Described are novel immunosuppressant drug resistant armored (IDRA) T cells that co-express an exogenous T cell receptor (TCR) and one or more exogenous inhibitors of an immunosuppressant. The TCR can bind to an antigen expressed by a tumor cell or virally infected cell. Also described are methods of producing the modified T cell, and methods of treating a subject using the modified T cells.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

T cells comprising an engineered genomic modification of the TGFBR2 gene are provided. The genomic modification can reduce receptor surface expression and/or reduce TGF-β induced signaling, and allows T cells having such TGFBR2 disruption to continue to proliferate and continue to kill target tumor cells even in the presence of physiologically relevant levels of TGF-β. In preferred embodiments, the T cells are further engineered to express a CAR or exogenous TCR. Methods of making the engineered T cells, pharmaceutical compositions comprising populations of such T cells, and methods of treating are also provided.

A method of treating a metastatic lesion that presents a peptide containing SLLQHLIGL (SEQ ID NO: 310) on a cell surface, including selecting a patient having a metastatic lesion and administering to the patient a composition containing recombinant T lymphocytes or activated T lymphocytes that express a T cell receptor, or a functional fragment thereof, that is reactive with, or binds to, an MHC ligand containing SLLQHLIGL (SEQ ID NO: 310).

A method of treating a metastatic lesion that presents a peptide containing SLLQHLIGL (SEQ ID NO: 310) on a cell surface, including selecting a patient having a metastatic lesion and administering to the patient a composition containing recombinant T lymphocytes or activated T lymphocytes that express a T cell receptor, or a functional fragment thereof, that is reactive with, or binds to, an MHC ligand containing SLLQHLIGL (SEQ ID NO: 310).

A method of treating a metastatic lesion that presents a peptide containing SLLQHLIGL (SEQ ID NO: 310) on a cell surface, including selecting a patient having a metastatic lesion and administering to the patient a composition containing recombinant T lymphocytes or activated T lymphocytes that express a T cell receptor, or a functional fragment thereof, that is reactive with, or binds to, an MHC ligand containing SLLQHLIGL (SEQ ID NO: 310).

A method of treating a metastatic lesion that presents a peptide containing SLLQHLIGL (SEQ ID NO: 310) on a cell surface, including selecting a patient having a metastatic lesion and administering to the patient a composition containing recombinant T lymphocytes or activated T lymphocytes that express a T cell receptor, or a functional fragment thereof, that is reactive with, or binds to, an MHC ligand containing SLLQHLIGL (SEQ ID NO: 310).

Provided are improved methods for making immune effector cells, as well as improved immune effector cells generated using the methods. The improved T cells have improved respiratory capacity and mitochondrial mass. Adoptive T cell immunotherapies using such cells demonstrate improved survival, expansion, and persistence in vivo.

The invention relates to cancer management, specifically to therapeutic combinations and methods for immunotherapy of tumors and malignancies. More specifically, embodiments of the invention provide compositions, methods, pharmaceutical packages and combined preparations employing the use of a SLAMF6-mediated T cell activator in combination with a LAG3 inhibitor.