Utilização da imunoterapia no tratamento da leishmaniose visceral canina / Use of immunotherapy in the treatment of canine visceral leishmaniasis

Background: Canine visceral leishmaniasis is a worldwide zoonosis, with dogs being the main urban reservoirs. It is caused by a protozoan of the genus Leishmania spp. and is transmitted to mammals through a vector belonging to the phlebotomines family. Its treatment aims to reduce the parasitic load preventing these animals from being transmitters. Immunotherapy has been shown to be efficient in stimulating the patients immune response, improving the general condition and preventing recurrence. This report describes the case of a dog diagnosed with canine visceral leishmaniasis submitted to immunotherapy and drug protocol, noting significant general improvement. Case: An 8-year-old female dog was treated with ulcerated lesions on the paw pads, nasal plane and lip region, onychogryphosis and ungeitis, in addition, hypertrophied popliteal lymph nodes and erosive lesions in the elbows, without improvement with previous treatments. Serological examination was then performed to diagnose leishmaniasis by the immunosorbent assay (ELISA) technique with negative results. In addition, was performed puncture of the popliteal lymph node, sample in which amastigote forms of Leishmania were observed and blood sample analysis by immunochromatographic rapid test showing reagent result, confirming the diagnosis of canine visceral leishmaniasis. The treatment protocol with marbofloxacin, allopurinol, prednisolone and domperidone was initiated. Thirty days later, there was a total improvement of the lesions and healing of the paw pads. Immunotherapy was then initiated by applying three double doses of recombinant vaccine against canine visceral leishmaniasis. The applications were made subcutaneously, with an interval of 21 days between them, still maintaining allopurinol. After six months a...(AU)

Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.

Antibody-based cancer therapy.

Over the past 25 years, antibody therapeutics have emerged as clinically and commercially successful pharmaceuticals, rapidly approaching 100 Food and Drug Administration approvals with combined annual global sales exceeding $100 billion. Nearly half of the marketed antibody therapeutics are used in oncology. These antibody-based cancer therapies can be broken down into three categories based on their different mechanisms of action, i.e., (i) natural properties, (ii) engagement of cytotoxic T cells, and (iii) delivery of cytotoxic payloads. Both natural and engineered properties of the antibody molecule are founded on its highly stable and modular architecture. In this review we provide an overview and outlook of the rapidly evolving landscape of antibody-based cancer therapy.

Modulation of the tumor micro-environment by CD8+ T cell-derived cytokines.

Upon their activation, CD8+ T cells in the tumor micro-environment (TME) secrete cytokines such as IFNγ, TNFα, and IL-2. While over the past years a major interest has developed in the antigenic signals that induce such cytokine release, our understanding of the cells that subsequently sense these CD8+ T-cell secreted cytokines is modest. Here, we review the current insights into the spreading behavior of CD8+ T-cell-secreted cytokines in the TME. We argue for a model in which variation in the mode of cytokine secretion, cytokine half-life, receptor-mediated clearance, cytokine binding to extracellular components, and feedback or forward loops, between different cytokines or between individual tumors, sculpts the local tissue response to natural and therapy-induced T-cell activation in human cancer.

Immunotherapy of melanoma: peptide mimics of a human high molecular weight-melanoma associated antigen

The realization that tumor cells utilize multiple mechanisms to escape from immune recognition and destruction has stimulated interest in developing and applying immunotherapeutic strategies which target both humoral and cellular immunity to malignant cells. As a result, the tumor-associated antigens (TAA) used as targets have to be expressed on the cell surface membrane of malignant cells. Furthermore, since most of the TAA used for active specific immunotherapy are self-antigens, a challenge facing tumor immunologists is to develop strategies which are effective in breaking tolerance to self-antigens. This chapter describes one strategy which relies on the use of peptide mimics of the human high molecular weight-melanoma associated antigen (HMW-MAA) as immunogens to implement active specific immunotherapy in patients with malignant melanoma. These mimics, which are isolated from phage display peptide libraries by panning with anti-HMW-MAA monoclonal antibodies, are expected to induce both humoral and cellular anti-HMW-MAA immunity.

Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments.

