The present application relates generally to genetically modified arenaviruses that are suitable vaccines against neoplastic diseases, such as cancer. The arenaviruses described herein may be suitable for vaccines and/or treatment of neoplastic diseases and/or for the use in immunotherapies. In particular, provided herein are methods and compositions for treating a neoplastic disease by administering a genetically modified arenavirus in combination with an immune checkpoint inhibitor, wherein the arenavirus has been engineered to include a nucleotide sequence encoding a tumor antigen, tumor associated antigen or antigenic fragment thereof.

The invention relates to a composition which induces, in a host, a cytotoxic cell response directed against cells expressing an antigen, in particular tumour cells, and which comprises red blood cells containing said antigen. These red blood cells may be in the form of an immune complex with an immunoglobulin, in particular IgG, which recognizes an epitope at the surface of the red blood cells, and/or be heat-treated or chemically treated so as to promote phagocytosis of said red blood cells by dendritic cells. As a variant, the red blood cells may be xenogenic red blood cells. The invention also relates to a therapeutic especially anti-tumour vaccine containing such a composition.

In certain embodiments, this disclosure relates to conjugates comprising GM-CSF and IL-7 and uses related thereto, e.g., enhancing the adaptive immune system. Typically the GM-CSF and IL-7 are connected by a polymer linker, e.g., polypeptide. In certain embodiments, the disclosure relates to nucleic acids encoding these polypeptide conjugates, vectors comprising nucleic acid encoding polypeptide conjugates, and protein expression systems comprising these vectors such as infectious viral particles and host cells comprising such a nucleic acids.

The present invention relates to a nucleic acid sequence, comprising or coding for a coding region, encoding at least one peptide or protein comprising a tumour antigen or a fragment, variant or derivative thereof, at least one histone stem-loop and a poly(A) sequence or a polyadenylation signal. Furthermore the present invention provides the use of the nucleic acid for increasing the expression of said encoded peptide or protein. It also discloses its use for the preparation of a pharmaceutical composition, especially a vaccine, e.g. for use in the treatment of cancer or tumour diseases. The present invention further describes a method for increasing the expression of a peptide or protein comprising a tumour antigen or a fragment, variant or derivative thereof, using the nucleic acid comprising or coding for a histone stem-loop and a poly(A) sequence or a polyadenylation signal.

The described invention provides a tumor cell vaccine comprising genetically modified tumor cell line of a particular tumor type that stably expresses high levels of two or more immunomodulators. According to some embodiments, an immunogenic amount of the tumor cell line variants may be selected for concomitant expression of two or more of recombinant membrane expressed IgG1, CD40L, TNF-alpha, as well as membrane and soluble forms of GM-CSF, and Flt-3L peptides that are effective to elicit an anti-tumor immune response compared to the parent unmodified tumor cell line as measured in vitro by a one-way mixed lymphocyte tumor reaction assay using human peripheral blood mononuclear cells and the genetically modified allogeneic cell vaccine candidate. According to some embodiments, the tumor cell vaccine candidate will induce an immune response in the recipient cancer patient that cross reacts with the patient's own (autologous) tumor cells, the effects of which will be sufficient to result in enhanced anti-tumor immunity contributing to the increased survival of a vaccinated patient cohort compared to a matched unvaccinated patient cohort.

In certain embodiments, this disclosure relates to conjugates comprising GM-CSF and IL-7 and uses related thereto, e.g., enhancing the adaptive immune system. Typically the GM-CSF and IL-7 are connected by a polymer linker, e.g., polypeptide. In certain embodiments, the disclosure relates to nucleic acids encoding these polypeptide conjugates, vectors comprising nucleic acid encoding polypeptide conjugates, and protein expression systems comprising these vectors such as infectious viral particles and host cells comprising such a nucleic acids.

A method is disclosed for treating a cancer in a subject. The method comprises administering to the subject a composition comprising a therapeutically effective amount of a checkpoint inhibitor and a therapeutically effective amount of a tumor vaccine. In some embodiments, the tumor vaccine comprises radiated autologous tumor cells and a cell line engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) and cluster of differentiation 40 (CD40) ligand. In some embodiments, the checkpoint inhibitor comprises an anti-programmed death-1 (anti-PD-1) antibody (e.g., BMS 936558), anti-programmed death ligand-1 (anti-PD-L1) antibody (e.g., cloneMIHI), anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) antibody (e.g., Ipilimumab, BMS), or any combination thereof.

In some aspects, the invention relates to compositions and methods of generating antigens, wherein the antigen is a biomolecule that is modified by a reactive oxygen species or a reactive nitrogen species. In some aspects, the invention relates to compositions and methods of generating antibodies that bind to biomolecules that have been modified by a reactive oxygen species or a reactive nitrogen species. In some aspects, the invention relates to compositions and methods of generating antibodies that bind to novel epitopes on unmodified biomolecules. In some aspects, the invention relates to the induction of active immunotherapeutic processes (e.g., using preventive or therapeutic vaccines), which may comprise administering neo-antigens generated through methods and compositions described herein.

The invention relates to a composition which induces, in a host, a cytotoxic cell response directed against cells expressing an antigen, in particular tumor cells, and which comprises red blood cells containing said antigen. These red blood cells may be in the form of an immune complex with an immunoglobulin, in particular IgG, which recognizes an epitope at the surface of the red blood cells, and/or be heat-treated or chemically treated so as to promote phagocytosis of said red blood cells by dendritic cells. As a variant, the red blood cells may be xenogenic red blood cells. The invention also relates to a therapeutic especially anti-tumor vaccine containing such a composition.

The present invention is related to the fields of Biotechnology and Medicine. Particularly, it describes therapeutic vaccine compositions able to produce an autoimmune reaction against haemopoietic growth factors such as G-SCF and/or GM-CSF bounded to other molecules or a fragment thereof by chemical conjugation or fusion. Such vaccines compositions are useful for the treatment of inflammatory diseases, especially wherein a pathological increasing of the circulating neutrophils occurs.