader use of idiotypic vaccines has been hampered by the fact that autologous Id is not only a weakly immunogenic, self antigen, but is also patient-specific so that the vaccine must be individually prepared for each patient. In this review we will first summarize the latest data from the clinical tests of experimental idiotypic vaccines and discuss issues relevant to the clinical application of cancer vaccines in general; we will then critically review new trends and achievements in the development of the second generation vaccine formulations. PMID 12217812

Optimizing dendritic cell-based immunotherapy in multiple myeloma.
Apr. 2002 | Yi, Qing; Desikan, Raman; Barlogie, Bart; Munshi, Nikhil
Vaccination with idiotype protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. These studies used immature DCs, which are less potent at activating T cells and could differentiate to macrophages once the cytokines were withdrawn. After intravenous administration, DCs accumulate in the lungs and liver for up to 48 h, thus reducing their potential to migrate to lymphoid organs and interact with T cells. To improve the efficacy of DC vaccination in myeloma, we investigated the use of idiotype-pulsed mature DCs administered subcutaneously. Five patients (three IgG and two IgA myeloma) with stable partial remission following high-dose chemotherapy were enrolled. DC vaccines were administered three times at 2-week intervals at least 4 months post transplantation. Idiotype-specific T-cell responses, detected using enzyme-linked immunospot (ELISPOT) (four patients) and proliferation (two patients) assays, were elicited in four and anti-idiotypic B-cell responses in all five patients. The cytokine-secretion profile of activated T cells demonstrated a type-1 response. A 50% reduction in serum M-component was observed in one immunologically responding patient that persisted for 6 months and stable disease (for 6 months) resulted in the other three patients. The remaining patient without an immune response to the vaccination relapsed. No major side-effects were noted. Thus, subcutaneous administration of idiotype-pulsed mature DCs induced idiotype-specific T- and B-cell responses. Current efforts are geared towards optimizing the conditions of DC generation and administration, and the development of in vitro assays to monitor the cytotoxicity of the T cells. PMID 11972511

Immunization against murine multiple myeloma with fusions of dendritic and plasmacytoma cells is potentiated by interleukin 12.
März 2002 | Gong, Jianlin; Koido, Shigeo; Chen, Dongshu; Tanaka, Yasuhiro; Huang, Lei; Avigan, David; Anderson, Kenneth; Ohno, Tsuneya; Kufe, Donald
Fusions of cancer cells and dendritic cells (DCs) are effective in the treatment of animal tumor models and patients with metastatic renal carcinoma. In this study, we have fused DCs with mouse 4TOO plasmacytoma cells. The results demonstrate that vaccination of mice with the fusion cells (FC/4TOO) is associated with induction of antitumor humoral and cytotoxic T lymphocyte (CTL) responses. Immunization with FC/4TOO cells protected mice against tumor challenge. In addition, treatment of established multiple myeloma with FC/4TOO cells was associated with prolongation of survival but not with eradication of disease. As interleukin (IL)-12 potentiates the induction of immune responses, recombinant mouse IL-12 was administered with the FC/4TOO vaccine. Treatment of mice with FC/4TOO and IL-12 was associated with increased CTL activity and T-cell proliferation responses. Treatment with FC/4TOO and IL-12 also resulted in eradication of established disease. These findings demonstrate that immunization with FC/4TOO fusion cells and IL-12 potentiates antitumor immunity and the treatment of murine multiple myeloma. PMID 11895787

Idiotype protein-pulsed dendritic cells produce strong anti-myeloma effects after syngeneic stem cell transplantation in mice.
Feb. 2002 | Zeis, M; Frenzke, H; Schmitz, N; Uharek, L; Steinmann, J
Dendritic cell (DC) vaccination represents an interesting immunotherapeutic option in the treatment of several malignancies. In multiple myeloma (MM) patients, vaccination with autologous idiotype (Id) protein-pulsed DC is feasible, but their antitumoral effectiveness was rather limited. To improve the therapeutic potential of DC therapy, we studied the immunological effects of syngeneic peripheral blood stem cell transplantation (PBSCT) given in conjunction with Id-loaded DC. Balb/c mice were inoculated i.p. with 5 x 10(5) of HOPC myeloma cells (Balb/c origin). Animals were immunized with three injections of 5 x 10(5) DC pulsed with the IgG2a(HOPC) or with a control immunoglobulin (Ig(control)). Some experimental groups of myeloma-bearing animals received total body irradiation (7.5 Gy) and a subsequent transplant of 2 x 10(7)syngeneic peripheral blood progenitor cells (PBPC) followed by DC therapy beginning at day 10 post transplant. Animals receiving DC therapy or syngeneic PBPCT alone neither induce long-term survival nor tumor-specific CTL reactivity in vitro. In marked contrast, combination of syngeneic PBPC transplantation and subsequent DC therapy resulted in 78% survival after a follow-up of 180 days. In addition, this treatment modality conferred a generation of Id peptide-specific CD8-mediated T cell reactivity. These data provide a rationale for DC-based vaccination in multiple myeloma patients administered post syngeneic transplantation. PMID 11859393

