US2021077612A1PendingUtilityA1

Generation of hpv-specific t-cells

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Assignee: BAYLOR COLLEGE MEDICINEPriority: Sep 16, 2016Filed: Jan 31, 2019Published: Mar 18, 2021
Est. expirySep 16, 2036(~10.1 yrs left)· nominal 20-yr term from priority
Inventors:Carlos A. RamosCliona M. RooneySandhya SharmaBenjamin Flyun Joon ShinAlex Salyer
A61K 40/11A61K 40/46A61K 2300/00A61K 2121/00A61K 2039/55527C12N 2710/20034C12N 2501/2315C12N 2501/2306C12N 2501/2307C12N 2501/2312C12N 2502/1121A61K 39/12A61P 31/20C12N 5/0636C12N 5/0639C12N 5/0638C12N 2501/056A61P 15/00A61P 31/12C12N 2501/25C12N 2501/22C12N 2501/24C12N 2501/05C12N 2501/051C12N 2502/1114A61K 2039/80A61P 13/00C12N 2501/2304C12N 2501/2301A61P 1/02C12N 2501/999C12N 2502/1107A61P 35/00C12N 2501/02A61K 2039/5158
65
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Claims

Abstract

Embodiments of the disclosure concern methods and compositions for immunotherapy for human papillomavirus infection and diseases associated therewith. In specific embodiments, methods concern production of immune cells that target one or more antigens of HPV16 and/or HPV18, including methods with stimulation steps that employ IL-7 and IL-15, but not IL-6 and/or IL-12. Other specific embodiments utilize stimulations in the presence of certain cells, such as costimulatory cells and certain antigen presenting cells.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of generating or expanding a population of immune cells specific for HPV, comprising a step of stimulating a population of immune cells, optionally PBMCs, by culture in the presence of antigen-presenting cells (APCs) presenting a peptide of a HPV antigen, in the presence of HLA-negative LCLs. 
     
     
         2 . The method according to  claim 1 , wherein the HLA-negative LCLs are EBV replication defective. 
     
     
         3 . The method according to  claim 1  or  claim 2 , wherein the APCs are activated T cells (ATCs), dendritic cells (DCs) or B-Blasts (BBs). 
     
     
         4 . The method according to  claim 3 , wherein the DCs are derived from CD14+ cells isolated from a population of peripheral blood mononuclear cells (PBMCs). 
     
     
         5 . The method according to  claim 3  or  claim 4 , wherein the DCs are derived from CD14+ cells by a method comprising culturing the CD14+ cells in the presence of IL-4 and GM-CSF to produce immature DCs (iDCs). 
     
     
         6 . The method according to  claim 5 , wherein the method by which the DCs are derived from CD14+ cells further comprises culturing the iDCs to produce mature DCs by culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         7 . The method according to  claim 3 , wherein the DCs are derived from immature DCs (iDCs) by a method comprising culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         8 . The method according to any one of  claims 1  to  7 , wherein the population of immune cells stimulated is depleted of CD45RA+ cells. 
     
     
         9 . The method according to any one of  claims 1  to  8 , wherein the stimulation is performed by culture in the presence of IL-7 and IL-15, optionally wherein the IL-15 is present in the culture at a final concentration greater than 15 ng/ml. 
     
     
         10 . The method according to any one of  claims 1  to  8 , wherein the stimulation is performed by culture in the presence of IL-4, IL-6, IL-7 and IL-15. 
     
     
         11 . A method of generating or expanding a population of immune cells specific for HPV, comprising stimulating a population of immune cells by culture in the presence of dendritic cells (DCs) presenting a peptide of a HPV antigen, wherein the DCs are derived from CD14+ cells isolated from a population of peripheral blood mononuclear cells (PBMCs). 
     
     
         12 . The method according to  claim 11 , wherein the DCs are derived from CD14+ cells by a method comprising culturing the CD14+ cells in the presence of IL-4 and GM-CSF to produce immature DCs (iDCs). 
     
