A Prospective, Cohort Study of SITOIGANAP to Treat Glioblastoma When Given in Combination With Granulocyte-Macrophage Colony-Stimulating Factor/Cyclophosphamide/Bevacizumab/Nivolumab or Granulocyte-Macrophage Colony-Stimulating Factor/Cyclophosphamide/Bevacizumab/Pembrolizumab in Patients Who Failed Prior Treatment With Surgical Resection, Radiation, and Temozolomide.

Background: Glioblastoma (GBM) is the most common primary, malignant brain tumor in adults and has a poor prognosis. The median progression-free survival (mPFS) of newly diagnosed GBM is approximately 6 months. The recurrence rate approaches 100%, and the case-fatality ratio approaches one.

Therapeutic Immunization against Glioblastoma.

Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients.

Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site.

First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity.

Glioblastoma multiforme (GBM) patients have a poor prognosis. After tumor recurrence statistics suggest an imminent death within 1-4.5 months.

Oil-based emulsion vaccine adjuvants.

Vaccine adjuvants are critical components in experimental and licensed vaccines used in human and veterinary medicine. When aiming to evoke an immune response to a purified antigen, the administration of antigen alone is often insufficient, unless the antigen contains microbial structures or has a natural particulate structure. In most cases, the rationale to use an adjuvant is obvious to the experimental immunologist or the professional vaccinologist, who is familiar with the nature of the antigen, and the aim of the vaccine to elicit a specific antibody response and/or a specific type of T cell response.

Development of immune memory to glial brain tumors after tumor regression induced by immunotherapeutic Toll-like receptor 7/8 activation.

The efficacy of immunotherapeutic TLR7/8 activation by resiquimod (R848) was evaluated in vivo, in the CNS-1 rat glioma model syngeneic to Lewis rats. The immune treatment was compared with cytotoxic cyclophosphamide chemotherapy, and as well, was compared with the combination cytotoxic and immunotherapeutic treatments. We found that parenteral treatment with the TLR7/8 agonist, resiquimod, eventually induced complete tumor regression of CNS-1 glioblastoma tumors in Lewis rats.

Exploring the Therapeutic Efficacy of Glioma Vaccines Based on Allo- and Syngeneic Antigens and Distinct Immunological Costimulation Activators.

The efficacy of a various immunotherapeutic immunisation strategies for malignant glioma brain cancer was evaluated in the syngeneic CNS-1 Lewis rat glioma model. A prototype glioma cancer vaccine, which was composed of multivalent antigens derived from allogeneic and syngeneic cells and lysates, formed the prototype preparation of antigens. These antigens reflect the autologous antigens derived from the patient's surgically removed tumor tissue, as well as allogeneic antigens form glioma tumor tissue surgically removed from donor patients.

Trends in vaccine adjuvants.

Adjuvants are essential components of most clinically used vaccines. This is because the majority of nonliving vaccines are relatively poor inducers of adaptive immunity unless effective adjuvants are co-administered. Aluminum salts (alum) have been used as adjuvants with great success for almost a century and have been particularly effective at promoting protective humoral immunity.

A novel soluble immune-type receptor (SITR) in teleost fish: carp SITR is involved in the nitric oxide-mediated response to a protozoan parasite.

Background: The innate immune system relies upon a wide range of germ-line encoded receptors including a large number of immunoglobulin superfamily (IgSF) receptors. Different Ig-like immune receptor families have been reported in mammals, birds, amphibians and fish. Most innate immune receptors of the IgSF are type I transmembrane proteins containing one or more extracellular Ig-like domains and their regulation of effector functions is mediated intracellularly by distinct stimulatory or inhibitory pathways.

Immunology of vaccine adjuvants.

In recent times vaccine adjuvants, or immunopotentiators, received abundant attention in the media as critical ingredients of current and future vaccines. Indeed, vaccine adjuvants are recognized to make the difference between competing vaccines based on identical antigens. Moreover, it is recognized that vaccines designed for certain indications require a matching combination of selected antigen(s) together with a critical immunopotentiator that selectively drives the required immune pathway with minimal adverse reactions.

Therapeutic vaccination against malignant gliomas based on allorecognition and syngeneic tumor antigens: proof of principle in two strains of rat.

In the present study we investigated whether allogeneic glioma cells can be utilized to evoke prophylactic or therapeutic immune-mediated elimination of syngeneic glioma in two rat strains. Fisher 344 and Sprague-Dawley (SD) rats were injected with two syngeneic glioma cell lines, 9L and C6, respectively, resulting in progressive tumor growth. 9L is syngeneic to the Fisher 344 and allogeneic to the SD rats, while C6 cells are syngeneic to SD rats and allogeneic to Fisher 344 rats.

Dose and timing requirements for immunogenicity of viral poultry vaccine antigen: investigations of emulsion-based depot function.

The release requirements for vaccine antigens delivered by adjuvants with presumed depot function are poorly understood. Water-in-oil (W/O) emulsions are routinely used in many poultry vaccines. They strongly activate antibody production, and are regarded as a depot from which antigens are slowly released, resulting in prolonged antigen residence.

Molecular immunophenotyping of lungs and spleens in naive and vaccinated chickens early after pulmonary avian influenza A (H9N2) virus infection.

In a respiratory-infection-model with the avian influenza A H9N2 virus we studied lung and splenic immune reactions in chickens using a recently developed 5K chicken immuno-microarray. Groups of chickens were either mock-immunized (referred to as non-immune), vaccinated with inactivated viral antigen only (immune) or with viral antigen in a water-in-oil (W/O) immunopotentiator (immune potentiated). Three weeks after vaccination all animals were given a respiratory infection.

