Method of Predicting Personalized Response to Cancer Therapy, Method of Treating Cancer, and Kit Therefor

Abstract

A method and a kit are provided for predicting a favorable or a non-favorable response of a cancer patient to treatment with a cancer therapy by determining in a biological sample obtained from the cancer patient, before and after the treatment, the changes of the levels of factors/biomarkers generated by the cancer patient in response to said treatment, and a method for treatment of a cancer patient.

1 . A method for predicting the response of a cancer patient to treatment with a cancer therapy, the method comprising the steps of:
 (i) performing an assay on a biological sample selected from blood plasma, whole blood, blood serum or peripheral blood mononuclear cells obtained from the cancer patient at a time period after a session of treatment with said cancer therapy, to determine the levels of one or more of a plurality of factors induced in the circulation of said cancer patient in response to treatment with said cancer therapy, said one or more of the plurality of factors promoting responsiveness or non-responsiveness of the cancer patient to the treatment with said cancer therapy;   (ii) obtaining reference levels for each of the one or more of the plurality of the induced factors of step (i) in a biological sample selected from blood plasma, whole blood, blood serum or peripheral blood mononuclear cells, obtained from the cancer patient before said session of treatment with the cancer therapy;   (iii) establishing the fold change for each of the one or more of the plurality of the induced factors of step (i) by comparing the level of each induced factor of step (i) with the reference level of step (ii) for the same factor; and   (iv) determining that the cancer patient has a favorable or a non-favorable response to the treatment with said cancer therapy based on the fold change established in step (iii) for one or more of the plurality of induced factors of step (i).   
     
     
         2 . The method of  claim 1 , wherein the biological sample of steps (i) and (ii) is blood plasma. 
     
     
         3 . The method of  claim 1 , wherein said session of treatment with the cancer therapy is the first session of treatment with said cancer therapy, the biological sample of step (i) is obtained from the cancer patient at about 20, 24, 30, 36, 40, 48, 50, 60, 72 hours or more, including up to one to three weeks or more, after said first session of treatment, and the reference biological sample of step (ii) is obtained from the cancer patient at a time point including at about 72 hours or less, including at about 60, 50, 48, 40, 36, 30, 24 or 20 hours or just before said first session of treatment with the cancer therapy. 
     
     
         4 . The method of  claim 1 , wherein said session of treatment with the cancer therapy is one of multiple sessions of treatment that is not the first session of treatment with the cancer therapy, and the biological sample is obtained from the cancer patient at any time point between two consecutive sessions of treatment, wherein said biological sample is simultaneously the biological sample of step (i) and the reference biological sample according to step (ii) for the next session assay according to step (i). 
     
     
         5 . The method of  claim 4 , wherein the time between two consecutive sessions of treatment is from one day to one to three weeks, depending on the cancer therapy, and the biological sample is obtained from the cancer patient at about 20, 24, 30, 36, 40, 48, 50, 60, 72 hours or more, including up to one to three weeks or more, after the session of treatment that is not the first session of treatment with the cancer therapy. 
     
     
         6 . The method of  claim 1 , wherein the fold-change established in step (iii) is defined by a fold change of ≥1.5 indicating upregulation or a fold change of ≤0.5 indicating down-regulation in the level of each of the one or more of the plurality of factors induced in the circulation of the cancer patient in response to the treatment with the cancer therapy, these values being considered significant and predictive of a non-favorable or favorable response of the cancer patient to the treatment with said cancer therapy. 
     
     
         7 . The method of  claim 6 , wherein the prediction of a favorable or a non-favorable response of the cancer patient to the treatment with the cancer therapy is based on significant fold changes of one or more, optionally two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, or 20-25 or more, of the induced factors. 
     
     
         8 . The method of  claim 1 , wherein the factors induced in the circulation of said cancer patient in response to treatment with said cancer therapy are molecular factors including cytokines, chemokines, growth factors, enzymes and soluble receptors. 
     
     
         9 . The method of  claim 8 , wherein the molecular factors are pro-tumorigenic or pro-metastatic factors, and the pro-tumorigenic factors may be pro-angiogenic, pro-inflammatory/chemotactic or proliferative growth factors. 
     
