Cell-based Cancer Vaccines Research Articles

Dendritic cell-based therapeutic cancer vaccines: past, present and future.

Dendritic cells (DCs) are professional antigen presenting cells, which play a pivotal role in antigen-specific (Ag-specific) T cell immunity. Malignancies have the capacity to inactivate DCs and effector T cells or to evade circulating antitumor immunity by expressing immune inhibitory molecules and/or secreting immunosuppressive cytokines. For this reason, ex-vivo-generated DCs [1] or in-vivo-DC-targeting [2] has been studied intensively over the past decade or development as a potential therapeutic cancer vaccine. Understanding how DCs induce, regulate, and maintain T cell immunity is essential for the design of novel cancer vaccines with improved clinical efficacy. Once activated, antigen-pulsed DCs are geared toward the launching of Ag-specific immunity, leading to T cell proliferation and differentiation into effector T cells. DCs are also important in triggering humoral immunity partly due to their capacity to directly interact with B cells and to present unprocessed antigens. There are examples of DC-based tumor vaccines being used successfully in clinical practice. Sipuleucel-T, the first Food and Drug Administration (FDA)-approved DC vaccine (Dendreon Corp.) has been found to be somewhat effective in the treatment of human prostate cancer [3]. As of 2014, 289 clinical studies of DC-based cancer vaccines are registered and under investigation (2014, http://www.clinicaltrials.gov). Among the 289 cases, 2 are in phase IV, 6 in phase III, 3 in phase II & III, 74 in phase II, 76 in phase I & II, 109 in phase I, and 3 in phase 0, underscoring the potential clinical significance of this therapy. In this editorial, we will discuss the evolution of DC-based cancer vaccine strategy, and future implications, with an emphasis on the efficacy and limitations of DC-based vaccine. Better understanding of DC biology and manipulation of activated DCs will allow DC scientists to produce the next generation of highly efficient cancer vaccines for cancer patients.

A Phase I/II study of vesigenurtacel-l (hs-410) or placebo in combination with Bacillus Calmette-Guérin (BCG) in patients with non-muscle invasive bladder cancer (NMIBC)

Meeting abstracts Vesigenurtacel-L is an allogeneic cell-based therapeutic cancer vaccine that was selected based on its expression of a range of tumor antigens (surviving, LAGE-1, MAGE-A3, MAGE-A11, PRAME and others) that are known to be expressed amongst a high proportion of primary bladder

A Phase II study of Viagenpumatucel-l (HS-110) in combination with low-dose Cyclophosphamide versus physician's choice in patients with advanced non-small cell lung cancer

Meeting abstracts Viagenpumatucel-L (HS-110) is an allogeneic cell-based therapeutic cancer vaccine for the treatment of advanced NSCLC. The vaccine is composed of a cell line expressing a defined repertoire of tumor antigens (MAGE-A3, NY-ESO-1, LAGE-1, and others) that are chaperoned by a modified

STAT3 Inhibition Promotes Potent Th1 Responses By Down Regulating Pdl-1 Expression On Tumor Cells

