Compositions and methods for treating peritoneal cancers
The present disclosure provides compositions and methods for treating a peritoneal cancer in a subject. The methods include administering a T cell which is genetically modified to express a chimeric T cell receptor protein. The chimeric T cell receptor protein may include a T cell receptor signaling domain fused to the tumor associated antigen-binding fragment of an antibody or a T cell receptor signaling domain fused to a naturally occurring ligand which specifically binds to a tumor cell surface protein. The compositions and methods disclosed herein are therapeutically effective to reduce, for example, tumor burden, abdominal ascites, peritoneal mucin, or serum tumor marker levels.
1. A method of treating a peritoneal cancer in a subject, comprising: infusing into the abdominal cavity of the subject a composition comprising a substantially pure population of genetically engineered T cells which express a chimeric ligand T cell receptor protein comprising anti-CEA scfv-CD28/CD3ζ (tandem) chimeric antigen receptor (CAR), wherein the chimeric ligand T cell receptor protein binds to an antigen expressed on malignant cells.
2. The method of claim 1 , wherein the malignant cells are present in the abdominal cavity.
3. The method of claim 1 , wherein the malignant cells are present outside of the abdominal cavity.
4. The method of claim 1 , further comprising infusing a second therapeutic agent into the abdominal cavity of the subject.
5. The method of claim 4 , wherein the infusing the second therapeutic agent is performed before, during or after the infusion of the composition comprising the genetically engineered T cells.
6. The method of claim 4 , wherein the second therapeutic agent is an inhibitor of GM-CSF, STAT3, PD-1, PD-L1, IL10 or TGFβ activity.
7. The method of claim 1 , wherein the composition is infused into the abdominal cavity of the subject once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.
8. The method of claim 1 , wherein the infusing into the abdominal cavity of the subject the composition comprises infusing 10 6 -10 11 genetically engineered T cells.
9. The method of claim 1 , wherein the infusing the composition results in a decrease in the number and/or size of peritoneal tumors, abdominal ascites, peritoneal mucin, and/or serum tumor marker levels.
10. The method of claim 1 , wherein the subject is human.
11. The method of claim 1 , wherein the anti-CEA CAR construct comprises the amino acid sequence of SEQ ID NO: 1.