     
         10 . The method of  claim 9 , wherein if there is an increase (up-regulation) of at least about 1.5-fold in the level of one or more of the pro-tumorigenic or pro-metastatic factors, then the prediction is of a non-favorable response of the cancer patient to the treatment with the cancer therapy, and if there is a decrease (down-regulation) of at least about 0.5-fold in the level of one or more of the pro-tumorigenic or pro-metastatic factors, then the prediction is of a favorable response of the cancer patient to the treatment with the cancer therapy. 
     
     
         11 . The method of  claim 1 , wherein the cancer therapy is a modality including chemotherapy, radiation therapy, surgery, targeted cancer therapy, hormonal therapy, thermotherapy, and combinations thereof. 
     
     
         12 . The method of  claim 11 , wherein the cancer therapy modality is chemotherapy as the sole therapy or chemotherapy in combination with another cancer therapy including surgery, radiation therapy or targeted cancer therapy. 
     
     
         13 . The method of  claim 12 , wherein the chemotherapy is carried out with one chemotherapeutic drug including paclitaxel, 5-fluorouracil, doxorubicin, gemcitabine and cyclophosphamide. 
     
     
         14 . The method of  claim 12 , wherein chemotherapy is carried out with a combination of 2 or 3 chemotherapeutic drugs chosen from: (i) anthracyclines including doxorubicin, pegylated liposomal doxorubicin, and epirubicin; (ii) taxanes including paclitaxel, albumin-bound paclitaxel and docetaxel; (iii) 5-fluorouracil; (iv) cyclophosphamide; (v) platinum agents including cisplatin, oxaliplatin and carboplatin; (vi) vinorelbine; (vii) capecitabine; (viii) gemcitabine; (ix) ixabepilone; and (x) eribulin. 
     
     
         15 . The method of  claim 14 , wherein said combination of 2 drugs includes doxorubicin (adriamycin) and cyclophosphamide (AC) and said combination of 3 drugs includes folinic acid, fluorouracil and oxaliplatin (FOLFOX). 
     
     
         16 . The method of  claim 11 , wherein the cancer therapy modality is radiation therapy alone or radiation in combination with surgery or chemotherapy. 
     
     
         17 . The method of  claim 11 , wherein the cancer therapy modality is surgery alone as the curative treatment or as the primary therapy in combination with radiation therapy or chemotherapy prior to or after the surgery. 
     
     
         18 . The method of  claim 11 , wherein the cancer therapy modality is a targeted cancer therapy selected from small-molecule drugs and monoclonal antibodies. 
     
     
         19 . The method of  claim 18 , wherein the small molecules include: (i) proteasome inhibitors including bortezomib, carfilzomib and ixazomib; (ii) tyrosine-kinase inhibitors (TKI) including dasatinib, erlotinib, gefitinib, imatinib mesylate, lapatinib, nilotinib, pazopanib, and sunitinib; and (iii) serine-threonine kinase (STK) inhibitors including dabrafenib, everolimus, temsirolimus, trametinib, and vemurafenib. 
     
     
         20 . The method of  claim 18 , wherein the targeted therapy is immunotherapy with a non-conjugated monoclonal antibody (mAb) including: alemtuzumab, bevacizumab, cetuximab, daratumumab, olaratumab, panitumumab, rituximab and trastuzumab; or with a monoclonal antibody conjugated to a chemotherapeutic drug or labeled with small radioactive particles. 
     
     
         21 . The method of  claim 18 , wherein the targeted therapy is anti-angiogenic therapy in which the antiangiogenic drug is either a monoclonal antibody that targets VEGF, including bevacizumab and panitumumab, or a tyrosine-kinase inhibitor including sunitinib that targets the VEGF receptors. 
     