STAT3 signaling is upregulated in cancer cells and is thought to be a critical mediator of tumor associated immune suppression. We examined the relationship of STAT3 and PDL-1, an important negative regulator of T cell immune responses via interactions with PD-1. The 5'upstream, putative promoter region of PDL-1 gene contains four potential STAT3 binding sites close to transcription start site, suggesting a possible role of STAT3 in transcriptional regulation of PDL-1. We investigated for a possible relationship between STAT3 and PDL-1 in multiple myeloma (MM-RPMI) cell line. Using chromatin immunoprecipitation assay (ChIP assay), we observed direct binding of STAT3 to the PDL-1 promoter region in MM-RPMI cells. Moreover, an enhanced occupancy of STAT3 on the PDL-1 promoter region was also observed when the cells were treated with IL-6 (20 ng/ml). Concurrent with the above observation, IL-6 treated MM-RPMI cells showed an enhanced expression of PDL-1 protein. Treatment of RPMI-MM cells with STAT3 inhibitors AG490 and CDDO-Me for 72 hrs resulted in PDL-1 expression levels of 24.5% and 15.1% respectively, compared to 97.5% for untreated control cells as determined by FACS analysis. Based on these observations, we evaluated the effect of STAT3 inhibition by exposure to small molecule STAT3 inhibitor on response to a tumor vaccine consisting of myeloma cells fused with dendritic cells (DC). DC/myeloma fusion cells were co-cultured with autologous T cells in the presence or absence of small molecule STAT3 inhibitor (CDDO-Me). Treatment of the cocultures with CDDO-Me resulted in an increased in the percentage of CD4/IFNγ (11.57±SEM 1.16; n=3) and CD8/IFNγ (23.37±SEM 2.25; n=3) expressing cells as compared to untreated cocultures (3.1± SEM 0.72; n=3) and (4.43±SEM 0.81; n=3) respectively. Moreover, we also observed a concomitant decrease in both CD4+ and CD8+ T cells expressing IL-10 or IL-4 compared to untreated cocultures. We also noted a decrease in the percentage of immunosuppressive regulatory T cells (CD4+/CD25+/FOXP3+) in treated cocultures (8.33±SEM 0.59; n=3) as compared to untreated cocultures (28.50±SEM 2.0; n=3). These findings indicate a pivotal role of inflammatory cytokine IL-6 and its downstream activator STAT3 in regulating PDL-1 expression. Thus, strategic inhibition of STAT3/IL-6 pathway and therefore down regulation of PDL-1 could enhance the potency of tumor/DC fusion cell based cancer vaccines for immunotherapeutic treatments. Furthermore, the data demonstrate that the availability of novel adjuvants offers the potential for combination therapy that may have profound effect on the potency and durability of responses to cellular immunotherapy. Disclosures:No relevant conflicts of interest to declare.

Therapeutic gene modified cell based cancer vaccines

History of cancer immunotherapy lasts for more than 120years. In 1891 William B. Coley injected bacteria into inoperable cancer (bone sarcoma) and observed tumor shrinkage. He is recognized as the "'"Father of Immunotherapy"'". Cancer immunotherapy is based on the ability of the immune system to recognize cancer cells and to affect their growth and expansion. Beside the fact that, tumor cells are genetically distinct from their normal counterparts, and should be recognized and eliminated by immune system, the tumor associated antigens (TAAs) are often poorly immunogenic due to immunoediting. This process allows tumor to evolve during continuous interactions with the host immune system, and eventually escape from immune surveillance. Furthermore, tumor microenvironment consists of immunosuppressive cells that release immunosuppressive factors including IL-6, IL-10, IDO, TGFβ or VEGF. Interactions between cancer and stroma cells create network of immunosuppressive pathways, while activation of immune defense is inhibited. A key to successful immunotherapy is to overcome the local immunosuppression within tumor microenvironment and activate mechanisms that lead to tumor eradication. There are two clinical approaches of immunotherapy: active and passive. Active immunotherapy involves stimulation of immune response to tumor associated antigens (TAAs), either non-specifically via immunomodulating agents or specifically employing cancer vaccines. This review presents the progress and breakthroughs in design, development and clinical application of selected cell-based tumor vaccines achieved due to the generation and development of gene transfer technologies.

Identification of biomarkers for overall survival of patients with metastatic renal cell carcinoma treated with MGN1601.

468 Background: The cell-based therapeutic cancer vaccine MGN1601 consists of two active pharmaceutical ingredients in fixed combination. Fourfold gene-modified, allogeneic tumor cells expressing IL-7, GM-CSF, CD80, and CD154 through MIDGE gene expression vectors are combined with the DNA-based immunomodulator dSLIMas a TLR-9 agonist. In the phase I-II clinical trial (ASET trial) heavily pre-treated patients with metastatic renal cell carcinoma (mRCC) were enrolled. Methods: TheASET study has been conducted as a multicenter, open, single-arm phase I-II study. The treatment phase (TP) consisted of 8 intradermal vaccinations, administered within 12 weeks. We analysed known mRCC prognostic factors for their predictive value, i.e. safety laboratory and immunological parameters, quality of life, local reactions and other patients’ characteristics. Results: 19 patients from the ASET study, who received at least one vaccination (ITT population), were included in the biomarker evaluation. The median overall survival (mOS) in the ITT population is currently 25 weeks. mOS of patients who discontinued TP prematurely was only 10 weeks. However, mOS of those patients who completed at least TP is not yet mature for statistical calculation (NR), but is currently estimated as 69 weeks, resulting in a highly significant difference (10 weeks vs. NR, p < 0.001). Patients with an absolute lymphocyte counts (ALC) at baseline of ≥1,000/μL had increased overall survival (mOS NR vs. 16 weeks, p = 0.013), if compared to those with an ALC <1,000/μL. Neutrophil lymphocyte ratios (NLR) at baseline of >3, bone and liver metastasis, high MSKCC score were identified as risk factors associated with lower overall survival. ALC ≥1,000/μL after three MGN1601 vaccinations (week 5) was even more significantly associated with increased overall survival (mOS NR vs. 17 weeks, p = 0.007). The NLR and quality of life improvement at week 5 as well as local reactions at injection sites seem to correlate with OS. Conclusions: MGN1601 shows promising efficacy in late stage mRCC patients. The identified parameters should be further investigated as potential biomarkers for efficacy. Clinical trial information: NCT01265368.

Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: Profile comparison

A dendritic cell-based cancer vaccine has recently received Food and Drug Administration approval in the USA based on its ability to prolong the survival of prostate cancer patients with advanced disease. However, tumor-mediated immunosuppressive mechanisms might represent an obstacle to optimal performance of this therapy. We have recently shown that monocytes from the blood of prostate cancer patients can fully mature to dendritic cells only after the tumor is removed. Here, we have tested the hypothesis that these tumor-driven monocytes correspond to the recently described subset of CD14(+) HLA-DR(low) immunosuppressor cells. Prostate cancer patients were studied before and 1 month after prostatectomy. Pre- and postsurgical patients with colorectal cancer were also included for comparison. Flow cytometric analysis was applied to define CD14(-) HLA-DR(low) CD33(+) CD11b(+) (myeloid) and CD14(+) HLA-DR(low) (monocytic) suppressor cells. Interferon-γ release was used to assess the immunocompetence of lymphocytes. In both prostate cancer and colorectal cancer patients, the percentage of CD14(+) HLA-DR(low) cells was several-fold higher compared with normal subjects. This was not the case for CD14(-) HLA-DR(low) CD33(+) CD11b(+) cells. Furthermore, postsurgical normalization of CD14(+) HLA-DR(low) cells only occurred in prostate cancer patients. In all patients, the interferon-γ response of T lymphocytes to phorbolmyristate acetate-ionomycin was higher compared with normal donors, but it was further increased after tumor ablation only in prostate cancer patients. The direct link between CD14(+) HLA-DR(low) increase and presence of primary tumor suggests a distinguishing immunosuppressive profile of prostate cancer. This observation supports the principle that the appropriate setting for prostate cancer vaccine therapy is a minimal disease status.

Toxoplasma gondii protein fractions for the generation of dendritic cell based cancer vaccine

Toxoplasma gondii protein fractions for the generation of dendritic cell based cancer vaccine

Therapeutic Applications of Herbal Medicines for Cancer Patients

Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL) of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines for various cancers and the development of randomized controlled trials (RCTs) in this emerging research area. In addition, we also report recent studies on the biochemical and cellular mechanisms of herbal medicines in specific tumor microenvironments and the potential application of specific phytochemicals in cell-based cancer vaccine systems. This review should provide useful technological support for evidence-based application of herbal medicines in cancer therapy.

Immunotherapy for colorectal cancer

The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.

Cellular Based Cancer Vaccines: Type 1 Polarization of Dendritic Cells

Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor-associated antigens introduced to dendritic cells (DCs) generated in vitro. This may in part result from suboptimal maturation of DCs leading to insufficient production of IL-12, a key driver of cellular immunity. Therefore, tremendous efforts have been put into the design of maturation cocktails that are able to induce IL-12 secreting type 1 polarized DCs mimicing pathogen-derived molecular activation of DCs. Correct timing and potential synergisms of clinical-grade toll-like receptor ligands, interferons (IFN) and CD40L enhance IL-12 production in DCs. However, cytokine exhaustion, predominant expression of tolerogenic molecules and activation-induced dendritic cell death should be avoided. Thus, compounds such as IFN-γ may initially induce immunity but later on tolerance. Maturation with PGE(2) obviously promotes migration via expression of CCR7 but on the down side PGE(2) limits the production of IL-12 especially following encounter with CD40L-expressing cells and furthermore, PGE(2) imprints DCs for preferential interaction with tolerogenic T cells. In addition, type 1 polarized DCs matured without PGE(2) also seem to be capable of migrating in vivo, although concomitant production of CCL19 seems to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines.