     
         13 . The method according to  claim 12 , wherein the method by which the DCs are derived from CD14+ cells further comprises culturing the iDCs to produce mature DCs by culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         14 . A method of generating or expanding a population of immune cells specific for HPV, comprising stimulating a population of immune cells by culture in the presence of dendritic cells (DCs) presenting a peptide of a HPV antigen, wherein the DCs are derived from immature DCs (iDCs) by a method comprising culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         15 . The method according to any one of  claims 11  to  14 , wherein the stimulation comprises culture in the presence of HLA-negative LCLs, optionally wherein the HLA-negative LCLs are EBV replication defective. 
     
     
         16 . The method according to any one of  claims 11  to  15 , wherein the population of immune cells stimulated is depleted of CD45RA+ cells. 
     
     
         17 . The method according to any one of  claims 11  to  16 , wherein the stimulation is performed by culture in the presence of IL-7 and IL-15, optionally wherein the IL-15 is present in the culture at a final concentration greater than 15 ng/ml. 
     
     
         18 . The method according to any one of  claims 11  to  16 , wherein the stimulation is performed by culture in the presence of IL-4, IL-6, IL-7 and IL-15. 
     
     
         19 . A method of generating or expanding a population of immune cells specific for HPV, comprising stimulating a population of immune cells depleted of CD45RA+ cells by culture in the presence of antigen-presenting cells (APCs) presenting a peptide of a HPV antigen. 
     
     
         20 . The method according to  claim 19 , wherein the stimulation comprises culture in the presence of HLA-negative LCLs, optionally wherein the HLA-negative LCLs are EBV replication defective. 
     
     
         21 . The method according to  claim 19  or  claim 20 , wherein the APCs are activated T cells (ATCs), dendritic cells (DCs) or B-Blasts (BBs). 
     
     
         22 . The method according to  claim 21 , wherein the DCs are derived from CD14+ cells isolated from a population of peripheral blood mononuclear cells (PBMCs). 
     
     
         23 . The method according to  claim 21  or  claim 22 , wherein the DCs are derived from CD14+ cells by a method comprising culturing the CD14+ cells in the presence of IL-4 and GM-CSF to produce immature DCs (iDCs). 
     
     
         24 . The method according to  claim 23 , wherein the method by which the DCs are derived from CD14+ cells further comprises culturing the iDCs to produce mature DCs by culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         25 . The method according to  claim 21 , wherein the DCs are derived from immature DCs (iDCs) by a method comprising culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         26 . The method according to any one of  claims 19  to  25 , wherein the stimulation is performed by culture in the presence of IL-7 and IL-15, optionally wherein the IL-15 is present in the culture at a final concentration greater than 15 ng/ml. 
     
     
         27 . The method according to any one of  claims 19  to  25 , wherein the stimulation is performed by culture in the presence of IL-4, IL-6, IL-7 and IL-15. 
     
     
         28 . A method of generating or expanding a population of immune cells specific for HPV, comprising a step of stimulating a population of immune cells by culture in the presence of antigen-presenting cells (APCs) presenting a peptide of a HPV antigen, in the presence of IL-7 and IL-15. 
     
     
         29 . The method according to  claim 28 , wherein the IL-15 is present in the culture at a final concentration greater than 15 ng/ml. 
     
     
         30 . A method of generating or expanding a population of immune cells specific for HPV, comprising a step of stimulating a population of immune cells by culture in the presence of antigen-presenting cells (APCs) presenting a peptide of a HPV antigen, in the presence of IL-4, IL-6, IL-7 and IL-15. 
     
     
         31 . The method according to any one of  claims 28  to  30 , wherein the stimulation comprises culture in the presence of HLA-negative LCLs, optionally wherein the HLA-negative LCLs are EBV replication defective. 
     
     
         32 . The method according to any one of  claims 28  to  31 , wherein the APCs are activated T cells (ATCs), dendritic cells (DCs) or B-Blasts (BBs). 
     
