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 . A method of enhancing the efficacy of an immunological checkpoint inhibitor administered to a patient suffering from a tumor comprising:
 Identifying a patient suffering from a tumor;   Administering an immunological checkpoint inhibitor to said patient to treat said tumor or ameliorate the effects of said tumor;   Extracorporeally removing immunological blocking factors that inhibit the effectiveness of said immunological checkpoint inhibitor in an amount sufficient to augment the efficacy of said immunological checkpoint inhibitor in either treating or ameliorating the effects of said tumor, wherein said extracorporeal removal is conducted at a time selected from the group consisting of: before, concurrently, and subsequent to the administration of said immunological checkpoint inhibitor.   
     
     
         2 . The method of  claim 1 , wherein said efficacy of said immunological checkpoint inhibitor is based on an endpoint selected from the 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) augmentation of cytokines associated with tumor inhibition; i) decrease in cytokines associated with tumor progression; j) suppression of angiogenesis; k) augmentation of tumor infiltrating lymphocytes; 1) switch of intratumoral macrophages from M2 to M1 phenotype; m) augmentation of tumor infiltrating dendritic cells; n) augmentation of tumor infiltrating killer T-cells o) reduction of tumor associated T regulatory cells; and p) reduction in tumor associated myeloid suppressor cells. 
     
     
         3 . The method of  claim 1 , wherein said checkpoint inhibitor is an agent capable of suppressing activity of a molecule selected from the group consisting of: PD-1, PD-L1, CTLA-4, PD-L2, LAG3, Tim3, 2B4, A2aR, ID02, B7-H3, B7-H4, BTLA, CD2, CD20, CD27, CD28, CD30, CD33, CD40, CD52, CD70, CD112, CD137, CD160, CD226, CD276, DR3, OX-40, GAL9, GITR, ICOS, HVEM, IDO1, KIR, LAIR, LIGHT, MARCO, PS, SLAM, TIGIT, VISTA, and VTCN1 
     
     
         4 . The method of  claim 1 , wherein said immunological blocking factor is soluble TNF-alpha receptor. 
     
     
         5 . The method of  claim 1 , wherein said immunological blocking factor is selected from the group consisting of: a) soluble HLA-G; b) soluble MICA; c) interleukin-10; d) interleukin-20; e) VEGF; f) soluble IL-2 receptor; g) soluble IL-15 receptor; h) interleukin-35 and i) soluble interferon gamma receptor. 
     
     
         6 . The method of  claim 4 , wherein said removal of soluble TNF-alpha receptor is performed by affinity capture to TNF-alpha trimers. 
     
     
         7 . The method of  claim 6 , wherein said checkpoint inhibitor is administered via a route selected from the group consisting of: intravenously, intramuscularly, parenterally, nasally, intratumorally, intraosseously, subcutaneously, sublingually, intrarectally, intrathecally, intraventricularly, orally, intraocularly, topically, or via inhalation, nanocell and/or nanobubble injection. 
     
     
         8 . The method of  claim 1  wherein the immunological checkpoint inhibitor is selected from the group consisting of PD-1, PD-L1, and CTLA-4. 
     
     
         9 . The method of  claim 8  wherein the inhibitor of PD-1 is an anti-PD-1 antibody selected from the group consisting of nivolumab and pembrolizumab. 
     
     
         10 . The method of  claim 8  wherein the inhibitor of PD-L1 is anti-PD-L1 antibody selected from the group consisting of: BMS-936559, durvalumab, atezolizumab, avelumab, MPDL3280A, MEDI4736, MSB0010718C, and MDX1105-01. 
     
     
         11 . The method of  claim 8  wherein the inhibitor of CTLA-4 is an anti-CTLA-4 antibody selected from the group consisting of ipilimumab and tremelimumab. 
     
     
         12 . The method of  claim 4 , wherein said removal of said soluble TNF-alpha receptor is performed using an extracorporeal affinity capture substrate comprising immobilized TNF-alpha molecules selected from the group consisting of: TNF-alpha trimers, native TNF-alpha molecules, and mutated forms of TNF-alpha, wherein said immobilized TNF-alpha molecules on the extracorporeal affinity capture substrate have at least one binding site capable of selectively binding to soluble TNF alpha receptor from a biological fluid. 
     
     
         13 . The method of  claim 1 , wherein said removal of immunological blocking factors is performed using an apheresis system utilizing centrifugal plasma separation. 
     
     
         14 . The method of  claim 1 , wherein said removal of immunological blocking factors is performed using an apheresis system utilizing membrane plasma separation. 
     
     
         15 . The method of  claim 1 , wherein enhancing efficacy of an immunological checkpoint inhibitor is accomplished by performing one or more clinical procedures involving the removal of tumor derived blocking factors to prepare and/or condition the patient. 
     
     
         16 . The method of  claim 15 , wherein said removal of soluble TNF-alpha receptor is performed by affinity capture to TNF-alpha trimers. 
     
     
         17 . The method of  claim 16 , wherein said checkpoint inhibitor is administered intravenously, intramuscularly, parenterally, nasally, intratumorally, intraosseously, subcutaneously, sublingually, intrarectally, intrathecally, intraventricularly, orally, topically, or via inhalation, nanocell and/or nanobubble injection. 
     
     
         18 . The method of  claim 1 , wherein extracorporeal removal of immunological blocking factors primes antigen presenting cells for enhanced ability to produce interleukin-12 subsequent to administration of a checkpoint inhibitor.