Combination Anti-CSF1R and Anti-PD-1 Antibody Combination Therapy for Pancreatic Cancer

Abstract

The present invention relates to methods of treating pancreatic cancer with particular dosage regimes of antibodies that bind colony stimulating factor 1 receptor (CSF1R) (e.g. cabiralizumab) in combination with antibodies that bind programmed cell death 1 (PD-1) (e.g. nivolumab).

1 .- 159 . (canceled) 
     
     
         160 . A method of treating pancreatic cancer in a subject, wherein the cancer has been determined to be microsatellite-stable (MSS), and wherein the cancer has been determined to have: (a) a tumor mutation burden (TMB) of less than 20 mutations/megabase, less than 15 mutations/megabase, or less than 10 mutations/megabase, as determined with a comprehensive genomic profiling assay, and/or (b) a TMB of less than 400, less than 300 or less than 200 missense mutations as determined by whole exome sequencing (WES), comprising administering to the subject an anti-CSF1R antibody once every two to four weeks and 400-600 mg of an anti-PD-1 antibody once every four weeks,
 wherein the anti-PD-1 antibody comprises a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 28, an HC CDR2 having the sequence of SEQ ID NO: 30, and an HC CDR3 having the sequence of SEQ ID NO: 32, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 35, a LC CDR2 having the sequence of SEQ ID NO: 37, and a LC CDR3 having the sequence of SEQ ID NO: 39.   
     
     
         161 . A method of treating pancreatic cancer in a subject, wherein the cancer has been determined to be microsatellite-stable (MSS), and wherein the cancer has been determined to have: (a) a tumor mutation burden (TMB) of less than 20 mutations/megabase, less than 15 mutations/megabase, or less than 10 mutations/megabase, as determined with a comprehensive genomic profiling assay, and/or (b) a TMB of less than 400, less than 300 or less than 200 missense mutations as determined by whole exome sequencing (WES), comprising administering to the subject an anti-CSF1R antibody once every two to four weeks and 400-600 mg of an anti-PD-1 antibody once every four weeks in combination with chemotherapy comprising gemcitabine or 5-fluorouracil (5-FU),
 wherein the anti-PD-1 antibody comprises a heavy chain comprising a heavy chain (HC) CDR1 having the sequence of SEQ ID NO: 28, an HC CDR2 having the sequence of SEQ ID NO: 30, and an HC CDR3 having the sequence of SEQ ID NO: 32, and a light chain comprising a light chain (LC) CDR1 having the sequence of SEQ ID NO: 35, a LC CDR2 having the sequence of SEQ ID NO: 37, and a LC CDR3 having the sequence of SEQ ID NO: 39.   
     
     
         162 . The method of  claim 161 , wherein the subject is administered 450-500 mg the anti-PD-1 antibody once every four weeks. 
     
     
         163 . The method of  claim 162 , wherein the subject is administered 480 mg the anti-PD-1 antibody once every four weeks. 
     
     
         164 . The method of  claim 161 , wherein the subject is administered chemotherapy comprising gemcitabine and nab-paclitaxel. 
     
     
         165 . The method of  claim 161 , wherein the subject is administered chemotherapy comprising FOLFOX. 
     
     
         166 . The method of  claim 161 , wherein the anti-CSF1R antibody and/or the anti-PD-1 antibody is a Fab, an Fv, an scFv, a Fab′, or a (Fab′)2 fragment. 
     
     
         167 . The method of  claim 161 , wherein (a) the anti-PD-1 antibody heavy chain comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 23 and wherein the anti-PD-1 antibody light chain comprises a light chain variable region comprising the sequence of SEQ ID NO: 25; (b) the anti-PD-1 antibody comprises a heavy chain comprising the sequence of each of SEQ ID NOs: 23 and 24 and wherein the anti-PD-1 antibody comprises a light chain comprising the sequence of each of SEQ ID NOs: 25 and 26; or (c) the anti-PD-1 antibody is nivolumab. 
     
     
         168 . The method of  claim 161 , wherein the subject meets one or more of the following criteria:
 has previously failed treatment with a standard therapy for pancreatic cancer or is not indicated for treatment with a standard therapy;   has previously received a PD-1/PD-L1 inhibitor therapy;   is a PD-1/PD-L1 inhibitor inadequate responder;   is refractory to a PD-1/PD-L1 inhibitor, e.g., after at least 2 doses;   has a localized adenocarcinoma of the pancreas;   has metastatic adenocarcinoma of the pancreas;   does not have active pancreatitis or ascites of Grade 2 or higher;   has a pancreatic tumor that is PD-L1 positive;   has reduced circulating CD14 +  CD16 ++  nonclassical monocytes after at least one dose of each of the anti-CSF1R antibody and the anti-PD-antibody; and   has a pancreatic cancer that has progressed after at least one gemcitabine-based or 5-fluorouracil-based chemotherapy regimen.   
     
     
         169 . The method of  claim 161 , wherein the subject has advanced pancreatic cancer.