Combination immunotherapy approach for treatment of cancer

Abstract

Disclosed herein are methods and compositions related to combination therapy for cancer. More specifically, several treatment modalities are used in combination to induce an effective anti-tumor immune response.

1 . A method for treating a cancer in a subject, comprising:
 (a) injecting into the subject a composition comprising an adipose-derived stromal vascular fraction (SVF), which comprises stem cells, wherein the stem cells comprise a lytic virus that kills tumor cells; and   (b) administering a treatment to the subject that activates a T-cell response within the subject, wherein step (a) is performed before step (b).   
     
     
         2 . The method of  claim 1 , wherein the lytic virus is a vaccinia virus. 
     
     
         3 . The method of  claim 1 , wherein the cancer comprises a solid tumor or a hematological malignancy. 
     
     
         4 . The method of  claim 3 , further comprising sensitizing the tumor to further treatment by administering to the subject a treatment that: (i) induces apoptosis in cells within the tumor, (ii) modifies the tumor microenvironment, (iii) stimulates tumor-infiltrating immune cells, or (iv) a combination of two or more thereof. 
     
     
         5 . The method of  claim 1 , further comprising treating the subject with radio-immunotherapy or chemotherapy. 
     
     
         6 . The method of  claim 1 , wherein the stem cells are allogeneic to the subject. 
     
     
         7 . The method of  claim 1 , wherein the stem cells are autologous to the subject. 
     
     
         8 . The method of  claim 1 , wherein step (b) comprises promoting simultaneous signaling through the T cell receptor and a costimulatory molecule. 
     
     
         9 . The method of  claim 8 , wherein the costimulatory molecule is CD28. 
     
     
         10 . The method of  claim 1 , wherein step (b) comprises administering to the tumor T-cells that express a growth factor. 
     
     
         11 . The method of  claim 1 , wherein step (b) comprises administering agonistic antibodies directed against activating co-stimulatory molecules. 
     
     
         12 . The method of  claim 11 , wherein the agonistic antibodies are selected from among CD28, OX40, GITR, CD137, CD27 and HVEM. 
     
     
         13 . The method of  claim 1 , wherein the stem cells are selected from among adult stem cells, embryonic stem cells, fetal stem cells, mesenchymal stem cells, neural stem cells, totipotent stem cells, pluripotent stem cells, multipotent stem cells, oligopotent stem cells, unipotent stem cells, adipose stromal cells, and endothelial stem cells, and combinations thereof. 
     
     
         14 . A method of treating a cancer in a subject, comprising:
 (a) injecting into the subject a composition comprising adipose-derived stromal stem cells, wherein the stem cells comprise a lytic virus that kills tumor cells; and   (b) administering a treatment to the subject that activates a T-cell response within the subject, wherein step (a) is performed before step (b).   
     
     
         15 . The method of  claim 14 , wherein the lytic virus is a vaccinia virus. 
     
     
         16 . The method of  claim 14 , wherein step (b) comprises promoting simultaneous signaling through the T cell receptor and a costimulatory molecule. 
     
     
         17 . The method of  claim 14 , wherein prior to step (a), the adipose-derived stromal stem cells are treated with a treatment selected from among:
 a Toll-like receptor (TLR) agonist; intravenous immunoglobulin (IVIG); monocyte conditioned media; supernatant from neutrophil extracellular trap-exposed peripheral blood mononuclear cells; co-culture with monocytes; co-culture with monocytes that have been pretreated with IVIG; co-culture with T cells; co-culture with T cells that have been exposed to a T cell stimulus; co-culture with natural killer cells; peptidoglycan isolated from Gram-positive bacteria; lipoarabinomannan isolated from mycobacteria; zymosan isolated from a yeast cell wall; polyadenylic-polyuridylic acid; poly (IC); lipopolysaccharide; monophosphoryl lipid A; flagellin; Gardiquimod; Imiquimod; Resiquimod; oligonucleosides containing CpG motifs; and 23S ribosomal RNA.   
     
     
         18 . The method of  claim 14 , wherein the adipose-derived stromal stem cells are autologous to the subject. 
     
     
         19 . The method of  claim 14 , wherein the adipose-derived stromal stem cells are allogeneic to the subject. 
     
     
         20 . The method of  claim 14 , wherein step (b) comprises administering blocking antibodies against negative co-stimulatory molecules selected from among PD-L1 and CTLA-4. 
     
     
         21 . The method of  claim 14 , wherein step (b) comprises administration of blocking antibodies against a negative co-stimulatory molecule selected from among CTLA-1, CTLA-4, PD-1, TIM-3, BTLA, VISTA, and LAG-3. 
     
     
         22 . The method of  claim 14 , wherein step (b) comprises administering a blocking antibody against a negative co-stimulatory molecule. 
     
     
         23 . The method of  claim 22 , wherein the blocking antibody is an inhibitor of the PD-1 pathway. 
     
     
         24 . The method of  claim 1 , wherein the cancer comprises a solid tumor selected from among glioblastoma, breast carcinoma, lung carcinoma, prostate carcinoma, colon carcinoma, ovarian carcinoma, neuroblastoma, central nervous system tumor, and melanoma. 
     
     
         25 . The method of  claim 14 , wherein the cancer comprises a solid tumor selected from among glioblastoma, breast carcinoma, lung carcinoma, prostate carcinoma, colon carcinoma, ovarian carcinoma, neuroblastoma, central nervous system tumor, and melanoma. 
     
     
         26 . The method of  claim 23 , wherein the inhibitor of the PD-1 pathway is selected from antibodies against PD-1 or against soluble PD-1 ligand. 
     
     
         27 . The method of  claim 23 , wherein the inhibitor of the PD-1 pathway is selected from AMP-244, MEDI-4736, MPDL3280A, or MIH1. 
     
     
         28 . The method of  claim 14 , wherein step (b) comprises administering an anti-CTLA-4 antibody, or an anti-PD-L1 antibody, or an anti-PD-1 antibody.