Described herein are compositions and methods for tissue-targeted expression of therapeutic genes, using AAV expression vectors that reduce the risk of toxicity associated with AAV gene therapy in the CNS by de-targeting the vulnerable neurons cells including the DRG cells on gene expression, and de-targeting the liver, a major suspect for over-expression in the periphery.

Described herein are compositions and methods for tissue-targeted expression of therapeutic genes, using AAV expression vectors that reduce the risk of toxicity associated with AAV gene therapy in the CNS by de-targeting the vulnerable neurons cells including the DRG cells on gene expression, and de-targeting the liver, a major suspect for over-expression in the periphery.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

Provided herein are combinations of an IL-2 molecule or mutein and a TNFR agonist, and complexes comprising IL-2/TNFR agonist molecules, such as Fc-bound IL-2/TNFR agonist molecules that preferentially expand and activate T regulatory cells and are amenable to large scale production. Also provided herein are methods of making and using the compositions of the present invention.

Provided herein are combinations of an IL-2 molecule or mutein and a TNFR agonist, and complexes comprising IL-2/TNFR agonist molecules, such as Fc-bound IL-2/TNFR agonist molecules that preferentially expand and activate T regulatory cells and are amenable to large scale production. Also provided herein are methods of making and using the compositions of the present invention.

The present invention relates to cytokine fusion proteins and to nucleic acid molecules encoding such cytokine fusion proteins. The present invention further relates to cells, non-human organisms. pharmaceutical compositions and kits comprising the cytokine fusion proteins or the nucleic acid molecules encoding them, as well as to their use as medicaments.

The present invention relates to cytokine fusion proteins and to nucleic acid molecules encoding such cytokine fusion proteins. The present invention further relates to cells, non-human organisms. pharmaceutical compositions and kits comprising the cytokine fusion proteins or the nucleic acid molecules encoding them, as well as to their use as medicaments.

The present invention provides for the intratumoral delivery of immunomodulators. In particular, it provides delivery of co-stimulatory molecules using intratumoral electroporation. The present invention provides a method for the treatment of malignancies, wherein the administration of a plasmid encoding for a therapeutic costimulatory protein, in combination with electroporation has a therapeutic effect on primary tumors as well as distant tumors and metastases.

The present invention relates to immunoconjugates, compositions, methods and uses for treating brain tumors, especially glioma, by administration of a tumour necrosis factor alpha (TNFα) immunoconjugate.