Abstract: Disclosed are means, methods, and compositions of matter useful for generation of viruses that selectively grow in the tumor endothelium and causes lysis or augmentation of tumor immunity. In one embodiment an oncolytic virus is selectively maintained in cells resembling tumor endothelium under conditions allowing for the oncolytic virus to capture immunogenic entities found on the cells resembling tumor endothelial cells. In another embodiment, the endothelial cells resembling tumor endothelial cells are utilized as a “Trojan horse” for selective delivery of virus into a tumor or tumor microenvironment.

Abstract: Disclosed are means of treatment of cancer by enhancing efficacy of oncolytic virus ability to eradicate tumors through the destruction/inactivation of cancer endothelial cells through immunological means. In one embodiment of the invention, administration of placental endothelial cells generated antitumor endothelial immune responses are used to sensitize tumors to oncolytic viral entry. In another embodiment, oncolytic viruses are utilized to enhance generation of cancer endothelial specific responses by causing localized inflammation in the tumor endothelium, which enhances efficacy of the tumor endothelial targeting vaccine. In another embodiment, the invention teaches the use of replication deficient oncolytic viruses to deliver proteins to tumor cells in an immunogenic manner such that proteins encoded by the oncolytic viruses induce immunity to tumor endothelial cell antigens.

Abstract: Disclosed are means, methods, and compositions, useful for augmenting immune response to tumor cell death occurring in the body, wherein the tumor cell death acts as a source of antigens to stimulate an anti-cancer immune response. In one embodiment of the invention cryosurgery is performed in a manner to facilitate immune mediated killing of distant tumors, in effect causing an abscopal reaction, the amplification of the abscopal reaction is performed by preimmunization with antigen compositions generated to target tumor endothelium. In another embodiment the invention teaches the amplification of abscopal effect by preimmunizing with placental and/or tumor antigens prior to induction of necrotic cell death through means such as cryoablation, hyperthermia, radiation therapy, radiation therapy and intravenous vitamin C, and chemotherapy.

Abstract: Disclosed are means, methods, and compositions of matter useful for augmentation of a vaccine induced antitumor immune response through immunological targeting of tumor endothelium. In one embodiment a cancer antigen specific vaccine is combined with an endothelial targeting vaccine in a manner to facilitate release of tumor antigens as a result of endothelial destruction. The released tumor antigens serve to amplify immune response induced by the cancer antigen specific vaccine. In one embodiment an endogenous cancer vaccine is utilized as a source of immunization. The endogenous cancer vaccine may be cancer cells induced to die locally such as by means of: hyperthermia, irradiation, oncolytic virus exposure, and embolization.

Abstract: Disclosed are methods of preventing pregnancy through induction of immunological responses through vaccination with placental extracts and products associated with placentation. In one particular embodiment an immune response is triggered towards pregnancy associated neoangiogenesis through administration of placental endothelial cells capable of triggering immunity. In other embodiments the process of replicating immunological events associated with pregnancy failure are recapitulated by stimulation of immunity to antigens such as VEGFR-1, VEGFR-2, CD105, FGF1-R, Integrin ?v?3, and CD-248.

Abstract: Disclosed are methods of selecting donors for production of anti-angiogenic vaccines in order to ensure maximal elicitation of immunity. In one embodiment, the invention teaches the purposeful mismatching of major and/or minor human leukocyte antigen (HLA) between the donor and recipient. In other embodiments the invention provides a system for generating a cell bank, said cell bank comprising different donor originals that are subsequently matched with recipients for optimal immune response. In another embodiment cells are transfected to induce immunogenicity, in some embodiments, transfected with allogeneic and/or syngeneic antigens.

Abstract: Disclosed are methods, compositions of matter, and kits useful for augmentation of cells through modification of cellular membrane properties following ex vivo treatment.

Abstract: Disclosed are methods, compositions of matter, and therapeutic protocols for treatment of cancer by selectively inducing immune responses against blood vessels feeding neoplastic tissue. In one embodiment, placental endothelial cells are stimulated with Phorbol Myristate Acetate (PMA) to induce release of nanoparticles that possess ability to: a) be taken up by antigen presenting; b) presented through direct and indirect presentation to CD4 and CD8 T cells, respectively; and c) utilized to stimulate cytoxic T cellular and humoral responses to selectively inhibit angiogenesis of tumors.

Abstract: Disclosed are materials, methods, and protocols for inducing a therapeutic response in ocular conditions, such as diabetic retinopathy and wet macular degeneration, by immunizing with placental endothelial cells. In one embodiment, the invention teaches the administration of placental endothelial cells or products thereof, in an immunogenic context to induce antibody and/or cellular immune responses towards ocular neovascularization. The immunogenicity may be endowed by treatment with interferon gamma or agents known to induce upregulation of HLA. In one embodiment, the invention produces antibodies selectively targeting VEGF-associated angiogenesis characterized by a higher degree of vascular permeability as compared to non-malignant angiogenesis. In another embodiment, the invention provides means of inducing antibodies to vasculature associated with aberrant ocular angiogenesis through immunization with endothelial cells grown in conditions resembling tumor endothelial cells.

Abstract: Disclosed are compositions of matter, protocols, and treatment means for inducing an enhanced immunity targeting tumor endothelium in order to prophylactically protect subjects from development of neoplasia. In one embodiment, the invention provides placental endothelial cells that are tissue culture expanded under proliferative conditions to resemble the tumor endothelial driven angiogenesis. The cells are subsequently treated with interferon gamma to increase immunogenicity and utilized as a prophylactic vaccine. Antibody and cell mediated immunity towards tumor endothelial associated antigens is quantified with the aim of establishing protective immunity which inhibits or blocks development of angiogenesis-dependent neoplasia.

Abstract: Disclosed are methods, protocols, and compositions of matter useful for treatment of cancer by elicitation of immunity towards tumor blood vessels. In one embodiment, the invention teaches the stimulation of expression of tumor blood vessel associated antigens in cells derived from endothelial progenitor cells, through culture of cells in conditions resembling the tumor microenvironment. In another embodiment, the invention teaches increasing immunogenicity of endothelial progenitor cells or progeny thereof through treatment with agents such as interferon gamma, which are capable of upregulating histocompatibility antigens, which allow for allogeneic rejection upon administration. In another embodiment, the invention teaches immunization with endothelial progenitor cells or progeny thereof treated under conditions to resemble tumor blood vessels, in which administered cells are purposely mismatched with recipient HLA in order to provide for enhanced allogenicity.

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: 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: 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: 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 methods, protocols, and compositions of matter useful for generation of lymphocytes with permanently inactivated immunological checkpoint genes, said genes comprising PD-1, CTLA-4, LAG-3, and TIM-3. The generated lymphocytes may be autologous or allogeneic, and are useful in the treatment of neoplastic, viral or bacterial infections.