Methods and compositions for infusion of transiently engrafting, selected populations of allogeneic lymphocytes to treat cancer

Abstract

The invention provides methods and compositions for administration of allogeneic lymphocytes as an exogenous source of CD4+ T cell help for endogenous, tumor-reactive CD8+ T cells. Depletion of CD8+ T cells from the donor lymphocyte infusion reduces the risk of sustained engraftment and graft-versus-host disease. Removal of regulatory T cells from the infused population may augment the ability of non-regulatory T cells to provide help for endogenous effectors of anti-tumor immunity. Allogeneic T cell therapy is typically given in the context of allogeneic stem cell transplantation, in which the patient receives highly immunosuppressive conditioning followed by an infusion of a stem cell graft containing unselected populations of mature T cells. In the treatment described here, the graft is engineered to minimize the possibility of sustained donor cell engraftment, and the anti-tumor effector T cells derive from the host.

1 - 129 . (canceled) 
     
     
         130 . A method of making an allogenic lymphocyte composition for administration to a human recipient, comprising:
 providing a peripheral blood cell composition from a human donor allogenic to the recipient, the peripheral blood cell composition comprising a number of CD4+ T-cells, a number of CD8+ T-cells, and a number of natural killer cells, wherein (i) the donor has CD4+ T-cell immunity against an antigen present in the recipient, (ii) the donor comprises at least one human leukocyte antigen (HLA) Class II allele match relative to the recipient and the HLA Class II allele match is at a gene selected from the group consisting of HLA-DRB1, HLA-DQB1, and HLA-DPB1, and (iii) the recipient does not have detectable antibodies reactive against human leukocyte antigens of the donor; and   making the allogenic lymphocyte composition from the peripheral blood cell composition by reducing the number of CD8+ T-cells in the peripheral blood cell composition by at least one order of magnitude, wherein (a) the number of CD4+ T-cells in the allogenic lymphocyte composition differs from the number of CD4+ T-cells in the peripheral blood cell composition by less than about 50%, and (b) the number of natural killer cells in the allogenic lymphocyte composition is less than or equal to the number of natural killer cells in the peripheral blood cell composition, with the proviso that the CD4+ T-cells of the allogenic lymphocyte composition are not activated ex vivo.   
     
     
         131 . The method of  claim 130 , wherein if the donor and recipient are ABO blood type incompatible and the peripheral blood cell composition comprises a number of red blood cells, then making the allogenic lymphocyte composition further comprises reducing the number red blood cells. 
     
     
         132 . The method of  claim 131 , wherein the number of red blood cells comprises less than or equal to about 50 ml in packed volume. 
     
     
         133 . The method of  claim 130 , wherein the antigen present in the recipient is selected from the group consisting of a neoplastic antigen, a neoplastic idiotype, a viral antigen, a bacterial antigen, a fungal antigen, a parasitic antigen, and a non-human animal antigen. 
     
     
         134 . The method of  claim 130 , wherein the antigen is a neoplastic antigen and the neoplastic antigen is a tumor antigen. 
     
     
         135 . The method of  claim 130 , wherein a subject selected from the group consisting of the recipient, the donor and one or more potential allogenic donor(s) has been screened for serological reactivity to an infectious agent antigen selected from the group consisting of a Human Immunodeficiency Virus (HIV) antigen, a Hepatitis Virus antigen, and a Cytomegalovirus antigen. 
     
     
         136 . The method of  claim 130 , wherein the antigen present in the recipient against which the donor has immunity is a viral antigen and the viral antigen is selected from the group consisting of a human papillomavirus antigen, an Epstein Barr Virus antigen, a Kaposi's sarcoma-associated herpesvirus (KSHV) antigen, a Hepatitis A virus antigen, a Hepatitis B virus antigen, and a Hepatitis C virus antigen. 
     
     
         137 . The method of  claim 136 , wherein the viral antigen is a human papillomavirus antigen and the human papillomavirus antigen is an E6 or an E7 antigenic peptide. 
     
     
         138 . The method of  claim 130 , wherein the number of CD4+ T-cells in the allogenic lymphocyte composition differs from the number of CD4+ T-cells in the peripheral blood cell composition by less than about 20%. 
     
