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 - 22 . (canceled) 
     
     
         23 . A method of treating a patient that has a tumor, the method comprising the steps of:
 administering a checkpoint inhibitor to the patient to treat the tumor or ameliorate an effect of the tumor; and   extracorporeally removing an antigen in an amount sufficient to augment an efficacy of the checkpoint inhibitor.   
     
     
         24 . The method of  claim 23 , wherein the checkpoint inhibitor is capable of suppressing activity of a molecule selected from a group consisting of: PD-1, PD-L1, CTLA-4, PD-L2, LAG3, TIM3, 2B4, A2AR, ID02, B7-H3, B7-H4, BTLA, CD2, CD20, CD30, CD33, CD52, CD70, CD160, CD226, CD276, DR3, GAL9, HVEM, IDO1, KIR, LAIR, LIGHT, MARCO, PS, SLAM, TIGIT, VISTA, and VTCN1. 
     
     
         25 . The method of  claim 24 , wherein the checkpoint inhibitor is capable of suppressing activity of PD-1. 
     
     
         26 . The method of  claim 23 , wherein the antigen is selected from a group consisting of: interleukin-6 (IL-6), IL-6 receptor, a tumor necrosis factor (TNF) family member, TNF-alpha, a TNF receptor superfamily member, and a death receptor family member. 
     
     
         27 . The method of  claim 26 , wherein the antigen is TNF-alpha. 
     
     
         28 . The method of  claim 23 , wherein the efficacy of the checkpoint inhibitor is based on an endpoint selected from a group consisting of:
 a) tumor regression,   b) tumor stabilization,   c) reduction in tumor growth,   d) inhibition of metastasis,   e) stabilization of metastasis,   f) reduction of metastatic growth,   g) encapsulation of tumor and/or metastasis,   h) suppression of angiogenesis,   i) reduction of regulatory T cells, and   j) reduction in myeloid suppressor cells.   
     
     
         29 . The method of  claim 28 , wherein the efficacy of the checkpoint inhibitor is based on reduction of regulatory T cells. 
     
     
         30 . The method of  claim 23 , wherein the extracorporeal removal of the antigen is conducted before the administration of the checkpoint inhibitor. 
     
     
         31 . The method of  claim 23 , wherein the extracorporeal removal of the antigen is conducted concurrently with the administration of the checkpoint inhibitor. 
     
     
         32 . The method of  claim 23 , wherein the extracorporeal removal of the antigen is conducted subsequent to the administration of the checkpoint inhibitor. 
     
     
         33 . The method of  claim 23 , wherein the checkpoint inhibitor is nivolumab.