Abstract: Disclosed are methods, protocols, and compositions of matter related to utilization of chimeric antigen receptor (CAR) expressing cells for the targeting of tumor endothelium utilizing chimeric antigen receptor expressing stem cells. In one embodiment tumor endothelium specific antigens are utilized as targets of the antigen binding domain of a CAR, which is attached to an extracellular hinge domain, a domain that transverses the T cell membrane and an intracellular domain associated with T cell signaling. Suitable antigens for the practice of the invention include TEM-1, ROBO-4, surviving, and FasL. In other aspects of the invention antigens are identified through serological analysis of recombinant cDNA expression libraries (SEREX) using plasma from a patient immunized with placental endothelial cells.

Abstract: Augmenting or stimulating an immune response, to tumor endothelial cells, by: a) obtaining a tumor endothelial antigen or composition of antigens; b) administering said tumor endothelial antigen or composition of antigens in an immunogenic manner to a host; and c) providing a probiotic and/or prebiotic mixture to said host being immunized.

Abstract: Adjuvants acting at the level of antigen presentation useful for stimulation of specific immunity against tumor endothelial cells. In one embodiment the invention teaches the use of activation of specific antigen presenting cell programs to selectively induce cytotoxic T cells and antibodies with complement activating ability while not evoking antigenic responses that potentially stimulate angiogenesis or growth of tumor endothelial cells. Specifically, the invention teaches selection and use of adjuvants that inhibit suppressive dendritic cell produced factors, surface bound and soluble, while stimulating activatory cytokines. Adjuvant means include innate activatory molecules, gene silencing means, alarmins, and other stimulatory means resembling “danger” signals.

Abstract: The invention provides pluripotent stem cells and methods for making and using pluripotent stem cells. Pluripotent stem cells, among other things, can differentiate into various cell lineages in vitro, ex vivo and in vivo. Pluripotent stem cells, among other things, can also be used to produce conditioned medium.

Abstract: Disclosed are compositions, methods of use, and pharmaceutical preparations useful for treatment of cancer. In one embodiment dendritic cells (DC) are generated from a patient in need of treatment, matured utilizing a leukocyte lysate, and readministered into the same patient without the use of antigen pulsing. DC from different tissues, different stages of maturation, and different methods of inducing DC maturation are disclosed.

Abstract: Compositions of matter, of production, and treatment modalities are disclosed for the prevention and/or therapeutic reduction of tumors through induction of immunity against tumor associated fibroblasts and components of tumor microenvironment. In one embodiment of the invention, placentally derived fibroblast cells are cultured under conditions replicating tumor microenvironment. Expression of CD248 on said cultured fibroblasts is used as a marker of effective manipulation. Cells expressing CD248 are utilized a immunogens for stimulation of immunity towards cancer associated fibroblastic cells.

Abstract: Disclosed are cells, compositions of matter, and protocols, useful for stimulation of antigen-specific immunity or tolerogenesis by gene editing of immune suppressive costimulatory molecules for induction of immune stimulation, and gene editing of immune stimulatory molecules for immune suppression. Provided are means of stimulating immunity to cancer, viral antigens, or bacterial antigens through pulsing, fusing, or administering antigenic compositions to antigen presenting cells that are gene silenced for immune suppressive genes. Provided are means of treating transplant rejection or autoimmunity by gene silencing immune stimulatory genes.

Abstract: The current invention provides monocytic cells transfected with chimeric antigen receptor (CAR) to selectively home to tumors and upon homing differentiate into dendritic cells capable of activating immunity which is inhibitory to said tumor. In one embodiment of the invention, monocytic cells are transfected with a construct encoding an antigen binding domain, a transcellular or structural domain, and an intracellular signaling domain. In one specific aspect of the invention, the antigen binding domain interacts with sufficient affinity to a tumor antigen, capable of triggering said intracellular domain to induce an activation signal to induce monocyte differentiation into DC.

Abstract: Disclosed are means of stimulating innate and/or adaptive immunity to cancer by administration of exosomes. Stimulation of innate immunity involves modifying exosomes by chemical addition of innate immune stimulators, whereas stimulation of adaptive immunity involves pulsing dendritic cells generating exosomes with antigens, in some cases, pulsing with Brother of the Regulator of Imprinted Sites (BORIS) proteins, peptides, or altered peptide ligands thereof.

Abstract: Disclosed is the new, useful, and unexpected finding that immunization to placental endothelial cells stimulated with interferon gamma result in antibodies to the checkpoint inhibitor PD-L1. In one embodiment, the invention teaches the use of ValloVax™ to induce immunological hyperresponsiveness and reduction of costimulatory need for T cell activation. In another embodiment the invention teaches means of selecting placental populations for enhanced expression of PD-L1 in order to augment immunity towards checkpoint inhibitors.

