Adoptive cell transfer and oncolytic virus combination therapy

Abstract

The present invention describes a method for treating cancer comprising adoptive transfer of tumor antigen specific CD8+ T cells and an oncolytic virus vaccine targeting the same antigen.

1 . A method of treating cancer in a subject in need thereof comprising the steps of:
 (i) administering to the subject an adoptive cell therapeutic (ACT) comprising a population of CD8+ T cells wherein at least about 50%, preferably at least about 60% or at least about 70%, of the CD8+ T cells display a central memory phenotype and are specific for a tumor antigen expressed by the cancer and   (ii) subsequently administering to the subject a replicative oncolytic virus (OV) vaccine, preferably an oncolytic rhabdovirus or vaccinia virus, expressing the tumor antigen.   
     
     
         2 . The method of  claim 1 , wherein the population of CD8+ T cells is prepared by ex vivo culture of tumor infiltrating lymphocytes (TILs) or peripheral blood mononuclear cells (PBMCs) having a histocompatible phenotype to the subject, more preferably autologous PBMCs, in the presence of a composition comprising IL21, the tumor antigen and antigen presenting cells (APCs) to enrich and program antigen specific CD8+ T cells, followed by a rapid expansion protocol (REP) comprising anti-CD3 and anti-CD28 antibodies and IL2. 
     
     
         3 . The method of  claim 1 , wherein the population of CD8+ T cells is prepared by ex vivo culture of PBMCs or TILs in the presence of the tumor antigen, APCs and a composition comprising or consisting essentially of IL21, IL15, and rapamycin, preferably for about one to three weeks, or least about one week, or at least about two weeks, or at least about three weeks, optionally followed by ex vivo culture of the PBMCs or TILs in a composition comprising or consisting essentially of IL21, IL15, and rapamycin and in the absence of the tumor antigen and APCs, preferably for about one week, to enrich and program antigen specific CD8+ T cells. 
     
     
         4 . The method of  claim 3 , wherein the composition comprising or consisting essentially of IL21, IL15 and rapamycin does not comprise IL2. 
     
     
         5 . The method of  claim 1 , wherein the population of CD8+ T cells is produced by transducing PBMCs with recombinant T cell receptor (TCR) or CAR specific for the tumor antigen and culturing the transduced PBMCs ex vivo. 
     
     
         6 . The method of  claim 2 , wherein the population of CD8+ T cells is produced by ex vivo culture of CD25-depleted PBMCs. 
     
     
         7 . The method of  claim 3 , wherein IL21 and IL15 are present at a concentration of about 1 ng/ml to about 20 ng/ml, preferably about 10 ng/ml, and rapamycin is present at a concentration of from about 10 ng/ml to about 30 ng/ml, preferably about 20 ng/ml. 
     
     
         8 . The method of  claim 2 , wherein ex vivo culture of the PBMCs or TILs for antigen-specific T cell enrichment and programing is followed by ex vivo expansion of the cells in culture, preferably in a composition comprising anti-CD3 and anti-CD28 antibodies and IL2, preferably for at least one to at least four weeks, wherein a T cell purification step (e.g. cell sorting) is not performed after ex vivo culture. 
     
     
         9 . The method of  claim 1 , wherein the subject is not administered IL2. 
     
     
         10 . The method of  claim 1 , wherein the replicative oncolytic virus is a rhabdovirus, preferably a vesiculovirus. 
     
     
         11 . The method of  claim 10 , wherein the rhabdovirus is a recombinant or wild type Maraba virus, preferably Maraba MG1 or a recombinant or wild type VSV, preferably VSVdelta51. 
     
     
         12 . The method of  claim 10 , wherein the rhabdovirus is administered intravascularly, preferably intravenously, to the subject. 
     
     
         13 . The method of  claim 1 , wherein the replicative oncolytic virus is a wild type or recombinant vaccinia virus. 
     
     
         14 . The method of  claim 13 , wherein the vaccinia virus is a Wyeth, Western Reserve or Copenhagen strain, preferably with a thymidine kinase deletion and/or a vaccinia growth factor gene deletion. 
     
     
         15 . The method of  claim 13 , wherein the vaccinia virus is administered intravascularly, intratumorally, intramuscularly, or intraperitoneally. 
     
     
         16 . The method of  claim 1 , wherein the OV is administered to the subject about one hour to about 31 days, preferably about one day to about 4 weeks, more preferably, about one day to about 3 weeks, about one day to about 2 weeks, about 12 hours to about 48 hours, about 20 hours to about 28 hours, or about 24 hours after the ACT therapy. 
     
     
         17 . The method of  claim 1 , wherein the subject does not undergo lymphodepletion prior to receiving the ACT. 
     