Although the discovery and characterization of multiple tumor antigens have sparked the development of many antigen/derived cancer vaccines, many are poorly immunogenic and thus, lack clinical efficacy. Adjuvants are therefore incorporated into vaccine formulations to trigger strong and long-lasting immune responses. Adjuvants have generally been classified into two categories: those that 'depot' antigens (e.g. mineral salts such as aluminum hydroxide, emulsions, liposomes) and those that act as immunostimulants (Toll Like Receptor agonists, saponins, cytokines). In addition, several novel technologies using vector-based delivery of antigens have been used. Unfortunately, the immune system declines with age, a phenomenon known as immunosenescence, and this is characterized by functional changes in both innate and adaptive cellular immunity systems as well as in lymph node architecture. While many of the immune functions decline over time, others paradoxically increase. Indeed, aging is known to be associated with a low level of chronic inflammation-inflamm-aging. Given that the median age of cancer diagnosis is 66 years and that immunotherapeutic interventions such as cancer vaccines are currently given in combination with or after other forms of treatments which themselves have immune-modulating potential such as surgery, chemotherapy and radiotherapy, the choice of adjuvants requires careful consideration in order to achieve the maximum immune response in a compromised environment. In addition, more clinical trials need to be performed to carefully assess how less conventional form of immune adjuvants, such as exercise, diet and psychological care which have all be shown to influence immune responses can be incorporated to improve the efficacy of cancer vaccines. In this review, adjuvants will be discussed with respect to the above-mentioned important elements.

Bacille Calmette-Guérin attenuates vascular amyloid pathology and maximizes synaptic preservation in APP/PS1 mice following active amyloid-ß immunotherapy.

Despite effective clearance of parenchymal amyloid-ß (Aß) in patients with Alzheimer's disease, Aß immunotherapy exacerbates the vascular Aß (VAß)-associated pathology in the brain. We have previously shown that BCG immunization facilitates protective monocyte recruitment to the brain of APP/PS1 mice. Here, we confirmed that the 4Aß1-15 vaccine exacerbates VAß deposits in this model, which coincides with a decrease in the number of cerebrovascular endothelial cells and pericytes, infiltration of neutrophils into the brain, and induction of cerebral microhemorrhage. Moreover, combined 4Aß1-15/BCG treatment abrogates the development of the VAß-associated pathology. In addition, BCG treatment is required for the upregulation of interleukin-10 in the brain. Notably, BCG treatment selectively enhances Aß phagocytosis by recruited macrophages. Furthermore, combined 4Aß1-15/BCG treatment is more effective than 4Aß1-15 monotherapy in synaptic preservation and the enhancement of the learning efficiency. Overall, our study suggests that the combination of Aß-targeted therapy with an immunomodulatory strategy may improve the efficacy of Aß vaccine in Alzheimer's disease.

A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint.

Epigenetic therapies may modulate the tumor microenvironment. We evaluated the safety and optimal sequence of combination DNA methyltransferase inhibitor guadecitabine with a granulocyte macrophage-colony-stimulating-factor (GM-CSF) secreting colon cancer (CRC) vaccine (GVAX) using a primary endpoint of change in CD45RO + T cells. 18 patients with advanced CRC enrolled, 11 underwent paired biopsies and were evaluable for the primary endpoint. No significant increase in CD45RO + cells was noted. Grade 3-4 toxicities were expected and manageable. Guadecitabine + GVAX was tolerable but demonstrated no significant immunologic activity in CRC. We report a novel trial design to efficiently evaluate investigational therapies with a primary pharmacodynamic endpoint.Trial registry Clinicaltrials.gov: NCT01966289. Registered 21 October, 2013.

Preventable public health challenge: Rabies suspected exposure and prophylaxis practices in southwestern of Turkey.

BACKGROUND: Rabies is found in many countries of the eastern Mediterranean and is one of the most important zoonotic diseases in the world. The study aims to describe rabies suspected exposures (RSE) and rabies prophylaxis practices in Antalya-Turkey between 2010 and 2013. METHODS: All 2513 RSE cases presenting to a rabies vaccination center in Antalya, southwestern Turkey, were retrospectively investigated. RESULTS: The mean age of the RSE cases was 30.04±19.63 years with male predominance (63.6%). The vast majority was from urban areas (91.7%), and a postexposure rabies vaccination program was applied to 79.7% of participants. Dogs were the primary source of RSE cases (61.2%). The 39.2% of animals were under observation, and 9.53% of them died. Forty-two animals (1.7%) were laboratory confirmed rabid; 61.9% of them were cows. The rabid animal rate in the rural area was significantly higher than the urban area (18.2% versus 0.2%; p=0.001). CONCLUSIONS: This study includes a large number of RSE cases and prophylaxis practices in southwestern Turkey. Most RSE cases had dog or cat contact. As most RSE cases were in urban areas; more focused efforts should be made for elimination and vaccination of feral dog and cat population in Turkey.

Metal-Phenolic Network-Encapsulated Nanovaccine with pH and Reduction Dual Responsiveness for Enhanced Cancer Immunotherapy.