Abstract: The invention discloses the utilization of DNA generated nanoparticles to block interaction between inhibitory signals in immune cells. Provided are compositions of matter, protocols and treatment methodologies for stimulation immunity through inhibiting suppressive molecules through the use of DNA based nanoparticles.

Abstract: Disclosed are compositions of matter, therapeutic protocols, and immunization means to induce an active immune response to vasculature feeding glioma or other brain neoplasia. In one embodiment the invention provides administration of placental derived endothelial cells at concentrations of 10 million to 50 million administered in a manner to stimulate immunity toward blood vessels supplying glioma or other brain neoplastic malignancies. The invention provides means of blocking augmenting efficacy of immunotherapy, chemotherapy, and radiotherapy.

Abstract: Disclosed are compositions of matter, methods, and protocols useful for treatment of cancer through induction of anti-angiogenic immune responses by vaccination together with immune modulation triggered by checkpoint inhibitors. The invention provides placenta, placental endothelial, placental fibroblasts, and mixtures thereof as immunogens, whose anti-angiogenic activity is augmented by utilization of checkpoint inhibitors. Means of differentiating tumor cells directly into endothelial or endothelial-like cells and utilizing said cells as immunogens for the purpose of inducing immunity against blood vessels feeding tumors. In one embodiment CTLA4 blockade is performed in combination with an immunogen capable of triggering immunity towards tumor endothelial cells. In another embodiment blockade of the PD1-PD1 ligand pathway is performed in combination with induction of anti-angiogenic immune response.

Abstract: Methods and compositions for treating or ameliorating lower back pain by administering an effective amount of one or more cell types, alone, and/or in combination with a matrix, and/or in combination with growth factors, in order to stimulate lumbar angiogenesis, decrease inflammation, and stimulating regeneration.

Abstract: Disclosed are methods of preparing and using placentally-derived stem cells and compositions useful for the treatment of cancer. Said stem cells and compositions function through inducing a “guided differentiation” program in cancer cells, thereby reducing malignancy. Further extension of the invention pertains to augmenting ability of administered cells to induce differentiation through the co-administration of known differentiation inducing agents. Within the context of this disclosure, methods for inducing host responses to cancer are also described.

Abstract: Disclosed are protocols, procedures and therapeutic compositions useful for augmentation of immunity to cancer and cancer associated endothelial cells by treatment with histone deacetylase (HDAC) inhibitors capable of augmenting stimulatory and costimulatory molecules on said cancer vaccines. Additionally, the invention teaches specific concentrations of HDAC inhibitors useful for stimulation of in vivo immunity to tumor and tumor endothelial cell targeting vaccines.

Abstract: Neutrophil extracellular traps (NETS) are webs of DNA held together with immunogenic peptides, released by neutrophils subsequent to activation. NETS are the most potent stimulator of dendritic cells, monocytes and T cells given their ability to activate TLR3, TLR4, TLR7 and TLR9. The use of NETS for in vivo stimulation of immunity in a therapeutic sense has not been utilized due to fear of anti-DNA antibody formation and subsequent development of systemic lupus erythromatosis. The current invention provides means of safely generating NETS in vitro through peripheral blood utilizing clinically safe means such as yeast-derived component zymosan, isolating said NETS, utilizing said NETS to in vitro activate cytokine production from PBMC in vitro, and concentrating said cytokines. Cytokines generated by this methodology have superior ability to stimulate NK cells in vitro as compared to isolated NK stimulatory cytokines.

Abstract: Disclosed are methods, compositions of matter, and cells, useful for the treatment of autism, social integrative disorders, and various cognitive abnormalities. The invention discloses, inter alia, means of inducing angiogenesis and immune modulation either in sequence or parallel in order to substantially ameliorate or reverse the progression of autism. The use of stem cells, and cells naturally possessing or endowed with angiogenic and anti-inflammatory activity are disclosed for autism either alone or in combination with various therapeutic interventions.

Abstract: Disclosed are methods of preparing and using placentally-derived stem cells and compositions useful for the treatment of cancer. Said stem cells and compositions function through inducing a “guided differentiation” program in cancer cells, thereby reducing malignancy. Further extension of the invention pertains to augmenting ability of administered cells to induce differentiation through the co-administration of known differentiation inducing agents. Within the context of this disclosure, methods for inducing host responses to cancer are also described.

Abstract: Disclosed is the new, useful, and unexpected finding that immunization to placental endothelial cells stimulated with interferon gamma result in antibodies to the checkpoint inhibitor PD-L1. In one embodiment, the invention teaches the use of ValloVax™ to induce immunological hyperresponsiveness and reduction of costimulatory need for T cell activation. In another embodiment the invention teaches means of selecting placental populations for enhanced expression of PD-L1 in order to augment immunity towards checkpoint inhibitors.