Embodiments of the present disclosure relate to compositions and methods of enhancing lymphocytes' ability to treat cancer patients. Embodiments relate to a polynucleotide comprising a nucleic acid encoding a chimeric antigen receptor (CAR), a nucleic acid encoding an Oxygen-Dependent Degradation domain (ODD), and a nucleic acid encoding one or multiple sequences of Hypoxia-Response Element (HRE).

The compositions and methods described herein are directed to treating solid tumor using CAR T therapy. For example, the compositions include CAR T cells comprising an extracellular domain that binds FCR1, MSLN, GPC-3, ALPP, CD70, CLDN6, ROR1, CD205, ACPP, ADAM12, or CLDN18.2.

The present invention includes compositions and methods for an DPP6 specific chimeric antigen receptor (CAR). In certain embodiments the DPP6 specific CAR is expressed on a T regulatory cell. In certain embodiments, the DPP6 specific CAR is used to treat type 1 diabetes.

The present invention includes compositions and methods for an DPP6 specific chimeric antigen receptor (CAR). In certain embodiments the DPP6 specific CAR is expressed on a T regulatory cell. In certain embodiments, the DPP6 specific CAR is used to treat type 1 diabetes.

Anti-ADAM12 agents are provided such as anti-ADAM12 antibodies (Abs), antigen-binding Ab fragments, multi-specific Abs and antigen-binding Ab fragments, antibody-drug conjugates (ADCs), and chimeric antigen receptors (CARs). Also, nucleic acid sequences and vectors are provided encoding, cells and pharmaceutical compositions comprising such anti-ADAM12 agents and methods for expanding such cells. Methods of treating, preventing, or diagnosing a disease such as cancer and methods of stimulating an immune response using such materials are also provided.

Provided herein is a cytotoxic immune cell that is primed by and/or whose cytotoxicity within the tumor microenvironment is enhanced by binding to a stromal marker, e.g., Fibroblast Activation Protein Alpha (FAP). In some embodiments, the cells may contain a protein circuit that contains at least two components, wherein one of the components binding-triggered transcriptional switch that is activated by binding to the stromal marker. The second component may be a nucleic acid encoding an immune receptor (e.g., a chimeric antigen receptor or TCR) that is activated by binding to a cancer-specific antigen and/or a pro-inflammatory cytokine.