Tumor-infiltrating lymphocytes for adoptive cell therapy

Abstract

Disclosed are compositions and methods for ex vivo expansion of tumorinfiltrating lymphocytes for use in adoptive cell therapy (ACT). Also disclosed are compositions and method for identifying an agent for ex vivo expansion of tumorinfiltrating lymphocytes for use in ACT. Also disclosed are methods for treating cancer using tumor-infiltrating lymphocytes expanded by the disclosed methods.

1 . A method for ex vivo expansion of tumor-infiltrating lymphocytes for use in adoptive cell therapy (ACT), comprising culturing the lymphocytes to produce expanded lymphocytes in a culture medium comprising a toll like receptor (TLR) agonist in an amount effective to improve the tumor-specificity of the expanded lymphocytes. 
     
     
         2 . A method for treating cancer in a subject comprising the steps of:
 a) obtaining autologous tumor-infiltrating lymphocytes from the subject,   b) culturing the lymphocytes in a culture medium comprising a toll like receptor (TLR) agonist to produce expanded lymphocytes,   c) treating the subject with nonmyeloablative lymphodepleting chemotherapy, and   d) administering the expanded lymphocytes to the mammal.   
     
     
         3 . The method of  claim 1 , wherein the TLR agonist is a ligand for a TLR selected from the group consisting of TLR1, TLR2, TLR3, TLR4, and TLR9. 
     
     
         4 . The method of  claim 1 , wherein the TLR agonist comprises a ligand selected from the group consisting of Pam3CSK4, Pam3CSK4, poly I:C, Ribomunyl, and CpG ODN. 
     
     
         5 . The method of  claim 1 , wherein the cancer is a solid tumor. 
     
     
         6 . The method of  claim 1 , wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, breast cancer, and colorectal cancer. 
     
     
         7 . The method of  claim 1 , wherein the cancer is metastatic. 
     
     
         8 . The method of  claim 1 , wherein the cancer is recurrent. 
     
     
         9 . The method of  claim 1 , wherein the subject is a human. 
     
     
         10 . A method for identifying an agent for ex vivo expansion of tumor-infiltrating lymphocytes for use in adoptive cell therapy (ACT), comprising
 contacting tumor-infiltrating lymphocytes with a candidate peptide or peptidomimetic from a peptide or peptidomimetic library for the ability to selectively bind the tumor-infiltrating lymphocytes; and   screening the effect of binding peptide or peptidomimetic on the proliferation of the tumor-infiltrating lymphocytes,   wherein identification of a candidate peptide or peptidomimetic that increases proliferation of the tumor-infiltrating lymphocytes identifies an agent for ex vivo expansion of tumor-infiltrating lymphocytes for use in ACT.   
     
     
         11 . A method for ex vivo expansion of tumor-infiltrating lymphocytes for use in adoptive cell therapy (ACT), comprising culturing the lymphocytes to produce expanded lymphocytes in a culture medium comprising a peptide or peptidomimetic. 
     
     
         12 . The method of  claim 11 , wherein the peptide or peptidomimetic is identified by the method of  claim 9 . 
     
     
         13 . The method of  claim 10 , wherein the peptidomimetic is a peptoid or peptide-peptoid hybrid. 
     
     
         14 . The method of  claim 13 , wherein the peptoid or peptide-peptoid hybrid is stabilized by a hydrocarbon staple.