     
         22 . The method of  claim 1 , wherein the factors induced by the cancer patient in response to the cancer therapy are pro-tumorigenic factors or pro-metastatic factors including: (i) the pro-angiogenic factors angiogenin; angiopoietin-1; angiopoietin-2; bNGF; cathepsin S; Galectin-7; GCP-2; G-CSF; GM-CSF; PAI-1; PDGF-AA; PDGF-BB; PDGF-AB; PlGF; PlGF-2; SDF-1; Tie2; VEGF-A; VEGF-C; VEGF-D; VEGF-R1; VEGF-R2; VEGF-R3; (ii) the pro-inflammatory and/or chemotactic factors 6Ckine; angiopoietin-1; angiopoietin-2; BLC; BRAK; CD186; ENA-78; Eotaxin-1; Eotaxin-2; Eotaxin-3; EpCAM; GDF-15; GM-CSF; GRO; HCC-4; I-309; IFN-γ; IL-1α; IL-1β; IL-1R4 (ST2); IL-2; IL-2R; IL-3; IL-3Rα; IL-5; IL-6; IL-6R; IL-7; IL-8; IL-8 RB; IL-11; IL-12; IL-12p40; IL-12p70; IL-13; IL-13 R1; IL-13R2; IL-15; IL-15Rα; IL-16; IL-17; IL-17C; IL-17E; IL-17F; IL-17R; IL-18; IL-18BPa; IL-18 Rα; IL-20; IL-23; IL-27; IL-28; IL-31; IL-33; IP-10; I-TAC; LIF; LIX; LRP6; MadCAM-1; MCP-1; MCP-2; MCP-3; MCP-4; M-CSF; MIF; MIG; MIP-1 gamma; MIP-1α; MIP-1β; MIP-1δ; MIP-3α; MIP-3β; MPIF-1; PARC; PF4; RANTES; Resistin; SCF; SCYB16; TACI; TARC; TSLP; TNF-α; TNF-R1; TRAIL-R4; TREM-1; (ii) the proliferative factors Activin A; Amphiregulin; Axl; BDNF; BMP4; cathepsin S; EGF; FGF-1; FGF-2; FGF-7; FGF-21; Follistatin; Galectin-7; Gas6; GDF-15; HB-EGF; HGF; IGFBP-1; IGFBP-3; LAP; NGF R; NrCAM; NT-3; NT-4; PAI-1; TGF-α; TGF-β; TGF-β3; TRAIL-R4; and (iv) the pro-metastatic factors ADAMTS1; cathepsin S; FGF-2; Follistatin; Galectin-7; GCP-2; GDF-15; IGFBP-6; LIF; MMP-9; pro-MMP9; RANK; RANKL; RANTES; SDF-1; and CXCR4. 
     
     
         23 . The method of  claim 22 , wherein the cancer therapy modality is chemotherapy and the induced factors indicating a host response to chemotherapy include: 6Ckine; Activin A; Amphiregulin; Angiogenin; Angiopoietin-1; Axl; BDNF; BLC; BMP4; bNGF; Cathepsin S; EGF; ENA-78; Eotaxin; Eotaxin-2; Eotaxin-3; EpCAM; Fcr RIIB/C; FGF-2; FGF-7; Follistatin; Galectin-7; GCP-2; G-CSF; GDF-15; GH; HB-EGF; HCC-4; I-309; IGFBP-1; IGFBP-6; IL-1α; IL-1β; IL-1ra; IL-2; IL-2 Rb; IL-8; IL-11; IL-12p40; IL-12p70; IL-13 R1; IL-13 R2; IL-16; IL-17; IL-17B; IL-17F; IL-18BPa; IL-23; IL-28A; IP-10; I-TAC; LAP; LIF; Lymphotactin; MCP-1; MCP-2; MCP-3; M-CSF; MDC; MIF; MIG; MIP-1α; MIP-1δ; MIP-3α; MIP-3β; MPIF-1; NGF-R; NrCAM; NT-3; NT-4; PAI-1; PARC; PDGF-AA; PDGF-AB; PDGF-BB; PF4; PlGF; PlGF-2; RANTES; Resistin; SCF; SDF-1α; ST2; TARC; TECK; TGFα; TGFβ; TGFβ3; Tie-2; TNFα; TNF-R1; TRAIL-R4; TREM-1; TLSP; VEGF; VEGF-D; VEGF-R1; VEGF-R2; and VEGF-R3. 
     
     
         24 . The method of  claim 23 , wherein the induced factors indicating a host response to chemotherapy with the combination Adriamycin/Cyclophosphamide (AC) or Folinic acid/Fluorouracil/Oxaliplatin (FOLFOX) include: (i) the pro-angiogenic factors angiogenin; angiopoietin-1; G-CSF; PDGF-AA; PDGF-AB; PDGF-BB; PlGF; SCF; Tie-2; VEGF A; and VEGF D; (ii) the pro-inflammatory and/or chemotactic factors BLC; ENA-78; Eotaxin-3; G-CSF; GDF-15; I-309; IL-1α; IL-1β; IL-1ra; IL-2; IL-8; IL-11; IL-12p40; IL-12p70; IL-13R1; IL-13R2; IL-16; IL-17; IL-17B; IL-17F; IL-18BPa; IL-23; IL-28A; IP-10 (CXCL10); MCP-3; M-CSF; MIF; MIG; MIP-1δ; MIP-3α; MIP-3β; RANTES; SCF; ST2; TARC); (iii) and the proliferative growth factors BDNF; EGF; FGF-7; IGFBP-1; NrCAM; NT-3; NT-4; TGF-α; and TGF-β. 
     