     
         33 . The method according to  claim 32 , wherein the DCs are derived from CD14+ cells isolated from a population of peripheral blood mononuclear cells (PBMCs). 
     
     
         34 . The method according to  claim 32  or  claim 33 , wherein the DCs are derived from CD14+ cells by a method comprising culturing the CD14+ cells in the presence of IL-4 and GM-CSF to produce immature DCs (iDCs). 
     
     
         35 . The method according to  claim 34 , wherein the method by which the DCs are derived from CD14+ cells further comprises culturing the iDCs to produce mature DCs by culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         36 . The method according to  claim 32 , wherein the DCs are derived from immature DCs (iDCs) by a method comprising culture in the presence of: (a) GM-CSF, IL-4, IL-1β, IL-6, TNFα and CD40L; (b) GM-CSF, IL-4, MPLA and IFNγ; (c) GM-CSF, IFNα; or (d) GM-CSF, IL-4, AmpB and IFNγ. 
     
     
         37 . The method according to any one of  claims 28  to  36 , wherein the population of immune cells stimulated is depleted of CD45RA+ cells. 
     
     
         38 . The method according to any one of  claims 1  to  37 , wherein the APCs or DCs have been pulsed with one or more peptides corresponding to one or more HPV antigens. 
     
     
         39 . The method according to  claim 38 , wherein the one or more HPV antigens are selected from E1, E2, E3, E4, E5, E6 and E7. 
     
     
         40 . The method according to  claim 38  or  claim 39 , wherein the one or more HPV antigens are antigens of HPV16, HPV18, HPV1, HPV2 and/or HPV3. 
     
     
         41 . The method according to any one of  claims 1  to  40 , wherein the population of immune cells stimulated is obtained from a prior stimulation of immune cells by culture in the presence of APCs presenting a peptide of a HPV antigen, optionally from within a population of PBMCs. 
     
     
         42 . The method according to any one of  claims 1  to  41 , wherein the method further comprises one or more further steps comprising stimulating a population of immune cells by culture in the presence of APCs presenting a peptide of a HPV antigen. 
     
     
         43 . A population of immune cells specific for HPV, wherein the population of immune cells specific for HPV is obtained according to the method of any one of  claims 1  to  42 . 
     
     
         44 . The population of immune cells according to  claim 43  for use in a method of treatment or prevention of a HPV-associated disease. 
     
     
         45 . Use of a population of immune cells according to  claim 43  in the manufacture of a medicament for use in the treatment or prevention of a HPV-associated disease. 
     
     
         46 . The population of immune cells for use according to  claim 43  of  claim 44 , or the use according to  claim 45 , wherein the treatment is a method of treatment or prevention of a HPV-associated disease by adoptive cell transfer (ACT). 
     
     
         47 . The population of immune cells for use or the use according to  claim 46 , wherein the method of treatment by ACT comprises administration to a subject of autologous cells or allogeneic cells. 
     
     
         48 . A method of treating or preventing a HPV-associated disease in a subject, the method comprising administering to a subject a therapeutically or prophylactically effective quantity of a population of immune cells according to  claim 43 . 
     
     
         49 . A method of treating or preventing a HPV-associated disease in a subject, the method comprising:
 (a) generating or expanding a population of immune cells specific for HPV according to the method of any one of  claims 1  to  42 , and   (b) administering a therapeutically or prophylactically effective quantity of the population of immune cells specific for HPV obtained at step (a) to a subject.   
     
     
         50 . The population of immune cells for use, the use or the method according to any one of  claims 44  to  49 , wherein the HPV-associated disease is a cancer. 
     
     
         51 . The population of immune cells for use, the use or the method according to  claim 50  wherein the cancer is selected from cervical cancer, anal cancer, vulvar cancer, vaginal cancer, penile cancer, oropharyngeal cancer, nasopharyngeal carcinoma, laryngeal papillomatosis, laryngeal cancer, head and neck cancer, or a dysplasia of any of site thereof.

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