     
         18 . The method of  claim 1 , wherein the tumor antigen is selected from the group consisting of alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA 125, Her2, dopachrome tautomerase (DCT), GP100, Melan-A/MART-1, MAGE proteins, BAGE proteins, GAGE proteins, NY-ESO1, WT-1, survivin, tyrosinase, SSX2, Cyclin-A1, KIF20A, MUC5AC, Meloe, Lengsin, Kallikrein 4, IGF2B3, glypican-3, HPV E6 and HPV E7. 
     
     
         19 . The method of  claim 1 , wherein the cancer is selected from the group consisting of melanoma, sarcoma, lymphoma, carcinoma, brain cancer (e.g. glioma), breast cancer, liver cancer, lung cancer, kidney cancer, pancreatic cancer, esophageal cancer, stomach cancer, colon cancer, colorectal cancer, bladder cancer, prostate cancer and leukemia. 
     
     
         20 . The method of  claim 1 , wherein the cancer is a solid tumor. 
     
     
         21 . The method of  claim 1 , wherein the cancer is a metastasis. 
     
     
         22 . The method of  claim 1 , wherein the tumor antigen is a tumor-specific antigen. 
     
     
         23 . The method of  claim 1 , wherein the tumor antigen is a self-antigen. 
     
     
         24 . The method of  claim 1 , wherein the OV is administered to the subject multiple times following administration of the ACT. 
     
     
         25 . The method of  claim 1 , wherein the subject is administered at least a first combination therapy and a second combination therapy, wherein the tumor antigen is the same for the first and second combination therapy. 
     
     
         26 . The method of  claim 1 , wherein the subject is administered at least a first combination therapy and a second combination therapy, wherein the tumor antigen is not the same for the first and second combination therapy. 
     
     
         27 . The method of  claim 1 , wherein the population of CD8+ T cells is autologous to the subject. 
     
     
         28 . The method of  claim 1 , wherein the subject is a human. 
     
     
         29 . The method of  claim 2 , wherein the antigen presenting cell is a dendritic cell. 
     
     
         30 . The method of  claim 2 , wherein the tumor antigen and antigen presenting cell are present in the form of tumor antigen peptide-loaded antigen presenting cells. 
     
     
         31 . The method of  claim 30 , wherein the tumor antigen peptide-loaded antigen presenting cells are obtained by (i) culturing adherent PBMCs from the subject with GM-CSF and IL-4 to obtain autologous dendritic cells, optionally followed by stimulation of the dendritic cells with TNFα, IL-1b, IL-6, PGE-2, IL-4 and GM-CSF (ii) pulsing the dendritic cells with tumor antigen peptide and (iii) irradiating the tumor antigen peptide loaded dendritic cells. 
     
     
         32 . The method of  claim 2 , wherein the tumor antigen is present in the composition in the form of tumor material from the subject. 
     
     
         33 . A method for preparing a population of tumor antigen-specific human CD8+ T cells with a central memory phenotype comprising
 (i) culturing peripheral blood mononuclear cells (PBMCs) or tumor infiltrating lymphocytes (TILs) obtained from a human ex vivo in the presence of a tumor antigen, APCs and a composition comprising or consisting essentially of IL15, IL21 and rapamycin and which does not comprise IL2, to obtain a population of tumor antigen-specific human CD8+ T cells with a central memory phenotype; and   (ii) expanding the obtained CD8+ T cells, preferably in culture medium comprising anti-CD3 and anti-CD28 antibodies and IL2.   
     
     
         34 . The method of  claim 33 , wherein the method does not comprise a T cell purification step (e.g. cell sorting) between steps (i) and (ii). 
     
     
         35 . The method of  claim 33 , wherein the PBMCs are obtained from a human with cancer. 
     
     
         36 . The method of  claim 33 , wherein CD25+ cells are depleted from the PBMCs before the PBMCs are cultured ex vivo. 
     
     
         37 . The method of  claim 33 , comprising
 (i) transducing PBMCs or TILs obtained from a human cancer subject with a recombinant TCR or CAR specific for a tumor antigen expressed by the cancer;   (ii) culturing the transduced PBMCs or TILs in culture medium in the presence of the tumor antigen, APCs and a composition comprising or consisting essentially of IL15, IL21 and rapamycin and which does not comprise IL2, to obtain a population of human CD8+ T cells with a central memory phenotype; and   (iii) expanding the obtained CD8+ T cells in culture, preferably in the presence of anti-CD3 and anti-CD28 antibodies and IL2.   
     
     
         38 . The method of  claim 33 , further comprising a step of administering the obtained population of human CD8+ T cells to the subject.