Monocyte-derived Dendritic Cell Vaccine Research Articles

IMG-07. Contralateral transient contrast enhancement in a patient with IDH1wt MGMT promoter-methylated GBM responding to TMZ and individualized multimodal immunotherapy

Abstract Immunotherapy-induced MRI changes remain challenging when treating GBM patients with immunotherapy as part of a combined treatment. The iRANO criteria provide a decision-tree in order to avoid over- and under-treatment reactions when contrast-enhancing lesions become visible and should be interpreted. We report a 34-year female, 34 weeks pregnant, who presented with epilepsy, and was diagnosed with IDH1wt MGMT promoter-methylated GBM after biopsy. On MRI, the left occipital lesion was mostly cystic-necrotic with peripheral contrast enhancement, and crossed over the corpus callosum to the right. The volume was calculated as 64 cm³ (abc/2 formula). She was treated with radiochemotherapy and 12 TMZm cycles. Within each TMZ cycle 5 days of immunogenic cell death (ICD) therapy (5 injections with Newcastle Disease Virus and 5 sessions of modulated electrohyperthermia (Oncotherm 50 min 40-60 Watt) was added at days 8 to 12. After all chemo-/ICD-therapy we continued with active specific immunotherapy: two autologous mature monocyte-derived dendritic cell vaccines loaded with ICD therapy-induced serum-derived antigenic extracellular microvesicles and apoptotic bodies (IO-Vac®). One month after the second IO-Vac®, 17 months after diagnosis, a temporal right FLAIR-visible region showed expansion, and three months later also diffuse contrast enhancement, which was confirmed in a control scan one month later. The original tumor was meanwhile reduced to 16 cm³. However, in the last available scan, two months after the former, the contrast enhancement was disappeared, and the pathologic area on FLAIR was diminished. The original tumor size was reduced to 2 cm³, two year after first diagnosis. She showed allergic skin reactions to TMZ, which was covered with systemic histamine intake. There were no side effects related to multimodal immunotherapy. Transient MRI changes can be observed even in distance from the original tumor and can be interpreted as immune-mediated effects when the original tumor is responding.

Impact of Transcriptome and Gut Microbiome on the Response of HIV-1 Infected Individuals to a Dendritic Cell-Based HIV Therapeutic Vaccine.

Therapeutic vaccines based on dendritic cells offer a good approach to HIV-specific T-cell responses and partial control of the viral load after antiretroviral therapy interruption. The aim of the present study was to identify mRNA expression profiles and to assess the impact of the gut microbiome composition for predicting the viral load control after antiretroviral therapy interruption. We enrolled 29 patients to receive either placebo or a monocyte-derived dendritic cell vaccine. Patients with a decrease in their viral load of >0.5 log10 copies/mL by 12 weeks after antiretroviral therapy interruption were considered responders. In total, 66 genes were considered differentially expressed between responders and non-responders. Enrichment analysis revealed several upregulated pathways involved in the host defense response to a virus via the type I interferon signaling pathway. Regarding the gut microbiota, responders showed enriched levels of Bacteroidetes (p < 0.005) and Verrucomicrobia (p = 0.017), while non-responders were enriched with Tenericutes (p = 0.049) and Actinobacteria (p < 0.005). We also found important differences at the genus level. However, we did not discover any effect of the dendritic cell vaccine on the transcriptome or the gut microbiota. An alternative analysis did characterize that the microbiota from responders were associated with the metabolic production of short-chain fatty acids, which are key metabolites in the regulation of intestinal homeostasis. The evidence now consistently shows that short-chain fatty acid depletion occurs in HIV-infected individuals receiving antiretroviral treatment.

Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial

BackgroundAutologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination.MethodsThis is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin. Primary objectives were to study immunogenicity and feasibility, and secondary objectives were to assess toxicity and survival.ResultsTwenty-two stage III and 32 stage IV melanoma patients were analyzed. Antigen-specific CD8+ T cells were found in 44% versus 67% and functional T cell responses in 28% versus 19% of skin-test infiltrating lymphocytes in patients receiving DC vaccination with and without cisplatin, respectively. Four patients stopped cisplatin because of toxicity and continued DC monotherapy. No therapy-related grade 3 or 4 adverse events occurred due to DC monotherapy. During combination therapy, one therapy-related grade 3 adverse event, decompensated heart failure due to fluid overload, occurred. The clinical outcome parameters did not clearly suggest significant differences.ConclusionsCombination of DC vaccination and cisplatin in melanoma patients is feasible and safe, but does not seem to result in more tumor-specific T cell responses or improved clinical outcome, when compared to DC vaccination monotherapy.

Cells to prevent/treat relapse following allogeneic stem cell transplantation.