     
         139 . The method of  claim 130 , with the further proviso that CD4+ T-cells obtained from the donor are not intentionally expanded or intentionally differentiated ex vivo. 
     
     
         140 . The method of  claim 130 , wherein reducing the CD8+ T-cells in the peripheral blood cell composition comprises using an anti-CD8+ antibody associated with magnetic particles or an anti-CD8+ antibody plus complement. 
     
     
         141 . An allogenic lymphocyte composition derived from a peripheral blood cell composition of a human, allogenic donor for administration to a human recipient, the allogenic lymphocyte composition comprising:
 a number of CD4+ T-cells and a number of natural killer cells from the peripheral blood cell composition of the donor, wherein (i) the donor has CD4+ T-cell immunity against an antigen present in the recipient, (ii) the donor comprises at least one human leukocyte antigen (HLA) Class II allele match relative to the recipient and the HLA Class II allele match is at a gene selected from the group consisting of HLA-DRB1, HLA-DQB1, and HLA-DPB1, (iii) the recipient does not have detectable antibodies reactive against human leukocyte antigens of the donor, (iv) the number of CD4+ T-cells in the allogenic lymphocyte composition differs from the number of CD4+ T-cells in the peripheral blood cell composition by less than about 50%, (v) the number of donor CD4+ T-cells based on an ideal body weight of the recipient in kilograms (kg) is between about 1×10 5  CD4+ T-cells/kg and about 1×10 9  CD4+ T-cells/kg, (vi) the number of natural killer cells in the allogenic lymphocyte composition is less than or equal to the number of natural killer cells in the peripheral blood cell composition, and (vii) the allogenic lymphocyte composition has at least one order of magnitude fewer CD8+ T-cells relative to the peripheral blood cell composition;   with the proviso that the CD4+ T-cells of the allogenic lymphocyte composition are not activated ex vivo.   
     
     
         142 . An allogenic lymphocyte composition derived from a peripheral blood cell composition of a human, allogenic donor for administration to a human recipient, the allogenic lymphocyte composition comprising:
 a number of CD4+ T-cells and a number of natural killer cells from the peripheral blood cell composition of the donor, wherein (i) the donor has CD4+ T-cell immunity against an antigen not present in the recipient, (ii) the donor comprises at least one human leukocyte antigen (HLA) Class II allele match relative to the recipient and the HLA Class II allele match is at a gene selected from the group consisting of HLA-DRB1, HLA-DQB1, and HLA-DPB1, (iii) the recipient does not have detectable antibodies reactive against human leukocyte antigens of the donor, (iv) the number of CD4+ T-cells in the allogenic lymphocyte composition differs from the number of CD4+ T-cells in the peripheral blood cell composition by less than about 50%, (v) the number of donor CD4+ T-cells based on an ideal body weight of the recipient in kilograms (kg) is between about 1×10 5  CD4+ T-cells/kg and about 1×10 9  CD4+ T-cells/kg, (vi) the number of natural killer cells in the allogenic lymphocyte composition is less than or equal to the number of natural killer cells in the peripheral blood cell composition, and (vii) the allogenic lymphocyte composition has at least one order of magnitude fewer CD8+ T-cells relative to the peripheral blood cell composition;   with the proviso that the CD4+ T-cells of the allogenic lymphocyte composition are not activated ex vivo.   
     
     
         143 . An allogenic lymphocyte composition derived from a peripheral blood cell composition of a human, allogenic donor, for use in a method of treating a disease or condition in a human subject, wherein:
 the allogenic lymphocyte composition comprising a number of CD4+ T-cells and a number of natural killer cells from the peripheral blood cell composition of the donor, wherein (i) the donor has CD4+ T-cell immunity against an antigen present in the subject, (ii) the donor comprises at least one human leukocyte antigen (HLA) Class II allele match relative to the subject and the HLA Class II allele match is at a gene selected from the group consisting of HLA-DRB1, HLA-DQB1, and HLA-DPB1, (iii) the subject does not have detectable antibodies reactive against human leukocyte antigens of the donor, (iv) the number of CD4+ T-cells in the allogenic lymphocyte composition differs from the number of CD4+ T-cells in the peripheral blood cell composition by less than about 50%, (v) the number of donor CD4+ T-cells based on an ideal body weight of the subject in kilograms (kg) is between about 1×10 5  CD4+ T-cells/kg and about 1×10 9  CD4+ T-cells/kg, (vi) the number of natural killer cells in the allogenic lymphocyte composition is less than or equal to the number of natural killer cells in the peripheral blood cell composition, and (vii) the allogenic lymphocyte composition has at least one order of magnitude fewer CD8+ T-cells relative to the peripheral blood cell composition;   with the proviso that the CD4+ T-cells of the allogenic lymphocyte composition are not activated ex vivo.   
     