Structure- and oil type-based efficacy of emulsion adjuvants.

Oil-based emulsions are well-known immunopotentiators for inactivated, "killed" vaccines. We addressed the relationship between emulsion structure and levels of in vivo antibody formation to inactivated New Castle Disease virus (NDV) and Infectious Bronchitis virus (IBV) as antigens in 3-week-old chickens. The use of a polymeric emulsifier allowed for direct comparison of three types of emulsions, water-in-oil (W/O), oil-in-water (O/W) and W/O-in-water (W/O/W), while maintaining an identical content of components for each vehicle.

Development of a chicken 5 K microarray targeted towards immune function.

Background: The development of microarray resources for the chicken is an important step in being able to profile gene expression changes occurring in birds in response to different challenges and stimuli. The creation of an immune-related array is highly valuable in determining the host immune response in relation to infection with a wide variety of bacterial and viral diseases.

Results: Here we report the development of chicken immune-related cDNA libraries and the subsequent construction of a microarray containing 5190 elements (in duplicate).

Potentiation of humoral immune responses to vaccine antigens by recombinant chicken IL-18 (rChIL-18).

Mammalian interleukin-18 (IL-18) is one of the pro-inflammatory cytokines involved in innate immune responses to microbial infection preceding the induction of both cellular and humoral immune responses. We assessed the potential of Escherichia coli-expressed His-tag purified recombinant chicken IL-18 (rHis-ChIL-18) as a potentiator of vaccine-induced immune responses in 3 week-old SPF chickens and compared it with several commonly used traditional immunostimulating adjuvants. We found that rHis-ChIL-18 significantly enhanced antibody responses to Clostridium perfringens alpha-toxoid and Newcastle disease virus (NDV) antigens, comparable to the Al(OH)3-gel, Miglyol and chitosan adjuvant.

Th1/Th2 polarization by viral and helminth infection in birds.

Mammals developed an immune system able to functionally polarize into so-called type 1 or type 2 immune pathways, to resolve infections with intracellular and extracellular pathogens, respectively. In the well-studied avian immune system of the chicken, however, no evidence for polarized immunity could be found, as yet. To investigate whether these two major arms of mammalian immunity, regulated by a T helper (Th)1/Th2 cytokine balance, evolved similarly in birds, chickens were exposed to a prevalent intracellular (viral) or extracellular (helminth) infection.

Immunisation with virion-loaded plasmacytoid or myeloid dendritic cells induces primary Th-1 immune responses.

Dendritic cells (DCs) induce different types of immune responses depending on their lineage and activation signals. When exposed to inactivated pseudorabiesvirus (iPRV), plasmacytoid but not myeloid DCs released IFN-alpha and IL-12. Remarkably, both iPRV-pulsed DC types were able to induce primary IFN-gamma producing T cells and IgG isotype switching in vivo.

Characterization of the first nonmammalian T2 cytokine gene cluster: the cluster contains functional single-copy genes for IL-3, IL-4, IL-13, and GM-CSF, a gene for IL-5 that appears to be a pseudogene, and a gene encoding another cytokinelike transcript, KK34.

A genomics approach based on the conservation of synteny was used to develop a bacterial artificial chromosome (BAC) contig across the chicken T2 cytokine gene cluster. Sequencing of representative BACs showed that the chicken genome encodes genes for the homologs of mammalian interleukin-3 (IL-3), IL-4, IL-5, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These sequences represent the first T2 cytokines found outside of mammals, and their location demonstrates that the T2 cluster is ancient (at least 300 million years old).

Structure-activity relations of water-in-oil vaccine formulations and induced antigen-specific antibody responses.

Water-in-oil (W/O) emulsions are known as most effective adjuvants to generate high and durable antibody responses to vaccine antigens following a single immunization. However, their structural requirements remain poorly understood. Here we addressed the significance of certain pharmaceutical characteristics including water/oil ratios--ranging from 60/40 to 30/70 (w/w(%))--droplet size and type of oil, i.

Host-dependent type 1 cytokine responses driven by inactivated viruses may fail to default in the absence of IL-12 or IFN-alpha/beta.

Replicating viruses generally induce type 1 immune responses, with high interferon (IFN)-gamma levels and antibodies of the IgG2a isotype. In the present study we demonstrate the intrinsic ability of non-replicating virions to induce comparable immune responses in the notable absence of any adjuvant. Injection of inactivated pseudorabies virus, an alphaherpesvirus, by various routes into mice resulted in the generation of T helper (Th) 1 type immune response.

Identification and molecular cloning of functional chicken IL-12.

By a combination of large-scale sequencing, bioinformatics, and traditional molecular biology, we identified the long-searched-for cDNA sequences encoding the homologues of the chicken IL-12p35 and IL-12p40 chains. These molecules are the first discovered nonmammalian IL-12 subunits. The homologies of the chicken IL-12p35 and IL-12p40 proteins to the corresponding known subunits of various species, i.

Vaccine adjuvant technology: from mechanistic concepts to practical applications.

Distinct types of immune responses are required for efficient elimination of different pathogens. Programming of the desired type of immune response by safe nonreplicating vaccines requires suitable vaccine adjuvants. Adjuvants largely determine the magnitude and quality of immune responses specific for the coadministered antigen.

Antigen delivery systems and immunostimulation.

The immune system evolved to free the host from invading noxious pathogens. Vaccines are inoculated as a prophylactic measure in order to program the immune system for accelerated recognition and elimination of specific pathogens. During vaccination the immune system is exposed to attenuated or inactivated microorganisms, or their fragments.