Relapse of cancer remains one of the primary causes of treatment failure and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). A multitude of approaches have been used in the management of posttransplant relapse. This review focuses on recent data with cellular therapies designed to treat or prevent posttransplant relapse of hematologic malignancies, although many of these therapeutic approaches also have applications to solid tumors and in the nontransplant setting. Currently available cell therapies include second transplant, natural killer cells, monocyte-derived dendritic cell vaccines, and lymphocytes via donor lymphocyte infusion, antigen-primed cytotoxic T lymphocytes, cytokine-induced killer cells, marrow-infiltrating lymphocytes, and chimeric antigen receptor T cells. These treatment options offer the prospect for improved relapse-free survival after HSCT.

Type I IFN-mediated synergistic activation of mouse and human DC subsets by TLR agonists.

Novel approaches of dendritic cell (DC) based cancer immunotherapy aim at harnessing the unique attributes of different DC subsets. Classical monocyte-derived DC vaccines are currently being replaced by either applying primary DCs or specifically targeting antigens and adjuvants to these subsets in vivo. Appropriate DC activation in both strategies is essential for optimal effect. For this purpose TLR agonists are favorable adjuvant choices, with TLR7 triggering being essential for inducing strong Th1 responses. However, mouse CD8α(+) DCs, considered to be the major cross-presenting subset, lack TLR7 expression. Interestingly, this DC subset can respond to TLR7 ligand upon concurrent TLR3 triggering. Nevertheless, the mechanism underlying this synergy remains obscure. We now show that TLR3 ligation results in the production of IFN-α, which rapidly induces the expression of TLR7, resulting in synergistic activation. Moreover, we demonstrate that this mechanism conversely holds for plasmacytoid DCs that respond to TLR3 ligation when TLR7 pathway is mobilized. We further demonstrate that this mechanism of sharpening DC senses is also conserved in human BDCA1(+) DCs and plasmacytoid DCs. These findings have important implications for future clinical trials as it suggests that combinations of TLR ligands should be applied irrespective of initial TLR expression profiles on natural DC subsets for optimal stimulation.

Stem cell-based dendritic cell vaccine development:

Background: Dendritic cell (DC) vaccines have significant potential in cancer immunotherapy. While autologous DCs can be derived from bone marrow, umbilical cord, and peripheral blood, monocyte-derived DC vaccines are most widely tested in clinical trials. However, producing autologous DC vaccines is labor intensive, has large variations among donors, and may not be feasible for patients with impaired cell function or requiring multiple vaccinations. Human pluripotent stem cells (hPSCs) have unlimited expansion potential while maintaining their pluripotency. They are being tested as a novel cell source to derive DCs for clinical application. Lung cancer is the leading cause for all cancer-related mortality. Efficient treatment of lung cancer by DC vaccines could offer great benefits in cancer immunotherapy. This review uses lung cancer as a case study to discuss the application of DC vaccines. Results: DC derivation from hPSCs has been demonstrated with high purity and comparable in vitro functions to autologous DCs derived from monocytes. The differentiation can be achieved either by co-culturing hPSCs with OP9 stromal cells or by the formation of three-dimensional embryoid bodies. As the scalable culture system is critical for hPSC-derived DC production, progress in the scalable culture systems for other hPSC-derived cells is reviewed and the use of relevant systems for hPSC-derived DCs is proposed. Conclusions: hPSCs provide a new source for DC production and have significant implication in DC-based cancer immunotherapy. Their use in clinical trials requires refinement of the culture expansion and differentiation protocols. Development of scalable culture systems is crucial in truly harnessing the potential of the hPSC-based DC immunotherapy in cancer treatment.

P19-45. Development of a therapeutic HIV vaccine comprised of autologous dendritic cells loaded with a mixture of lipopeptide HIV antigens

Background Clinical trials have shown that dendritic cell (DC)-based vaccines can induce antigen-specific immune responses as well as clinical responses in patients with stage IV cancer. In this study, a monocyte-derived DC vaccine pulsed with HIV antigen lipopeptides (LIPO5) was developed in preparation for a pilot vaccine clinical trial (DALIA) aimed at boosting the cellular immune response in chronic HIV infected patients on highly-active antiretroviral therapy (HAART).