Cancer nanovaccines have been widely explored to enhance immunotherapy efficiency, in which the significant irritation of antigen-specific cytotoxic T cells (CTLs) is the critical point. In this study, we developed a pH and reduction dual-sensitive nanovaccine (PMSN@OVA-MPN) composed of two parts. The inner part was made up of polyethyleneimine (PEI)-modified mesoporous silica nanoparticles (MSNs) loaded with model antigen ovalbumin (OVA) and the outer part was made up of disulfide bond-involved metal-phenolic networks (MPNs) as a protective corona. In vitro release experiments proved that PMSN@OVA-MPN could intelligently release OVA in the presence of reductive glutathione, but not in neutral phosphate-buffered saline (PBS). Moreover, in vitro cell assays indicated that the nanovaccine promoted not only the OVA uptake efficiency by DC2.4 cells but also antigen lysosome escape due to the proton sponge effect of PEI. Furthermore, in vivo animal experiments indicated that PMSN@OVA-MPN induced a large tumor-specific cellular immune response so as to effectively inhibit the growth of an existing tumor. Finally, the immune memory effect caused by the nanovaccine afforded conspicuous prophylaxis efficacy in neonatal tumors. Hence, the multifunctional vaccine delivery system prepared in this work exhibits a great application potential in cancer immunotherapy and offers a platform for the development of nanovaccines.

Phase II Adjuvant Cancer-specific Vaccine Therapy for Esophageal Cancer Patients Curatively Resected After Preoperative Therapy With Pathologically Positive Nodes; Possible Significance of Tumor Immune Microenvironment in its Clinical Effects.

OBJECTIVES: To elucidate the efficacy of adjuvant vaccine monotherapy using 3 Human Leukocyte Antigen (HLA)-A∗24-restricted tumor-specific peptide antigens for ESCC, upregulated lung cancer 10, cell division cycle associated 1, and KH domain-containing protein overexpressed in cancer 1. SUMMARY OF BACKGROUND DATA: ESCC patients with pathologically positive nodes (pN(+)) have a high risk for postoperative recurrence, despite curative resection after preoperative therapy. Subclinical micrometastases are an appropriate target for cancer vaccine. METHODS: This is a non-randomized prospective phase II clinical trial (UMIN000003557). ESCC patients curatively resected after preoperative therapy with pN(+) were allocated into the control and vaccine groups (CG and VG) according to the HLA-A status. One mg each of three epitope peptides was postoperatively injected 10 times weekly followed by 10 times biweekly to the VG. The primary and secondary endpoints were relapse-free survival (RFS) and esophageal cancer-specific survival (ECSS), respectively. RESULTS: Thirty were in the CG and 33 in the VG. No significant difference was observed in RFS between the CG and VG (5-year RFS: 32.5% vs 45.3%), but the recurrence rate significantly decreased with the number of peptides which induced antigen-specific cytotoxic T lymphocytes. The VG showed a significantly higher 5-year ECSS than the CG (60.0% vs 32.4%, P = 0.045) and this difference was more prominent in patients with CD8+ and programmed death-ligand 1 double negative tumor (68.0% vs 17.7%, P = 0.010). CONCLUSIONS: Our cancer peptide vaccine might improve the survival of ESCC patients, which is warranted to be verified in the phase III randomized controlled study.

Multifactorial Design of a Supramolecular Peptide Anti-IL-17 Vaccine Toward the Treatment of Psoriasis.

Current treatments for chronic immune-mediated diseases such as psoriasis, rheumatoid arthritis, or Crohn's disease commonly rely on cytokine neutralization using monoclonal antibodies; however, such approaches have drawbacks. Frequent repeated dosing can lead to the formation of anti-drug antibodies and patient compliance issues, and it is difficult to identify a single antibody that is broadly efficacious across diverse patient populations. As an alternative to monoclonal antibody therapy, anti-cytokine immunization is a potential means for long-term therapeutic control of chronic inflammatory diseases. Here we report a supramolecular peptide-based approach for raising antibodies against IL-17 and demonstrate its efficacy in a murine model of psoriasis. B-cell epitopes from IL-17 were co-assembled with the universal T-cell epitope PADRE using the Q11 self-assembling peptide nanofiber system. These materials, with or without adjuvants, raised antibody responses against IL-17. Exploiting the modularity of the system, multifactorial experimental designs were used to select formulations maximizing titer and avidity. In a mouse model of psoriasis induced by imiquimod, unadjuvanted nanofibers had therapeutic efficacy, which could be enhanced with alum adjuvant but reversed with CpG adjuvant. Measurements of antibody subclass induced by adjuvanted and unadjuvanted formulations revealed strong correlations between therapeutic efficacy and titers of IgG1 (improved efficacy) or IgG2b (worsened efficacy). These findings have important implications for the development of anti-cytokine active immunotherapies and suggest that immune phenotype is an important metric for eliciting therapeutic anti-cytokine antibody responses.

The evolution of interventional oncology in the 21st century.