     
         25 . The method of  claim 23 , wherein the induced factors indicating a host response to chemotherapy with paclitaxel or Folinic acid/Fluorouracil/Oxaliplatin (FOLFOX) include: (i) the pro-angiogenic factors SDF-1 and VEGF-C; (ii) the pro-inflammatory and/or chemotactic factors CXCL14 (BRAK); CXCL16; CXCR2 (IL-8 RB); CXCR6; GM-CSF; IL-1alpha; IL-1R4 (ST2); IL-3Ralpha; IL-7Ralpha; IL-9R; IL-10; IL-11; IL-12p70; IL-15; IL-15Ralpha; IL-17; IL-17R; IL-18R alpha; IL-20; IL-27; IL-28; IL-31; LIF; LIX; LRP-6; MadCAM-1; MCP-1; M-CSF; MIP-1gamma; MIP-2; TACI; and TARC; (iii) the proliferative growth factors IGFBP-1; TGF-beta1; and TGF-beta2; and (iv) the pro-metastatic factor MMP-9. 
     
     
         26 . The method of  claim 22 , wherein the cancer therapy is targeted therapy with the protease inhibitor bortezomib, and the induced factors indicating a host response to therapy with bortezomib include: (i) the pro-angiogenic factors PlGF-2 and VEGF-D; (ii) the pro-inflammatory and/or chemotactic factors CCL28; IL-1alpha; IL-1R4 (ST2); IL-3; IL-5; IL-6; IL-6R; IL-10; IL-11; IL-12p70; IL-13; IL-17C; IL-17E; IL-31; MCP-1; M-CSF; and MIP-3beta; and (iii) the proliferative growth factors IGFBP-1; IGFBP-3; and TGF-beta 3. 
     
     
         27 . The method of  claim 22 , wherein the cancer therapy is radiation therapy alone and the induced factors indicating a host response to radiation therapy include: (i) the pro-angiogenic factors angiogenin; angiopoietin-1; PDGF-AA; PDGF-BB; PLGF-2; SDF-1; (ii) the pro-inflammatory and/or chemotactic factors IL-10; MCP-1; and (iii) the proliferative growth factors EGF; FGF-1. 
     
     
         28 . The method of  claim 22 , wherein the cancer therapy is surgery alone and the induced factors indicating host response to surgery include: (i) the pro-angiogenic factors angiopoietin-1; PDGF-AA; PDGF-BB; and PLGF-2; and (ii) the pro-inflammatory and/or chemotactic factor MCP-1. 
     
     
         29 . A kit comprising a plurality of antibodies, at least part of the antibodies of the plurality of antibodies each selectively binding to each of a plurality of factors that promote responsiveness or non-responsiveness of a cancer patient to treatment with a cancer therapy, and instructions for use. 
     
     
         30 . The kit of  claim 29 , wherein said kit is a sandwich or an enzyme-linked immunosorbent assay (ELISA) kit. 
     
     
         31 . The kit of  claim 29 , comprising a plurality of human monoclonal antibodies, at least part of them each binding specifically to a pro-tumorigenic or pro-metastatic factor, wherein the pro-tumorigenic factors have pro-angiogenic, pro-inflammatory/chemotactic, or proliferative activity, at least some of these pro-tumorigenic and pro-metastatic factors being predictive of a favorable or a non-favorable response of a cancer patient to treatment with a cancer therapy. 
     