Immunoregulatory T cells in the peripheral blood of melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cell vaccination

Regulatory T cells (Treg) may inhibit monocyte-derived melanoma antigen-pulsed dendritic cells (DC) vaccination in treatment of melanoma. However, the Treg level in peripheral blood mononuclear cells (PBMCs) following DC vaccination has not been examined in melanoma patients in Japan. To evaluate differences in the helper T cell and Treg population and mRNA levels of Treg in pre- and post-DC vaccination PBMCs obtained from melanoma patients. Levels of intracellular forkhead box protein 3 (Foxp3) mRNA as well as levels of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(+) T cells were examined by real-time PCR and flow cytometry using PBMCs from 9 patients who received DC vaccination. Eight of the 9 cases and 7 of the 9 cases showed increased populations of CD4(+)CD25(+) T cells and CD4(+)CD25(+)Foxp3(+) T cells, respectively after repeated DC vaccination. Five of 8 cases showed an increase of Foxp3 mRNA after treatment. Four of these 5 cases also had increased CD4(+)CD25(+) and CD4(+)CD25(+)Foxp3(+) T cells, but the fifth case showed a decrease in CD4(+)CD25(+)Foxp3(+) T cells. Three cases showed a decrease of Foxp3 mRNA. One of these 3 cases showed decreased population of CD4(+)CD25(+)Foxp3(+) T cells, but two cases showed increased population of CD4(+)CD25(+)Foxp3(+) T cells. In 3 of 8 cases Foxp3 expression at the cellular (protein) and mRNA level were inconsistent. Repeated DC vaccination may commonly induce Treg and helper T cells at the cellular level. However, there are a few discrepancies of Treg expression at cellular and mRNA level.

Immunohistological analysis of peptide-induced delayed-type hypersensitivity in advanced melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cell vaccination

In melanoma patients vaccinated with monocyte-derived melanoma peptide-pulsed dendritic cells (DC), the delayed-type hypersensitivity (DTH) reactions have been examined as a surrogate marker to determine if acquired immunity is induced by DC vaccination. To date, however, only limited information has been reported as for histopathological analyses of DTH. To evaluate tumor-specific immunomonitoring histopathologically after DC vaccination in melanoma patients. Seven patients previously vaccinated with monocyte-derived melanoma peptide-pulsed DCs were challenged with recall antigenic peptide injection in the skin of the forearm. Using immunohistochemical techniques, the presence of immune cells and the expression of CD4, CD8, interleukin (IL)-2, IL-4, IL-10, Foxp3, CD1a, CD1d, and interferon (IFN)-gamma was investigated at the site of injection where a DTH reaction developed. Strong DTH reactions from infiltrated erythema to bullae formation were detected in all 7 cases. Biopsies taken from the DTH site revealed heavy infiltration of mononuclear cells and eosinophils in the dermis and subcutaneous tissue. Cells staining positively for CD4, CD8, IL-2, IL-4, Foxp3, CD1d, and IFN-gamma were increased at the site 48h after antigen injection in all cases. Cells positive for IL-10 were never found in any patient. Regulatory T cells appeared 6h after injection and reached their maximum at day 7. The significant induction of CD8(+)T cells as well as both Th1 and Th2-type cells at the site of DTH suggests that effective antigen presentation leading to anti-tumor immune responses has taken place. Inhibitory mechanisms may also develop as the disappearance of the DTH response could be related to an increase in Foxp3+ cells.

Notes from the Arbeitsgemeinschaft Dermatologische Forschung (ADF), Berlin,

Notes from the Arbeitsgemeinschaft Dermatologische Forschung (ADF), Berlin,

Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation

Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation

Generation of an Optimized Polyvalent Monocyte-Derived Dendritic Cell Vaccine by Transfecting Defined RNAs after Rather Than before Maturation

Transfection with RNA is an attractive method of Ag delivery to dendritic cells (DCs), but has not yet been standardized. We describe in this study the methods to efficiently generate an optimized mature monocyte-derived DC vaccine at clinical scale based on the electroporation of several RNAs either into immature DC followed by maturation or, alternatively, directly into mature DCs, which has not been possible so far with such high efficiency. Electroporation of DCs resulted in high yield, high transfection efficiency (>90%), and high migration capacity. Intracellular staining allowed the study of the expression kinetics of Ags encoded by the transfected RNAs (MelanA, MAGE-3, and survivin) and a validation of the vaccine (>/=90% transfection efficiency). Expression of all three Ags peaked 3-4 h after electroporation in DC transfected either before or after maturation, but decreased differently. The DC vaccine can also be cryopreserved and nevertheless retains its viability, stimulatory capacity as well as migratory activity. In addition, we uncover that DC transfected after rather than before maturation appear to be preferable vaccines not only from a production point of view but also because they appear to be immunologically superior for CTL induction in sharp contrast to common belief. DCs transfected after maturation not only more effectively generate and present the Mage-3.A1 and MelanA.A2.1 epitopes to T cell clones, but they even are superior in priming to the standard proteasome-dependent MelanA.A2.1 wild-type prototype tumor epitope, both in terms of T cell expansion and effector function on a per cell basis.