Immunotherapy of multiple myeloma.
Aug. 2001 | Ruffini, P A; Kwak, L W
The failure of chemotherapy to cure a significant proportion of multiple myeloma (MM) patients and increasing knowledge of tumor immunology and MM biology have generated considerable interest in immunotherapy for this lethal disease. Immunotherapy for MM can be divided into three broad categories: passive antibody-mediated immunotherapy, active specific immunization (vaccination), and adoptive T-cell immunotherapy. Early clinical trials using anti-CD20 monoclonal antibodies (mAbs) have met with limited success so far but have also suggested that selected patient subgroups may benefit from this treatment. The availability of a truly tumor-specific antigen such as immunoglobulin idiotype, the recent demonstration that MM cells process and present idiotype to T lymphocytes, and formal evidence of an antitumor effect of idiotypic vaccination in follicular lymphoma provide the framework for applying idiotypic vaccination in MM. The ability to generate ex vivo functional dendritic cells has made it possible to fuse them with patients' MM cells, thus producing a different type of customized vaccine. Dendritic cells are also a pivotal reagent to generate ex vivo MM-specific cytotoxic T lymphocytes (CTLs) to be reinfused into the patient for adoptive immunotherapy. This review summarizes achievements in MM immunotherapy based on data reported since 1998. PMID 11486314

Dendritic cells derived from multiple myeloma patients efficiently internalize different classes of myeloma protein.
Feb. 2001 | Butch, A W; Kelly, K A; Munshi, N C
Myeloma protein is a unique tumor antigen that can be used to devise tumor-specific vaccination strategies. As dendritic cells (DCs) are extremely potent at inducing T-cell responses, clinical protocols have been designed using myeloma protein-pulsed DCs to elicit anti-tumor cell responses in vivo. To optimize antigen pulsing of DCs, we investigated mechanisms of antigen uptake and evaluated various laboratory parameters including class of myeloma protein, antigen exposure time, and DC maturational stage.DCs were generated by culturing peripheral blood stem cells from myeloma patients in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Myeloma proteins were labeled with fluorescein isothiocyanate (FITC) and internalization of protein by DCs was measured by flow cytometry.IgG, IgA, and free-kappa light chain myeloma proteins were all rapidly internalized by DCs in a time-dependent fashion. Maturation of DCs with tumor necrosis factor-alpha (TNF-alpha) resulted in diminished uptake. Endocytosis of myeloma protein by DCs was primarily mediated by fluid-phase macropinocytosis based on morphology, nonsaturable uptake kinetics, and sensitivity to drugs that inhibit membrane ruffling. Pulse-chase experiments revealed that the majority of internalized myeloma protein disappeared within 4 hours but was retained in the presence of chloroquine, indicating antigen processing had occurred. Cultured DCs from myeloma patients are functional and can efficiently endocytose different classes of myeloma protein by the mechanism of macropinocytosis. This demonstrates the feasibility of using all classes of myeloma protein for producing DC vaccines, and defines culture conditions for optimizing antigen loading of DCs for induction of anti-myeloma responses. PMID 11164109

Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects.
Juni 2000 | Titzer, S; Christensen, O; Manzke, O; Tesch, H; Wolf, J; Emmerich, B; Carsten, C; Diehl, V; Bohlen, H
Multiple myeloma (MM) is characterized by a clonal proliferation of malignant plasma cells in the bone marrow secreting a monoclonal immunoglobulin (paraprotein) with specific antigenic determinants, the idiotype (Id), which can be regarded as a tumour-associated antigen (TAA). In order to analyse the impact of a dendritic cell (DC)-based vaccine, 11 patients with advanced MM were treated with CD34 stem cell-derived dendritic cells that were pulsed with Id peptides. Subsequently, the patients received three boost immunizations every other week with a combination of Id and granulocyte-macrophage colony-stimulating factor (GM-CSF) (nine patients) or with Id peptide-pulsed dendritic cells again (two patients). The treatment was well tolerated with no side-effects. The present clinical study was a proof of concept analysis of dendritic cell-based vaccines in MM. The capacity of the dendritic cells to activate idiotype-specific T cells was verified by in vitro stimulation experiments before the vaccination therapy. Immunological effects of the Id vaccination were analysed by monitoring changes in anti-idiotype antibody titres and idiotype-specific T-cell activity. After vaccination, three out of 10 analysed patients showed increased anti-idiotype antibody serum titres, indicating the induction of an idiotype-specific humoral immune response. The idiotype-specific T-cell response analysed by ELISpot was increased in four out of 10 analysed patients after vaccination, and one patient had a decreased plasma cell infiltration in the bone marrow. In conclusion, five out of 11 patients showed a biological response after vaccination. Thus, our data indicate that immunotherapy with Id-pulsed DCs in MM patients is feasible and safe. DC generated from CD34+ progenitor cells can serve as a natural adjuvant for the induction of clinically relevant humoral and cellular idiotype-specific immune responses in patients suffering from advanced MM. PMID 10792287

Dendritic cell biology and the application of dendritic cells to immunotherapy of multiple myeloma.
Mai 2000 | Hájek, R; Butch, A W
Dendritic cells (DCs) are extremely efficient antigen-presenting cells that are potent stimulators of both B and T cell immune responses. Although DCs are normally present in extremely small numbers in the circulation, recent advances in DC biology have made it possible to generate DCs in culture. DCs can be generated in vitro from various cellular sources including bone marrow, cord blood and peripheral blood. Although culture conditions are extremely diverse, the majority of protocols grow DCs in GM-CSF and either TNF-alpha and/or IL-4. The addition of other growth factors such as SCF and Flt-3 ligand can dramatically enhance DC recovery. It is important to appreciate that DC subsets have been identified. Thus, DC at different stages of maturation, based on phenotype and capacity to capture antigen, can be obtained depending on culture conditions. For clinical applications, DCs can be generated in serum-free media and cryopreserved for future clinical applications. The ability to obtain DCs in numbers suitable for manipulating immune responses has pushed DC-based immunotherapies into the spotlight for treatment of various malignancies, including multiple myeloma, a B cell malignancy that is presently incurable. Although high-dose chemotherapy and transplantation have improved complete remission rates and overall survival in myeloma, immunotherapeutic strategies are needed for the additional cytoreduction needed to achieve a cure. Because DCs specialize in antigen capture and are extremely potent at stimulating T cell responses, they are ideally suited for generating anti-myeloma T cell responses in vivo. Several studies have demonstrated that myeloma protein, also called idiotype (Id), is sufficiently immunogenic and can be used to generate in vivo T cell responses in myeloma patients. Clinical trials using Id-pulsed DCs as a vaccine to treat minimal residual disease or relapsed myeloma are currently underway. Feasibility studies indicate that antigen-pulsed autologous DCs can be used to elicit in vivo Id-specific T cell responses. Additional studies are needed to optimize current DC vaccination protocols and determine clinical benefits associated with this approach. It is hoped that, following conventional therapies, a combination of adoptive immunotherapeutic modalities such as DCs together with myeloma-specific T cells may lead to improved clinical responses in multiple myeloma, and ultimately lead to complete remission and cure. PMID 10713654

Generation of anti-idiotype immune responses following vaccination with idiotype-protein pulsed dendritic cells in myeloma.
Jan. 2000 | Cull, G; Durrant, L; Stainer, C; Haynes, A; Russell, N
Myeloma cells produce immunoglobulin which is unique to the malignant clone and presents antigenic determinants, or idiotypes, which may function as a tumour-specific antigen. The availability of significant quantities of idiotype protein in the serum makes immunotherapeutic strategies utilizing this protein to generate an anti-idiotype immune response an attractive prospect. We treated two patients with advanced refractory myeloma with a series of four vaccinations using autologous idiotype-protein pulsed dendritic cells combined with adjuvant GM-CSF. The vaccinations were well tolerated with a mild fever post-vaccination in one patient. An idiotype-specific T-cell proliferative response developed in both patients. This T-cell response was associated with the production of gamma-interferon, indicating a TH-1-like response. Furthermore, one patient developed anti-idiotype IgM antibodies. However, no idiotype-specific cytotoxic T-cell response could be demonstrated. Further investigation is warranted to define the optimal conditions for dendritic cell culture and priming to maximize the anti-tumour immune response. PMID 10583271