Interventional oncology (IO) has proven to be highly efficient in the local therapy of numerous malignant tumors in addition to surgery, chemotherapy, and radiotherapy. Due to the advent of immune-oncology with the possibility of tumor control at the molecular and cellular levels, a system change is currently emerging. This will significantly rule oncology in the coming decades. Therefore, one cannot think about IO in the 21st century without considering immunology. For IO, this means paying much more attention to the immunomodulatory effects of the interventional techniques, which have so far been neglected, and to explore the synergistic possibilities with immuno-oncology. It can be expected that the combined use of IO and immuno-oncology will help to overcome the limitations of the latter, such as limited local effects and a high rate of side-effects. To do this, however, sectoral boundaries must be removed and interdisciplinary research efforts must be strengthened. In case of success, IO will face an exciting future.

Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine.

BACKGROUND: While prophylactic human papillomavirus (HPV) vaccines will certainly reduce the incidence of HPV-associated cancers, these malignancies remain a major health issue. PDS0101 is a liposomal-based HPV therapeutic vaccine consisting of the immune activating cationic lipid R-DOTAP and HLA-unrestricted HPV16 peptides that has shown in vivo CD8+ T cell induction and safety in a phase I study. In this report, we have employed the PDS0101 vaccine with two immune modulators previously characterized in preclinical studies and which are currently in phase II clinical trials. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domains of the transforming growth factor-ß receptor type II (TGFßRII) fused to a human IgG1 monoclonal antibody blocking programmed cell death protein-1 ligand (PDL1), designed both as a checkpoint inhibitor and to bring the TGFßRII 'trap' to the tumor microenvironment (TME). NHS-interleukin-12 (NHS-IL12) is a tumor targeting immunocytokine designed to bring IL-12 to the TME and thus enhance the inflammatory Th1 response. METHODS: We employed TC-1 carcinoma (expressing HPV16 E6 and E7 and devoid of PDL1 expression) in a syngeneic mouse model in monotherapy and combination therapy studies to analyze antitumor effects and changes in immune cell types in the spleen and the TME. RESULTS: As a monotherapy, the PDS0101 vaccine generated HPV-specific T cells and antitumor activity in mice bearing HPV-expressing mEER oropharyngeal and TC-1 lung carcinomas. When used as a monotherapy in the TC-1 model, NHS-IL12 elicited antitumor effects as well as an increase in CD8+ T cells in the TME. When used as a monotherapy, bintrafusp alfa did not elicit antitumor effects or any increase in T cells in the TME. When all three agents were used in combination, maximum antitumor effects were observed, which correlated with increases in T cells and T-cell clonality in the TME. CONCLUSION: These studies provide the rationale for the potential clinical use of combinations of agents that can (1) induce tumor-associated T-cell responses, (2) potentiate immune responses in the TME and (3) reduce immunosuppressive entities in the TME.

Investigation of the combination of anti-PD-L1 mAb with HER2/neu-loaded dendritic cells and QS-21 saponin adjuvant: effect against HER2 positive breast cancer in mice.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is overexpressed in a subset of cancers including 25% of breast cancers. Since combination therapy consisting of multiple therapeutic approaches is considered a promising regimen, we examined combination treatment modalities in a xenograft model in Balb/c mice injected with 4T1-HER2 cells. We used HER2/neu-loaded bone marrow-derived dendritic cells (BM-DC's) along with anti-PD-L1 monoclonal antibody in a new combination immunotherapy model. METHODS: The combination was composed of an active immunotherapy (i.e. BM-DC-based vaccine) designed to boost the immune response against target antigen and was augmented by using anti-PD-L1 mAb to prevent immune evasion by the xenografted tumors. The vaccine combination was further supported using a QS-21 saponin adjuvant and the immune response was evaluated. RESULTS: Mice treated with HER2/neu-loaded BM-DCs, combined with QS-21 and anti-PD-L1 mAb had significantly decreased tumor sizes and their splenocytes had enhanced cytotoxic activity, based on the lactate dehydrogenase (LDH) assay, compared to vaccine and adjuvant groups alone. The same vaccination group demonstrated a remarkable increase in IFN-γ secreting CD8+ T-cells analyzed by flow cytometry. ELISA data also revealed a significant increase in the serum anti-HER2 IgG1 response; in addition, there was significant splenocyte proliferation upon stimulation with antigen compared to vaccine and adjuvant groups. Consistently, a significant infiltration of CD4+, CD8+ immune cells in and around the tumors was observed. CONCLUSIONS: Our data suggest that the BM-DC + HER2/neu + QS-21 + anti-PD-L1 vaccine combination paradigm synergistically generates anti-tumor activity and immune responses against HER2 overexpressing breast cancer in mice.