The present disclosure provides compositions and methods for producing modified cells (e.g., synthetic tumor-infiltrating lymphocytes or TILs). The modified cells can be used to prepare a pharmaceutical composition to be administered into a subject in need thereof. The modified cells can be polyclonal TCR-T cells expressing two or more different subject-specific T-cell receptors (TCRs).

The invention relates to the field of immunotherapy, more in particular to a composition for use in the treatment of cancer. The invention also relates to a composition obtainable by such a method, such as a pharmaceutical composition. More in particular, the invention relates to an ex vivo method for obtaining a composition suitable for the treatment of cancer in a subject, comprising the steps of providing primary tumor cells derived from the subject, and ex vivo contacting the tumor cells with an inhibitor of a bromodomain and extra-terminal domain family member (BET inhibitor).

Contemplated compositions and methods are directed to in vivo stimulation of T.sub.N cells to differentiate to T.sub.SCM cells in the presence of tumor cells expressing tumor associated antigens or tumor and patient specific neoepitopes using a pharmaceutical composition that includes an IL-15 portion and an IL-7 portion. The T.sub.SCM cells are then isolated and expanded in vitro, preferably using a pharmaceutical composition that includes an IL-15 portion, an IL-7 portion, and an IL21 portion, and subsequently administered to the patient.

Provided herein are exosomes (such as modified exosomes) that include or express one or more surface proteins that are covalently linked to an immunomodulatory molecule or a therapeutic molecule. In particular examples, the exosomes are from a cancer cell, a stem cell, or an immune cell. Also provided are methods of making and using the modified exosomes, for example for treating cancer.

The present invention provides a method for the expansion of HPV immunogen specific T cells, comprising the steps of: i. providing a phagocytosable particle comprising a core and a human papillomavirus (HPV) immunogen tightly associated to the core; wherein the HPV immunogen has an amino acid sequence that corresponds to the amino acid sequence of a HPV protein, or has an amino acid sequence that corresponds to an amino acid sequence of a part of a HPV protein; ii. providing APCs; iii. contacting the phagocytosable particle comprising a core and a HPV immunogen with the APCs from step ii in vitro, and under conditions allowing phagocytosis of the HPV immunogen by the APCs; iv. providing T-cells that have been harvested from a subject; v. contacting the T-cells with the APCs from step iii) in vitro, and under conditions allowing specific activation of HPV immunogen specific T-cells. The invention further provides an expanded population of therapeutically useful T-cells and their use in the treatment or prevention of cancer, particularly HPV positive cancers.

Described herein are compositions and methods for treating a disease, particularly a cancer, with an immune checkpoint modulatory agent and a strain of an Arbovirus or a strain of an Alphavirus. Also provided herein are also methods for combination therapy comprising administration of an immune checkpoint modulatory agent, tumor antigen primed dendritic cells and an Alphavirus or an Arbovirus.

The present disclosure provides methods and compositions for immunotherapy employing a modified T cell or NK cell comprising a receptor that binds to newly identified tumor antigens that can be administered to patients for disease (e.g., cancer) treatment. Also described are polynucleotides and vectors encoding the same.

Disclosed herein is a method of reprogramming highly motile cells found in tumors, such as these highly motile GSC and/or MDSC clones, into auto-destructive cell missiles (referred to herein as therapeutic stealth cells) that can seek and destroy new foci of recurrence within the body, such as the brain. Cells with enhanced motility can be sorted out from heterogeneous populations and then be rendered auto-destructive by deterministic delivery of an anti-cancer agent, such as an oncolytic virus plasmid cocktail.

The present specification provides methods for augmenting the antigenic content, especially of tumor-associated antigens (TAA), and immunogenicity of cancer cells; methods for enhancing cross-presentation in dendritic cells, compositions comprising such manipulated cells derived from single cancer patients; and methods of using those compositions as a personal immunotherapeutic product to treat the donor patient's cancer.

The present disclosure provides methods for genetically modifying lymphocytes and methods for performing adoptive cellular therapy that include transducing T cells and/or NK cells. The methods can include inhibitory RNA molecule(s) and/or engineered signaling polypeptides that can include a lymphoproliferative element, and/or a chimeric antigen receptor (CAR), for example a microenvironment restricted biologic CAR (MRB-CAR). Additional elements of such engineered signaling polypeptides are provided herein, such as those that drive proliferation and regulatory elements therefor, as well as replication incompetent recombinant retroviral particles and packaging cell lines and methods of making the same. Numerous elements and methods for regulating transduced and/or genetically modified T cells and/or NK cells are provided, such as, for example, those including riboswitches, MRB-CARS, recognition domains, and/or pH-modulating agents.