Combination immune therapy and cytokine control therapy for cancer treatment

Abstract

Compositions disclosed herein, and methods of use thereof included those for inhibiting or reducing the incidence of cytokine release syndrome or cytokine storm in a subject undergoing CAR T-cell therapy, methods of treating a cancer or tumor, methods of reducing tumor load, methods of reducing the size or growth rate of a cancer or a tumor, and methods of extending of the survival of a subject suffering from a cancer or tumor, wherein the subjects are administered compositions comprising apoptotic cells or apoptotic cell supernatants. Compositions and methods of use thereof may increase the efficacy of a CAR T-cell cancer therapy. Disclosed herein are also compositions and methods of use thereof for decreasing or inhibiting cytokine production in a subject experiencing cytokine release syndrome or cytokine storm. In certain instances compositions may include additional chemotherapeutic or immunomodulatory agents.

What is claimed is: 
     
         1 . A method of treating, preventing, inhibiting the growth of, delaying disease progression, reducing the tumor load, or reducing the incidence of a cancer or a tumor in a subject, or any combination thereof, comprising a step of administering a composition comprising an irradiated early apoptotic mononuclear-enriched cell population to said subject, wherein said irradiation occurred after induction of apoptosis, wherein at least 50% of said cells are Annexin V positive and less than 5% of said cells are propidium iodide positive, and wherein said method treats, prevents, inhibits the growth of, delays the disease progression, reduces the tumor load, or reduces the incidence of the cancer or a tumor in said subject, or any combination thereof, compared with a subject not administered the early apoptotic cell population. 
     
     
         2 . The method of  claim 1 , wherein the size or the growth rate or a combination thereof, of said cancer or tumor is reduced. 
     
     
         3 . The method of  claim 1 , wherein the survival of said subject is increased. 
     
     
         4 . The method of  claim 1 , wherein said early apoptotic cell population comprises a mononuclear early apoptotic cell population comprising a decrease of non-quiescent non-apoptotic cells, a suppressed cellular activation of any living non-apoptotic cells, or a reduced proliferation of any living non-apoptotic cells, or any combination thereof. 
     
     
         5 . The method of  claim 1 , wherein said early apoptotic cell population comprises a pooled population of early apoptotic cells. 
     
     
         6 . The method of  claim 1 , wherein said subject is a human subject. 
     
     
         7 . The method of  claim 1 , wherein said cancer or tumor comprises a solid tumor or non-solid tumor. 
     
     
         8 . The method of  claim 7 , wherein said non-solid cancer or tumor comprises a hematopoietic malignancy, a blood cell cancer, a leukemia, a myelodysplastic syndrome, a lymphoma, a multiple myeloma (a plasma cell myeloma), an acute lymphoblastic leukemia, an acute myelogenous leukemia, a chronic myelogenous leukemia, a Hodgkin lymphoma, a non-Hodgkin lymphoma, or plasma cell leukemia. 
     
     
         9 . The method of  claim 7 , wherein said solid tumor comprises a sarcoma or a carcinoma, a fibrosarcoma, a myxosarcoma, a liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, an Ewing's tumor, a leiomyosarcoma, a rhabdomyosarcoma, a colon carcinoma, a pancreatic cancer or tumor, a breast cancer or tumor, an ovarian cancer or tumor, a prostate cancer or tumor, a squamous cell carcinoma, a basal cell carcinoma, an adenocarcinoma, a sweat gland carcinoma, a sebaceous gland carcinoma, a papillary carcinoma, a papillary adenocarcinomas, a cystadenocarcinoma, a medullary carcinoma, a bronchogenic carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a choriocarcinoma, a seminoma, an embryonal carcinoma, a Wilm's tumor, a cervical cancer or tumor, a uterine cancer or tumor, a testicular cancer or tumor, a lung carcinoma, a small cell lung carcinoma, a bladder carcinoma, an epithelial carcinoma, a glioma, an astrocytoma, a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodenroglioma, a schwannoma, a meningioma, a melanoma, a neuroblastoma, or a retinoblastoma. 
     
     
         10 . The method of  claim 1 , wherein said tumor or cancer comprises a metastasis of a tumor or cancer. 
     