     
         32 . The kit of  claim 31 , wherein the monoclonal antibodies each specifically binds to a factor selected from the factors angiogenin; angiopoietin-1; angiopoietin-2; bNGF; cathepsin S; Galectin-7; GCP-2; G-CSF; GM-CSF; PAI-1; PDGF-AA; PDGF-BB; PDGF-AB; PlGF; PlGF-2; SDF-1; Tie2; VEGF-A; VEGF-C; VEGF-D; VEGF-R1; VEGF-R2; VEGF-R3; 6Ckine; angiopoietin-1; angiopoietin-2; BLC; BRAK; CD186; ENA-78; Eotaxin-1; Eotaxin-2; Eotaxin-3; EpCAM; GDF-15; GM-CSF; GRO; HCC-4; I-309; IFN-γ; IL-1α; IL-1β; IL-1R4 (ST2); IL-2; IL-2R; IL-3; IL-3Rα; IL-5; IL-6; IL-6R; IL-7; IL-8; IL-8 RB; IL-11; IL-12; IL-12p40; IL-12p70; IL-13; IL-13 R1; IL-13R2; IL-15; IL-15Rα; IL-16; IL-17; IL-17C; IL-17E; IL-17F; IL-17R; IL-18; IL-18BPa; IL-18 Rα; IL-20; IL-23; IL-27; IL-28; IL-31; IL-33; IP-10; I-TAC; LIF; LIX; LRP6; MadCAM-1; MCP-1; MCP-2; MCP-3; MCP-4; M-CSF; MIF; MIG; MIP-1 gamma; MIP-1α; MIP-1β; MIP-1δ; MIP-3α; MIP-3β; MPIF-1; PARC; PF4; RANTES; Resistin; SCF; SCYB16; TACI; TARC; TSLP: TNF-α; TNF R1; TRAIL-R4; TREM-1; Activin A; Amphiregulin; Axl; BDNF; BMP4; cathepsin S; EGF; FGF-1; FGF-2; FGF-7; FGF-21; Follistatin; Galectin-7; Gas6; GDF-15; HB-EGF; HGF; IGFBP-1; IGFBP-3; LAP; NGF R; NrCAM; NT-3; NT-4; PAI-1; TGF-α; TGF-β; TGF-β3; TRAIL-R4; ADAMTS1; cathepsin S; FGF-2; Follistatin; Galectin-7; GCP-2; GDF-15; IGFBP-6; LIF; MMP-9; pro-MMP9; RANK; RANKL; RANTES; SDF-1; and CXCR4. 
     
     
         33 . A method of treating a cancer patient with a cancer therapy, the method comprising the steps of:
 (i) performing an assay on a biological sample selected from blood plasma, whole blood, blood serum or peripheral blood mononuclear cells obtained from the cancer patient at a time period after a session of treatment with said cancer therapy, to determine the levels of one or more of a plurality of factors induced in the circulation of said cancer patient in response to treatment with said cancer therapy, said one or more of the plurality of factors promoting responsiveness or non-responsiveness of the cancer patient to the treatment with said cancer therapy;   (ii) obtaining reference levels for each of the one or more of the plurality of the induced factors of step (i) in a biological sample selected from blood plasma, whole blood, blood serum or peripheral blood mononuclear cells, obtained from the cancer patient before said session of treatment with the cancer therapy;   (iii) establishing the fold change for each of the one or more of the plurality of the induced factors of step (i) by comparing the level of each induced factor of step (i) with the reference level of step (ii) for the same factor;   (iv) determining that the cancer patient has a favorable or a non-favorable response to the treatment with said cancer therapy based on the fold change established in step (iii) for one or more of the plurality of induced factors of step (i); and   (iva) if the cancer patient has a non-favorable response to the treatment with said cancer therapy based on the fold change established in (iii) for one or more of the plurality of the induced factors, then selecting a dominant factor among the one or more factors showing a fold change indicative of said non-favorable response, and treating the patient with the cancer therapy in combination with an agent that neutralizes or blocks the dominant factor; or   (ivb) if the cancer patient has a favorable response to the treatment with said cancer therapy based on the fold change of the level of the one or more factors established in (iii), then continuing the treatment of the cancer patient with the same cancer therapy.   
     
     
         34 . The method of  claim 33 , wherein the biological sample of steps (i) and (ii) is blood plasma. 
     
     
         35 . The method of  claim 33 , wherein said session of treatment with the cancer therapy is the first session of treatment with said cancer therapy, the biological sample of step (i) is obtained from the cancer patient at about 20, 24, 30, 36, 40, 48, 50, 60, 72 hours or more, including up to one to three weeks or more, after said first session of treatment, and the reference biological sample of step (ii) is obtained from the cancer patient at a time point including at about 72 hours or less, including at about 60, 50, 48, 40, 36, 30, 24 or 20 hours or just before said first session of treatment with the cancer therapy. 
     
