The inventive subject matter relates to methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, provided that said allogeneic donor is not MHC-matched to said subject. The inventive methods can be further enhanced by genetic engineering for targeted immunotherapy.

The field of the present invention relates to immunotherapeutic peptides, peptide binding agents, and their use, for example, in the immunotherapy of cancer.

The present invention relates to antibody molecules which bind to programmed death-ligand 1 (PD-L1) and lymphocyte-activation gene 3 (LAG-3). The antibody molecules preferably comprise a CDR-based antigen binding site for PD-L1, and a LAG-3 antigen binding site which may be located in two or more structural loops of a CH3 domain of the antibody molecule. The antibody molecules of the invention find application, for example, in cancer therapy.

The present invention relates to a cancer-specific tumor antigen neoepitope represented by any one of SEQ ID NOs: 1 to 184, an antigen-presenting cell loaded with the neoepitope, and a method for activating T cells for cancer treatment using the antigen-presenting cell. An antigen-presenting cell, that is, a dendritic cell, loaded with a cancer-specific tumor antigen epitope provided in the present invention enables rapid and effective induction of differentiation and proliferation of cancer antigen-specific T cells, preferably memory T cells, and the memory T cells thus activated can treat a cancerous or neoplastic condition or prevent recurrence, progression, or metastasis of cancer while avoiding the defense mechanism of cancer cells.

Disclosed are methods of preparing an isolated population of dendritic cells, isolated populations of dendritic cells prepared by the methods, and pharmaceutical compositions comprising the isolated population of dendritic cells. Also disclosed are methods of treating or preventing cancer using the isolated population of dendritic cells or pharmaceutical compositions.

Contemplated compositions and methods counteract evasive measures of a tumor by rendering access to the tumor microenvironment, tagging the tumor microenvironment with chemoattractant and/or cytokines, delivering or facilitating a cell-based therapy in the tumor microenvironment while providing inhibition of immune suppressor cells in the tumor microenvironment.

Contemplated compositions and methods counteract evasive measures of a tumor by rendering access to the tumor microenvironment, tagging the tumor microenvironment with chemoattractant and/or cytokines, delivering or facilitating a cell-based therapy in the tumor microenvironment while providing inhibition of immune suppressor cells in the tumor microenvironment.

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have observed the emergence of acquired resistance in non-small cell lung cancer patients that were initially responsive to immune checkpoint blockade. Resistance occurred 4-11 months after the initiation of immunotherapy and both clinical response and therapeutic resistance were associated with changes in T cell clonality but not with changes in expression of PD-L1. Genomic analyses of responsive and resistant tumors from the same patients identified loss of 7 to 18 mutation-associated putative neoantigens in resistant clones that were predicted to have high MHC binding affinity. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations. These analyses provide insights into the mechanisms of evasion to immune checkpoint blockade and immune therapies that target tumor neoantigens.

The present disclosure relates to immune cells that express an exogenous neoantigen and an immunogenicity enhancer, or to T cells that express an exogenous neoantigen, and their use in treating a disease or disorder, such as cancer for tumor associated neoantigens. Related expression constructs, kits, host cells, pharmaceutical compositions, and methods are also provided.

The inventive subject matter relates to methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, provided that said allogeneic donor is not MHC-matched to said subject. The inventive methods can be further enhanced by genetic engineering for targeted immunotherapy.