Increasing responses to checkpoint inhibitors by extracorporeal apheresis

Abstract

The invention provides means, methods, and compositions of matter useful for enhancing tumor response to checkpoint inhibitors. In one embodiment, the invention teaches utilization of extracorporeal apheresis, specifically removal of various tumor derived, or tumor microenvironment derived immunological “blocking factors”. In one embodiment the invention provides the removal of soluble TNF-alpha receptors (sTNF-Rs) as a means of augmenting efficacy of immune checkpoint inhibitors. In one specific embodiment removal of sTNF-Rs is utilized to enhance efficacy of inhibitors of the PD-1/PD-L1 pathway, and/or the CD28/CTLA-4 pathway.

1 - 18 . (canceled) 
     
     
         19 . A method of enhancing an efficacy of an antibody administered to a patient, comprising the steps of:
 (a) administering an antibody capable of suppressing activity of a checkpoint protein selected from a group consisting of a LAG3, a Tim3, a 2B4, a A2aR, a ID02, a BTLA, a DR3, a GAL9, a HVEM, a ID01, a KIR, a LAIR, a LIGHT, a MARCO, a PS, a SLAM, a TIGIT, a VISTA, a VTCN1, a CD2, a CD20, a CD30, a CD33, a CD52, a CD70, a CD112, a CD160, and a CD226 molecule;   (b) extracorporeally removing an immunological blocking factor that inhibits the effectiveness of the antibody from blood or a blood component of the patient.   
     
     
         20 . The method of  claim 19 , wherein the antibody is selected from a group consisting of IMP321, ibritumomab tiuxetan, ofatumumab, rituximab, obinutuzumab, tositumomab, brentuximab vedotin, gemtuzumab ozogamicin, and alemtuzumab. 
     
     
         21 . The method of  claim 19 , wherein the immunological blocking factor is a soluble tumor necrosis factor (TNF)-alpha receptor. 
     
     
         22 . The method of  claim 21 , wherein step (b) is performed using an affinity capture substrate that comprises an immobilized TNF-alpha molecule comprising one or more of a native TNF-alpha molecule and a mutated TNF-alpha molecule. 
     
     
         23 . The method of  claim 22 , wherein the immobilized TNF-alpha molecule is a trimer. 
     
     
         24 . The method of  claim 19 , further comprising after step (b) administering an antibody capable of suppressing activity of a checkpoint protein selected from a group consisting of a LAG3, a Tim3, a 2B4, a A2aR, a ID02, a BTLA, a DR3, a GAL9, a HVEM, a ID01, a KIR, a LAIR, a LIGHT, a MARCO, a PS, a SLAM, a TIGIT, a VISTA, a VTCN1, a CD2, a CD20, a CD30, a CD33, a CD52, a CD70, a CD112, a CD160, and a CD226 molecule one or more additional times to the patient. 
     
     
         25 . The method of  claim 19 , further comprising after step (b) extracorporeally removing one or more additional times an immunological blocking factor that inhibits the effectiveness of the antibody from blood or a blood component of the patient. 
     
     
         26 . The method of  claim 19 , wherein step (a) is performed before step (b). 
     
     
         27 . The method of  claim 19 , wherein step (b) is performed before step (a). 
     
     
         28 . An extracorporeal system for enhancing an efficacy of an antibody administered to a patient, comprising:
 a column configured to deplete a portion of an immunological blocking factor that reduces the efficacy of the antibody from blood or a blood component of the patient;   
       wherein the antibody is capable of suppressing activity of a checkpoint protein selected from the group consisting of a LAG3, a Tim3, a 2B4, a A2aR, a ID02, a BTLA, a DR3, a GAL9, a HVEM, a ID01, a KIR, a LAIR, a LIGHT, a MARCO, a PS, a SLAM, a TIGIT, a VISTA, a VTCN1, a CD2, a CD20, a CD30, a CD33, a CD52, a CD70, a CD112, a CD160, and a CD226 molecule. 
     
     
         29 . The system of  claim 28 , wherein the antibody is selected from a group consisting of IMP321, ibritumomab tiuxetan, ofatumumab, rituximab, obinutuzumab, tositumomab, brentuximab vedotin, gemtuzumab ozogamicin, and alemtuzumab. 
     
     
         30 . The system of  claim 28 , wherein the immunological blocking factor is a soluble tumor necrosis factor (TNF)-alpha receptor. 
     
     
         31 . The system of  claim 30 , wherein the column comprises an affinity capture substrate that comprises an immobilized TNF-alpha molecule comprising one or more of a native TNF-alpha molecule and a mutated TNF-alpha molecule. 
     
     
         32 . The system of  claim 31 , wherein the affinity capture substrate is a trimer.