     
         36 . The method of  claim 34 , wherein said session of treatment with the cancer therapy is one of multiple sessions of treatment that is not the first session of treatment with the cancer therapy, and the biological sample is obtained from the cancer patient at any time point between two consecutive sessions of treatment, wherein said biological sample is simultaneously the biological sample of step (i) and the reference biological sample according to step (ii) for the next session assay according to step (i). 
     
     
         37 . The method of  claim 36 , wherein the time between two consecutive sessions of treatment is from one day to 1 or 3 weeks, depending on the cancer therapy, and the biological sample is obtained from the cancer patient at about 20, 24, 30, 36, 40, 48, 50, 60, 72 hours or more, including up to one to three weeks or more, after the session of treatment that is not the first session of treatment with the cancer therapy. 
     
     
         38 . The method of  claim 33 , wherein the fold-change established in step (iii) is defined by a fold change of ≥1.5 indicating upregulation or a fold change of ≤0.5 indicating down-regulation in the level of each of the one or more of the plurality of factors induced in the circulation of the cancer patient in response to the treatment with the cancer therapy, these values being considered significant and predictive of a non-favorable or favorable response of the cancer patient to the treatment with said cancer therapy. 
     
     
         39 . The method of  claim 38 , wherein the prediction of a favorable or a non-favorable response of the cancer patient to the treatment with the cancer therapy is based on significant fold changes of one or more, optionally two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, or 20-25 or more, of the induced factors. 
     
     
         40 . The method of  claim 33 , wherein the factors induced in the circulation of said cancer patient in response to treatment with said cancer therapy are molecular factors including cytokines, chemokines, growth factors, enzymes and soluble receptors. 
     
     
         41 . The method of  claim 40 , wherein the factors are pro-tumorigenic or pro-metastatic factors, and the pro-tumorigenic factors may be pro-angiogenic, pro-inflammatory/chemotactic or proliferative growth factors. 
     
     
         42 . The method of  claim 41 , wherein if there is an increase (up-regulation) of at least about 1.5-fold in the level of one or more of the pro-tumorigenic factors, then the prediction is of a non-favorable response of the cancer patient to the treatment with the cancer therapy, and if there is a decrease (down-regulation) of at least about 0.5-fold in the level of one or more of the pro-tumorigenic factors, then the prediction is of a favorable response of the cancer patient to the treatment with the cancer therapy. 
     
     
         43 . The method of  claim 33 , wherein the selected dominant factor shows a fold change of ≥1.5 indicative of a non-favorable response of the cancer patient to the treatment with the cancer therapy, and proceeding with the treatment of the patient with said cancer therapy in combination with an agent that blocks said dominant factor or the receptor thereof. 
     
     
         44 . The method of  claim 43 , wherein the dominant factor is selected from factors including EGF, EGFR, FGF, IFN-γ, IL-1β, IL-2, IL-6, PDGF, TNF-α and VEGF-A. 
     
     
         45 . The method of  claim 44 , wherein the dominant factor is IL-1β, the cancer therapy is chemotherapy, and the cancer patient is treated with chemotherapy in combination with an agent that blocks the activity of IL-1β or blocks its receptor IL-1R, said agent including: (a) an IL-1 receptor antagonist (IL-1Ra); (b) a soluble decoy IL-1 type II receptor; (c) an anti-IL-1β neutralizing monoclonal antibody; (d) an anti-IL-1R neutralizing monoclonal antibody; (e) an IL-1β-converting enzyme (ICE) inhibitor; and (0 an IL-1β vaccine. 
     
     
         46 . The method of  claim 44 , wherein the dominant factor is IL-6, the cancer therapy is chemotherapy, and the cancer patient is treated with chemotherapy in combination with: (a) an agent that blocks the activity of IL-6, said agent including a human or humanized monoclonal antibody such as Siltuximab, Clazakizumab, Olokizumab, Elsilimomab, or Sirukumab; or (b) an agent that blocks the receptor IL-6R, said agent including a human or humanized monoclonal antibody such as Tocilizumab, Sarilumab or a nanobody such as Vobarilizumab.