Immune modulation with tlr9 agonists for cancer treatment

Abstract

The present invention relates to methods for treating a tumor, including a metastatic tumor, with TLR9 agonist in combination with an immune checkpoint inhibitor therapy.

What is claimed is: 
     
         1 . A method for treating a cancer patient, comprising intratumorally administering an oligonucleotide TLR9 agonist to a cancer patient, and administering an immune checkpoint inhibitor therapy to the patient beginning one week or more after the initial TLR9 agonist dose. 
     
     
         2 . The method of  claim 1 , wherein the immune checkpoint inhibitor targets PD-1, PD-L1, PD-L2, CTLA-4, LAG3, TIM3, and/or IDO. 
     
     
         3 . The method of  claim 1  or  2 , wherein the patient showed no response to prior treatment with PD-1 blockade therapy. 
     
     
         4 . The method of  claim 3 , wherein the patient experienced at least one immune-related adverse event to the prior PD-1 blockade therapy. 
     
     
         5 . The method of  claim 3  or  4 , wherein the prior PD-1 blockade therapy includes therapy with nivolumab or pembrolizumab. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the cancer is a primary cancer. 
     
     
         7 . The method of any one of  claims 1  to  5 , wherein the cancer is a metastatic cancer. 
     
     
         8 . The method of  claim 6  or  7 , wherein the cancer originates from skin, colon, breast, or prostate. 
     
     
         9 . The method of  claim 6  or  7 , wherein the cancer is melanoma, lung cancer, kidney cancer, prostate cancer, cervical cancer, colorectal cancer, pancreatic cancer, ovarian cancer, urothelial cancer, gastric/GEJ cancer, head and neck cancer, glioblastoma, Merkel cell cancer, head and neck squamous cell carcinoma (HNSCC), non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer, prostate cancer or hematologic malignancies. 
     
     
         10 . The method of  claim 9 , wherein the cancer is metastatic melanoma. 
     
     
         11 . The method of any one of  claims 1  to  10 , wherein the TLR9 agonist is IMO-2125. 
     
     
         12 . The method of  claim 11 , wherein the IMO-2125 is administered intratumorally at from about 4 mg to about 64 mg per dose. 
     
     
         13 . The method of  claim 12 , wherein the IMO-2125 is administered intratumorally at from about 4 to about 12 mg per dose. 
     
     
         14 . The method of  claim 11 , wherein the IMO-2125 is administered intratumorally at about 8 mg per dose. 
     
     
         15 . The method of  claim 12 , wherein the IMO-2125 is administered at from about 20 mg to about 64 mg per dose. 
     
     
         16 . The method of  claim 15 , wherein the IMO-2125 is administered at from about 20 mg to about 48 mg per dose. 
     
     
         17 . The method of any one of  claims 1  to  16 , wherein about 3 to about 12 doses of the TLR9 agonist are administered. 
     
     
         18 . The method of  claim 17 , wherein about 4 to about 8 doses of the TLR9 agonist are administered over 10 to 12 weeks. 
     
     
         19 . The method of  claim 18 , wherein about 6 doses of the TLR9 agonist are administered over 10 to 12 weeks. 
     
     
         20 . The method of  claim 18  or  19 , wherein therapy is initiated with 3 to 5 weekly doses of the TLR9 agonist, followed by 3 to 8 maintenance doses administered about every three weeks. 
     
     
         21 . The method of  claim 20 , wherein the TLR9 agonist is IMO-2125, which is administered in weeks 1, 3, 5, 8, and 11. 
     
     
         22 . The method of any one of  claims 1  to  21 , wherein the patient receives an anti-CTLA-4 agent beginning on week 2 or week 3. 
     
     
         23 . The method of  claim 22 , wherein the anti-CTLA-4 agent is administered from 2 to 6 times, and optionally about 4 times. 
     
     
         24 . The method of  claim 23 , wherein the anti-CTLA-4 agent is administered every three weeks. 
     
     
         25 . The method of any one of  claims 22  to  24 , wherein the anti-CTLA-4 agent is ipilimumab. 
     
     
         26 . The method of any one of  claims 1  to  21 , wherein the patient receives an anti-PD-1 agent beginning on week 2 or week 3. 
     
     
         27 . The method of  claim 26 , wherein the PD-1 agent is administered from 2 to 6 times, and optionally about 4 times. 
     
     
         28 . The method of  claim 27 , wherein the anti-CTLA-4 agent is administered every three weeks. 
     
     
         29 . The method of any one of  claims 26  to  28 , wherein the anti-PD-1 agent is pembrolizumab or nivolumab. 
     
     
         30 . The method of any one of  claims 1  to  29 , wherein the immune checkpoint inhibitor therapy is administered parenterally, and optionally by intravenous infusion, subcutaneous injection, or intratumoral injection. 
     
     
         31 . A method for treating metastatic melanoma, comprising administering IMO-2125 intratumorally to a metastatic melanoma patient previously found to be unresponsive or only partially responsive to PD-1 blockade therapy; the IMO-2125 being administered at a dose of from 4 to 32 mg per dose in weeks 1, 2, 3, 5, 8, and 11; with ipilimumab or pembrolizumab administered intravenously at from 2 to 4 mg/kg every three weeks beginning in week 2.