Method and compositions for treatment of cancers

Abstract

A method to treat cancer uses ultrapheresis, refined to remove compounds of less than 120,000 daltons molecular weight, followed by administration of replacement fluid, to stimulate the patient's immune system to attack solid tumors. In the preferred embodiment, the patient is ultrapheresed using a capillary tube ultrafilter having a pore size of 0.02 to 0.05 microns, with a molecular weight cutoff of 120,000 daltons, sufficient to filter one blood volume. The preferred replacement fluid is ultrapheresed normal plasma. The patient is preferably treated daily for three weeks, diagnostic tests conducted to verify that there has been shrinkage of the tumors, then the treatment regime is repeated. The treatment is preferably combined with an alternative therapy, for example, treatment with an anti-angiogenic compound, one or more cytokines such as TNF, gamma interferon, or IL-2, or a procoagulant compound. The treatment increases endogenous, local levels of cytokines, such as TNF. This provides a basis for an improved effect when combined with any treatment that enhances cytokine activity against the tumors, for example, treatments using alkylating agents, doxyrubicin, carboplatinum, cisplatinum, and taxol. Alternatively, the ultrapheresis treatment can be combined with local chemotherapy, systemic chemotherapy, and/or radiation.

1 . A system for inducing an immune response against transformed, infected, or diseased tissue comprising a device for removing only components present in blood or plasma having a molecular weight of 120,000 daltons or less, having an inlet and outlet for connection to a pump and tubing to recirculate the blood or plasma of a patient through the device. 
     
     
         2 . A system according to  claim 1 , where said device has immobilized therein absorbents to remove specific cytokine or cellular inhibitors selectively from the blood, wherein said cytokine or cellular inhibitors are selected from the group consisting of soluble tumor necrosis factor receptor-1 (sTNFR-1), soluble tumor necrosis factor receptor-2 (sTNFR-2), soluble interleukin-2 receptor (sIL-2R), soluble interleukin-1 receptor (sIL-1R), soluble interleukin-6 receptor (sIL-6R), and soluble interferon-gamma receptor (sIFN-gammaR). 
     
     
         3 . The system of  claim 1  wherein the device is a capillary membrane filter with a pore size of between about 0.02 and 0.05 microns. 
     
     
         4 . The system of  claim 1  wherein the device is a parallel plate filter with a pore size of between about 0.04 and 0.08 microns. 
     
     
         5 . The system of  claim 1  wherein the device comprises filters with different pore sizes or geometries to provide for staggered removal of materials from the blood. 
     
     
         6 . The system of  claim 1  wherein the device is an absorbent column selectively removing specific cytokine or cellular inhibitors from the blood or plasma. 
     
     
         7 . The system of  claim 6  wherein the cytokine or cellular inhibitors are selected from the group consisting of sTNFR-1, sTNFR-2, sIL-2R, sIL-1R, sIL-6R, and sIFN-gammaR. 
     
     
         8 . The system of  claim 7 , where the absorbent column comprises cytokines or antibody or antibody fragments immunoreactive with the cytokine or cellular inhibitors. 
     
     
         9 . The system of  claim 8  wherein the patient's blood or plasma is circulated through the absorbent column prior to being returned to the patient. 
     
     
         10 . The system of  claim 1  further comprising a radiation source operable to treat the patient. 
     
     
         11 . A method of inducing an immune response against transformed, infected, or diseased tissue comprising administering to a patient blood, plasma, or a blood fraction from which only components having a molecular weight of 120,000 daltons or less have been removed, whereby administration of said blood, plasma, or blood fraction induces an immune response against transformed, infected, or diseased tissue in the patient until the transformed, infected, or diseased tissue is reduced in amount. 
     
     
         12 . A method of inducing an immune response against transformed, infected, or diseased tissue comprising administering to a patient blood, plasma, or a blood fraction from which only components having a molecular weight of 120,000 daltons or less have been removed by the system of  claim 1 , whereby administration of said blood, plasma, or blood induces an immune response against transformed, infected, or diseased tissue in the patient until the transformed, infected, or diseased tissue is reduced in amount. 
     
     
         13 . The method of  claim 12  wherein the tissue is a solid tumor. 
     
     
         14 . The method of  claim 12  wherein the components are removed from one volume of blood or plasma. 
     
     
         15 . The method of  claim 12  wherein the components are removed in multiple treatments. 
     
     
         16 . The method of  claim 12  wherein the tissue is to be treated further with an agent selected from the group consisting of anti-angiogenic compounds, procoagulant compounds, cytokines, chemotherapeutic agents, and radiation. 
     
     
         17 . The method of  claim 16  wherein the agent is a cytokine, and the cytokine is selected from the group consisting of GM-CSF, erythropoietin, thrombopoetin, G-CSF, M-CSF, and SCF. 
     
     
         18 . The method of  claim 12  wherein the removal of the components comprises selectively removing soluble cytokine receptor molecules. 
     
     
         19 . The method of  claim 18  wherein the soluble cytokine receptor molecules are removed by binding of the molecules to a filter. 
     
     
         20 . The method of  claim 19  wherein the soluble cytokine receptor molecules are selected from the group consisting of sTNFR-1 and sTNFR-2. 
     
     
         21 . The method of  claim 16  wherein the agent is thalidomide. 
     
     
         22 . The method of  claim 12  wherein the patient is to be vaccinated with a vaccine against the transformed, infected or diseased tissue. 
     
     
         23 . A method for preparing blood, plasma, or a blood fraction ex vivo for inducing an immune response against transformed, infected, or diseased tissue until the transformed, infected, or diseased tissue is reduced in amount, the method comprising removing from provided blood or plasma ex vivo only components having a molecular weight of 120,000 daltons or less. 
     
     
         24 . A method for inducing an immune response against transformed, infected, or diseased tissue in a patient by administering an agent selected from the group consisting of anti-angiogenic compounds, procoagulant compounds, cytokines, and chemotherapeutic agents to a patient treated with blood, plasma, or a blood fraction from which only components having a molecular weight of 120,000 or less have been removed. 
     
     
         25 . The method of  claim 24  wherein the agent is a cytokine and the cytokine is selected from the group consisting of GM-CSF, erythropoietin, thrombopoetin, G-CSF, M-CSF, and SCF. 
     
     
         26 . A kit for treatment of a patient to induce an immune response against transformed, infected or diseased tissue comprising:
 a device for removing only components present in blood or plasma having a molecular weight of 120,000 daltons or less and an agent selected from the group consisting of anti-angiogenic compounds, procoagulant compounds, cytokines, chemotherapeutic agents, and a radiation source, in a dosage formulation for treatment of the patient.   
     
     
         27 . The kit of  claim 26  wherein the agent is an anti-angiogenic compound. 
     
     
         28 . The kit of  claim 26  wherein the agent is a procoagulant compound. 
     
     
         29 . The kit of  claim 26  wherein the agent is a cytokine. 
     
     
         30 . The kit of  claim 29  wherein the cytokine is selected from the group consisting of GM-CSF, erythropoietin, thrombopoetin, G-CSF, M-CSF, and SCF. 
     
     
         31 . The kit of  claim 26  wherein the agent is a chemo-therapeutic agent. 
     
     
         32 . The kit  claim 31  wherein the agent is selected from the group consisting of alkylating agents, doxorubicin, carboplatin, cisplatin, and taxol. 
     
     
         33 . The kit of  claim 26  further comprising an anticoagulant to treat the device prior to use. 
     
     
         34 . The kit of  claim 27  wherein the agent is thalidomide.