     
         11 . The method of  claim 1 , wherein said administering comprises a single infusion of said irradiated early apoptotic cell population. 
     
     
         12 . The method of  claim 1 , wherein said administering comprises multiple infusions of said irradiated early apoptotic cell population. 
     
     
         13 . The method of  claim 1 , further comprising administering an additional immune therapy, a chemotherapeutic agent, or an immune modulator to said subject, or any combination thereof. 
     
     
         14 . The method of  claim 13 , wherein said additional immune therapy, a chemotherapeutic agent, or an immune modulator is administered prior to, concurrent with, or following administration of said early apoptotic cells. 
     
     
         15 . The method of  claim 13 , wherein the immune therapy comprises administration of CAR T-cells. 
     
     
         16 . The method of  claim 15 , wherein said method increases the efficacy of said CAR T-cells, compared with a subject administered CAR T-cells and not administered early apoptotic cells 
     
     
         17 . The method of  claim 13 , wherein said immune modulator comprises an antibody or a functional fragment thereof. 
     
     
         18 . The method of  claim 17 , wherein said antibody or functional fragment thereof comprises a rituximab (RtX) antibody or functional fragment thereof. 
     
     
         19 . The method of  claim 1 , wherein said method comprises a first-line therapy. 
     
     
         20 . The method of  claim 1 , wherein said method comprises an adjuvant therapy. 
     
     
         21 . The method of  claim 1 , wherein said method reduces the minimal residual disease, increases remission, increases remission duration, reduces tumor relapse rate, prevents metastasis of said tumor or said cancer, or reduces the rate of metastasis of said tumor or said cancer, or any combination thereof. 
     
     
         22 . A method for producing a population of mononuclear-enriched early apoptotic cells comprising a decreased percent of non-quiescent non-apoptotic viable cells; a suppressed cellular activation of any living non-apoptotic cells; or a reduced proliferation of any living non-apoptotic cells; or any combination thereof, said method comprising the following steps,
 (a) obtaining a mononuclear-enriched cell population of peripheral blood;   (b) freezing said mononuclear-enriched cell population in a freezing medium comprising an anticoagulant;   (c) thawing said mononuclear-enriched cell population;   (d) incubating said mononuclear-enriched cell population in an apoptosis inducing incubation medium comprising methylprednisolone at a final concentration of about 10-100 μg/mL and an anticoagulant;   (e) resuspending said early apoptotic cell population of step (d) in an administration medium; and   (f) inactivating said early apoptotic mononuclear-enriched cell population of step (e),   
       wherein said inactivation occurs following step (e), 
       wherein said method produces a population of mononuclear-enriched early apoptotic cells comprising a decreased percent of non-quiescent non-apoptotic cells; a suppressed cellular activation of any living non-apoptotic cells; or a reduced proliferation of any living non-apoptotic cells; or any combination thereof. 
     
     
         23 . The method of  claim 22 , wherein the percent of non-quiescent non-apoptotic cells is decreased to about 10%. 
     
     
         24 . The method of  claim 22 , wherein the percent of non-quiescent non-apoptotic cells is decreased to about 0%. 
     
     
         25 . The method of  claim 22 , wherein said mononuclear-enriched cell population is selected from the group consisting of lymphocytes, monocytes, dendritic cells, and natural killer cells. 
     
     
         26 . The method of  claim 22 , wherein said incubating is for about 2-12 hours. 
     
     
         27 . The method of  claim 22 , wherein said step (f) inactivating said mononuclear-enriched population comprises suppressing or eliminating an immune response, suppressing or eliminating cross-reactivity of cells, or reducing or eliminating T-cell receptor activity, and wherein said population comprises a decreased the percent of living non-apoptotic cells, a suppress cellular activation of any living non-apoptotic cells, or a reduced proliferation of any living non-apoptotic cells, or any combination thereof. 
     
     
         28 . The method of  claim 22 , wherein said step (f) inactivating comprises irradiating a mononuclear-enriched apoptotic cell population produced in step (e). 
     
     
         29 . The method of  claim 28 , wherein said irradiation comprises gamma irradiation or UV irradiation. 
     
     
         30 . The method of  claim 29 , wherein said irradiation comprises about 25-50 Grey units (Gy).