813P - The Novel Cancer Vaccine, Consisting of Genetically Modified Allogeneic Tumor Cells and Immunomodulator MGN1601: Updated Results of a Phase 1-2 Study in Patients with Advanced Renal Cell Carcinoma

ABSTRACT Background MGN1601 consists of two active pharmaceutical ingredients: genetically modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 and a TLR9 agonist, synthetic DNA-based immunomodulator dSLIM®. The first-in-man phase 1–2 clinical trial (ASET trial) has been conducted in patients with advanced renal cell carcinoma failed previous therapy lines and without further available standard therapy. Methods The ASET study is a multicentric, open, single-arm phase 1-2 clinical study and consists of the treatment, extension and follow up phases. The safety, efficacy and immunogenicity parameters were evaluated based on clinical and laboratory assessments, monitoring of patients' quality of life (QoL) with QLQ-C30, immunological tests, and central radiological investigations according to RECIST 1.1 as well as immune related Response Criteria. Results Ten of nineteen study patients completed the treatment per protocol (TPP). Two patients with disease control after 12-weeks continued treatment in the extension phase. One of them is still under therapy showing tumor remission since 48 weeks. The second patient developed radiological PD after 60 weeks of treatment. Seven patients from the TPP population are still alive with stable disease for up to 65 weeks. Evaluation of the QoL showed that patients of the TPP group have improved median symptom score from 45.8 to 58.3 in course of treatment. Drug-related AE included mild fever, edema, exanthema, pruritus, intermittent arthralgia, fatigue, and moderate soft tissue infection. Local reactions on injection site consisted mostly of redness up to 50 mm, which were available up to 7 days. The local reactions have no negative impact on the quality of life and daily activities of the patients. Six of ten TPP patients showed significant improvement in the immune status in lymphocyte transformation test. Conclusions The allogeneic tumor cell-based cancer vaccine MGN1601 shows promising efficacy and a favourable safety profile in the late stage mRCC patients. A phase 2 clinical study in mRCC patients with MGN1601 as third-line therapy is under development. Disclosure M. Schroff: Board member of Mologen. M. Schmidt: Mologen employee. E. Weith: Mologen empoyee. M. Tschaika: Mologen employee. B. Wittig: Member of Scientific Advisory Board of Mologen. All other authors have declared no conflicts of interest.

Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested damage-associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines.

Retrospective analysis of the clinical efficacy of a dendritic cell-based cancer vaccine in patients with advanced or recurrent breast cancer

Tumor-specific cytotoxic T lymphocytes can be efficiently activated in vivo by dendritic cell (DC)-based vaccination. This trial assessed the clinical efficacy and toxicity of DC-based immunotherapy in patients with advanced breast carcinoma. DC-based immunotherapy (DC vaccine alone or DC vaccine plus lymphokine-activated natural killer (NK) cell therapy) was administered to 26 patients with unresectable breast carcinoma refractory to standard treatment. After leukapheresis, DCs were generated from CD14+ monocytes by 6 day cultivation with GM-CSF and IL-4. DCs were then matured by OK-432 treatment and pulsed with cancer-associated antigens, such as WT1, MUC1, and HER2. DCs were administered 5–8 times intradermally at 14-day intervals. Twenty-six patients with performance status (PS) of 0 (n = 4), 1 (n = 14), 2 (n = 4) and 3 (n = 4), and a median age of 55.5 years were eligible for this study. Of the 26 patients, DC vaccine was administered in combination with chemotherapy in 50%. Best response by RECIST, 1 patient showed a complete response (CR), 14 had partial response (PR), and 17 had stable disease (SD). The response ratio was 15.4％. None of the patients experienced adverse events of grade 2 or higher during the treatment period. The median overall survival (OS) time was 552.9 days (95% CI; 402.6–703.3 days). Log-rank test analysis demonstrated that the better PS groups (i.e., 0, 1) had significantly better survival times compared to those in poorer PS groups (i.e., 2, 3) (MST, 709.6 days, 95% CI, 502.2–917.0; vs. 200.4 days, 95% CI, 0–410.7; P < 0.001). DC vaccine-based immunotherapy demonstrates promising OS times and tolerable toxicities in the setting of breast carcinoma. A full risk/benefit analysis of DC-based vaccines in patients with metastatic breast carcinoma will be determined in a future phase II trial.

Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine.

Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria-mediated apoptosis and increase the expression of all five tested damage-associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines.

Abstract LB-233: Immune-related efficacy data of the phase 1-2 study of an with fourfold gene-modified allogeneic tumor cell based vaccine in patients with advanced renal cell carcinoma

Abstract Background. The first-in-man phase 1-2 clinical study (ASET study) of the cell-based therapeutic cancer vaccine MGN1601 included patients with advanced renal cell carcinoma (RCC) who failed previous therapies and had no further standard therapy available. MGN1601 consists of two active pharmaceutical ingredients in fixed combination: fourfold gene-modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 through MIDGE® vectors and a TLR-9 agonist, the DNA-based immunomodulator dSLIM®. Methods. The ASET study is conducted as a multicentric, open, single-arm Phase 1-2 clinical trial. Clinical response (PD, SD, PR, CR) was evaluated using CT scans according to RECIST 1.1 criteria and immune related Response Criteria (irRC). The efficacy data were evaluated in terms of progression-free survival (PFS) and overall survival (OS) for the intended to treat (ITT) and the treated per protocol (TPP) populations of patients.Immune response was determined by the following parameters: ELISA of serum cytokines and chemokines, DTH to MGN1601, LTT assay to standard antigens, frequency and activation of plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), monocytes, natural killer cells (NK), NKT-, B-, and T cells. Blood mRNA and frequency of cytotoxic T cells by ELISPOT as well as tumor tissue were analyzed in a patient subgroup. Results. Nineteen patients, who had advanced stage RCC and failed up to 7 previous therapy lines (median 3 lines), were included. Nine of these patients completed the treatment phase per protocol (TPP), the others discontinued the study earlier due to PD. Currently, one patient is still in treatment phase. Median PFS in the TPP group was 12 weeks (3 months) and OS (not reached yet) 45 weeks (11 months). Three patients achieved disease control (one PR and two SD) after 12 weeks according to RECIST 1.1 criteria. Two patients are continuing treatment in the extension phase and are progression free since 37 and 46 weeks, respectively. Re-evaluation of tumor response data using irRC revealed one additional patient, who had a delayed tumor response 4 weeks after stop of treatment. Herewith, 4 out of 9 TPP patients (45%) achieved disease control. Of six patients receiving a targeted therapy following progress, four had substantial objective responses, suggesting that the study drug rendered their tumors more vulnerable to subsequent therapies. Immune analysis of the cell populations after 12 weeks showed trends towards increases of T cell, NKT-cell and pDC frequencies in those patients with clinical responses to the therapy, indicating anti-tumor immunity due to the study treatment. Conclusions. The therapeutic cancer vaccine MGN1601 shows promising efficacy in late stage mRCC patients. Results warrant further clinical studies with MGN1601. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-233. doi:1538-7445.AM2012-LB-233

Combination Therapy of Cancer – Escalating the Effect of Dendritic Cell-based Cancer Vaccine in the Tumour Micro-environment

A key factor in initiating and operating the immune system against tumour cells, the dendritic cell (DC) has been regarded as the next possible breakthrough in new cancer therapy. However, the results of more than 15 years of clinical studies with DC vaccine revealed the difficulties fulfilling this expectation. Evidence has disclosed that the DC activation required for proper tumour-specific effector CD4+ and CD8+ T cell stimulation is inhibited in the micro-environment of tumour. Studies have further reported that DC phenotypes in tumour tissue and draining lymph nodes are mostly immature, which results in regulatory immune responses. Also, the existence of MDSCs and TAMs adversely affect both DC function and immune suppression in the cancer-environment. In this review, efforts to overcome the tumour or host-dependent hindering which inhibit the effect of cancer vaccine will be discussed. The combination therapy of cancer with DC vaccine and other immune modulators may improve the clinical efficacy.

