Neutralization of inhibitory pathways in lymphocytes

Abstract

This invention relates to the use of NKG2A-neutralizing agents to treat cancers that are poorly responsive to PD-1 neutralizing agents, as well as to the combined use of NKG2A-neutralizing agents and PD-1 neutralizing agents for the treatment of cancer.

1 . (canceled) 
     
     
         2 . A method of treating a cancer in an individual comprising administering an antibody that neutralizes the activity of NKG2A in combination with an antibody that neutralizes the activity of PD-1, wherein:
 a) the antibody that neutralizes the activity of NKG2A comprises heavy chain CDR1, CDR2 and CDR3 domains of a heavy chain having the sequence set forth in any one of SEQ ID NOs: 4, 5, 6, 7, or 8 and CDR1, CDR2 and CDR3 domains of a light chain having the sequence of SEQ ID NO: 9;   b) the antibody that neutralizes the activity of PD-1 is selected from the group consisting of pembrolizumab, nivolumab, AMP-514, MEDI-4736, pidlizumab and MPDL3280A; and   c) the cancer is:
 i) selected from the group consisting of squamous cell cancer, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, head and neck cancer, prostate cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, skin cancer; leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, Burketts lymphoma, multiple myeloma; acute myelogenous leukemia, chronic myelogenous leukemia, promyelocytic leukemia, myelodysplastic syndrome, fibrosarcoma, rhabdomyosarcoma; melanoma, seminoma, terato-carcinoma, neuroblastoma, glioma; astrocytoma, neuroblastoma, glioma, schwannomas, and thyroid follicular cancer; 
 ii) selected from the group consisting of a non-small cell lung cancer (NSCLC), kidney cancer, gastrointestinal cancer, pancreatic adenocarcinoma, esophagus adenocarcinoma, breast cancer, renal cell carcinoma (RCC), melanoma, colorectal cancer and ovarian cancer; or 
 iii) an advanced and/or refractory solid tumor; or 
 iv) an advanced refractory solid or hematological tumor or a progressing solid or hematological tumor. 
   
     
     
         3 . The method according to  claim 2 , wherein the cancer is a head and neck cancer. 
     
     
         4 . The method according to  claim 3 , wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). 
     
     
         5 . The method according to  claim 2 , wherein the cancer is a lung cancer. 
     
     
         6 . The method according to  claim 5 , wherein the lung cancer is a non-small cell lung cancer (NSCLC). 
     
     
         7 . The method according to  claim 2 , wherein the cancer is a non-small cell lung cancer (NSCLC), kidney cancer, gastrointestinal cancer, pancreatic adenocarcinoma, esophagus adenocarcinoma, breast cancer, renal cell carcinoma (RCC), melanoma, colorectal cancer or ovarian cancer. 
     
     
         8 . The method according to  claim 2 , wherein the antibody that neutralizes the activity of NKG2A comprises a heavy chain comprising SEQ ID NO: 4 and a light chain comprising SEQ ID NO: 9. 
     
     
         9 . The method according to  claim 2 , wherein the antibody that neutralizes the activity of NKG2A comprises a heavy chain comprising SEQ ID NO: 5 and a light chain comprising SEQ ID NO: 9. 
     
     
         10 . The method according to  claim 2 , wherein the antibody that neutralizes the activity of NKG2A comprises a heavy chain comprising SEQ ID NO: 6 and a light chain comprising SEQ ID NO: 9. 
     
     
         11 . The method according to  claim 2 , wherein the antibody that neutralizes the activity of NKG2A comprises a heavy chain comprising SEQ ID NO: 7 and a light chain comprising SEQ ID NO: 9. 
     
     
         12 . The method according to  claim 2 , wherein the antibody that neutralizes the activity of NKG2A comprises a heavy chain comprising SEQ ID NO: 8 and a light chain comprising SEQ ID NO: 9. 
     
     
         13 . The method according to  claim 2 , wherein the antibody that neutralizes the activity of PD-1 is MEDI-4736. 
     
     
         14 . The method according to  claim 2 , wherein the antibodies are formulated for combined administration. 
     
     
         15 . The method according to  claim 2 , wherein the antibodies are formulated for separate administration and are administered concurrently or sequentially. 
     
     
         16 . The method according to  claim 2 , wherein said cancer is an advanced and/or refractory solid tumor. 
     
     
         17 . The method according to  claim 2 , wherein said cancer is an advanced refractory solid or hematological tumor or a progressing solid or hematological tumor.