Compositions and methods for TCR reprogramming using fusion proteins

A method of treating mesothelin-expressing cancer in a human subject comprising administering to the human subject a therapeutically effective amount of

• (i) a recombinant nucleic acid encoding a T cell receptor (TCR) fusion protein (TFP) comprising
• (a) a TCR subunit comprising a full-length TCR extracellular domain and a TCR intracellular domain comprising a stimulatory domain from an intracellular signaling domain of CD3 epsilon or CD3 gamma, and
• (b) an antibody domain comprising an antigen binding domain that is an anti-mesothelin binding domain;
• or
• (ii) a human T cell expressing the TFP,
• wherein the TFP lacks (i) a costimulatory domain, (ii) a heterologous stimulatory domain, or (iii) a combination thereof,
• wherein the mesothelin-expressing cancer is selected from the group consisting of mesothelioma, ovarian cancer, papillary serous ovarian adenocarcinoma, clear cell ovarian carcinoma, mixed Mullerian ovarian carcinoma, endometroid mucinous ovarian carcinoma, pancreatic cancer, pancreatic adenocarcinoma, ductal pancreatic adenocarcinoma, uterine serous carcinoma, lung cancer, lung adenocarcinoma, extrahepatic bile duct carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, colorectal adeno-carcinoma, breast cancer, breast adenocarcinoma, cholangiocarcinoma, and combinations thereof.