Cellular MRI as a suitable, sensitive non-invasive modality for correlating in vivo migratory efficiencies of different dendritic cell populations with subsequent immunological outcomes

The clinical application of dendritic cells (DC) as adjuvants in immunotherapies such as the cell-based cancer vaccine continues to gain interest. The overall efficacy of this emerging immunotherapy, however, remains low. Studies suggest the stage of maturation and activation of ex vivo-prepared DC immediately prior to patient administration is critical to subsequent DC migration in vivo, which ultimately affects overall vaccine efficacy. While it is possible to generate mature and activated DC ex vivo using various stimulatory cocktails, in the case of cancer patients, the qualitative and quantitative assessment of which DC stimulatory cocktail works most effectively to enhance subsequent DC migration in vivo is difficult. Thus, a non-invasive imaging modality capable of monitoring the real-time migration of DC in long-term studies is required. In this paper, we address whether cellular magnetic resonance imaging (MRI) is sufficiently sensitive to quantitatively detect differences in the migratory abilities of two different DC preparations: untreated (resting) versus ex vivo matured in a mouse model. In order to distinguish our ex vivo-generated DC of interest from surrounding tissues in magnetic resonance (MR) images, DC were labeled in vitro with the superparamagnetic iron oxide (SPIO) nanoparticle FeREX®. Characterization of DC phenotype and function following addition of a cytokine maturation cocktail and the toll-like receptor ligand CpG, both in the presence and in the absence of SPIO, were also carried out. Conventional histological techniques were used to verify the quantitative data obtained from MR images. This study provides important information relevant to tracking the in vivo migration of ex vivo-prepared and stimulated DC.

Emerging cancer vaccines: the promise of genetic vectors.

Therapeutic vaccination against cancer is an important approach which, when combined with other therapies, can improve long-term control of cancer. In fact, the induction of adaptive immune responses against Tumor Associated Antigens (TAAs) as well as innate immunity are important factors for tumor stabilization/eradication. A variety of immunization technologies have been explored in last decades and are currently under active evaluation, such as cell-based, protein, peptide and heat-shock protein-based cancer vaccines. Genetic vaccines are emerging as promising methodologies to elicit immune responses against a wide variety of antigens, including TAAs. Amongst these, Adenovirus (Ad)-based vectors show excellent immunogenicity profile and have achieved immunological proof of concept in humans. In vivo electroporation of plasmid DNA (DNA-EP) is also a desirable vaccine technology for cancer vaccines, as it is repeatable several times, a parameter required for the long-term maintenance of anti-tumor immunity. Recent findings show that combinations of different modalities of immunization (heterologous prime/boost) are able to induce superior immune reactions as compared to single-modality vaccines. In this review, we will discuss the challenges and requirements of emerging cancer vaccines, particularly focusing on the genetic cancer vaccines currently under active development and the promise shown by Ad and DNA-EP heterologous prime-boost.

Cellular magnetic resonance imaging of monocyte-derived dendritic cell migration from healthy donors and cancer patients as assessed in a scid mouse model

BACKGROUND AIMS. The use of dendritic cells (DC) as an adjuvant in cell-based immunotherapeutic cancer vaccines is a growing field of interest. A reliable and non-invasive method to track the fate of autologous DC following their administration to patients is required in order to confirm that clinically sufficient numbers are reaching the lymph node (LN). We demonstrate that an immunocompromised mouse model can be used to conduct translational studies employing cellular magnetic resonance imaging (MRI). Such studies can provide clinically relevant information regarding the migration potential of clinical-grade DC used in cancer immunotherapies. METHODS. Human monocyte-derived dendritic cells (mo-DC) were generated from negatively selected monocytes obtained from either healthy donors or cancer patients. DC were labeled with superparamagnetic iron oxide (SPIO) nanoparticles in order to track them in vivo in a CB17scid mouse model using cellular MRI. SPIO did not have any adverse effects on DC phenotype or function, independent of donor type. Cellular MRI readily detected migration of SPIO-loaded DC in CB17scid mice. No differences in migration were observed between DC obtained from healthy donors and those obtained from donors undergoing autologous stem cell transplant for cancer therapy. CONCLUSIONS. Cellular MRI provided semi-quantitative image data that corresponded with data obtained by digital morphometry, validating cellular MRI's potential to assess DC migration in DC-based cancer immunotherapy clinical trials.