     
         144 . An allogenic lymphocyte composition derived from a peripheral blood cell composition of a human, allogenic donor for use in a method of treating a disease or condition in a subject, wherein the allogenic lymphocyte composition comprises a number of CD4+ T-cells and a number of natural killer cells from the peripheral blood cell composition of the donor, wherein (i) the donor has CD4+ T-cell immunity against the antigen, (ii) the donor comprises at least one human leukocyte antigen (HLA) Class II allele match relative to the subject and the HLA Class II allele match is at a gene selected from the group consisting of HLA-DRB1, HLA-DQB1, and HLA-DPB1, (iii) the subject does not have detectable antibodies reactive against human leukocyte antigens of the donor, (iv) the number of CD4+ T-cells in the allogenic lymphocyte composition differs from the number of CD4+ T-cells in the peripheral blood cell composition by less than about 50%, (v) the number of donor CD4+ T-cells based on an ideal body weight of the subject in kilograms (kg) is between about 1×10 5  CD4+ T-cells/kg and about 1×10 9  CD4+ T-cells/kg, (vi) the number of natural killer cells in the allogenic lymphocyte composition is less than or equal to the number of natural killer cells in the peripheral blood cell composition, and (vii) the allogenic lymphocyte composition has at least one order of magnitude fewer CD8+ T-cells relative to the peripheral blood cell composition;
 with the proviso that the CD4+ T-cells of the allogenic lymphocyte composition are not activated ex vivo; and 
 wherein the subject has been injected with a nanoparticle composition into a tumor, wherein the nanoparticle composition comprises nanoparticles comprising an antigen not present in the subject. 
 
     
     
         145 . An allogenic lymphocyte composition for use according to  claim 143 , wherein prior to administering to the subject the allogenic lymphocyte composition the method further comprises administering a lymphoreductive non-lymphoablative treatment to the subject to induce transient lymphopenia in the subject; administering a treatment to deplete or inhibit myeloid-derived suppressor cells; administering a treatment to deplete or inhibit tumor associated macrophage cells or administering a treatment to deplete regulatory T cells; or
 wherein subsequent to administering to the subject the allogenic lymphocyte composition the method further comprises administering a drug to induce selective depletion of alloreactive T-cells.   
     
     
         146 . An allogenic lymphocyte composition for use according to  claim 145 , wherein prior to administering to the subject the allogenic lymphocyte composition the treatment comprises administration of a drug selected from the group consisting of dasatinib, 5-fluorouracil, taxotere, clodronate, gemcitabine, cyclophosphamide, denileukin diftitox, and daclizumab. 
     
     
         147 . The lymphocyte composition of  claim 141 , wherein the antigen is selected from the group consisting of a neoplastic antigen, a neoplastic idiotype, a viral antigen, a bacterial antigen, a fungal antigen, a parasitic antigen, and a non-human animal antigen. 
     
     
         148 . The lymphocyte composition of  claim 147 , wherein the antigen is a viral antigen and the viral antigen is selected from the group consisting of a human papillomavirus antigen, an Epstein Barr Virus antigen, a Kaposi's sarcoma-associated herpesvirus (KSHV) antigen, a Hepatitis A virus antigen, a Hepatitis B virus antigen, a Hepatitis C virus antigen, and an influenza antigen. 
     
     
         149 . The lymphocyte composition of  claim 147 , wherein the viral antigen is a human papillomavirus antigen and the human papillomavirus antigen is an E6 or an E7 antigenic peptide, or wherein the viral antigen is an influenza antigen and the influenza antigen is a hemagglutinin antigen or a neuraminidase antigen. 
     
     
         150 . The lymphocyte composition of  claim 141  wherein the allogenic lymphocyte composition is not immunologically reactive to a Cytomegalovirus antigen. 
     
     
         151 . The lymphocyte composition of  claim 141  wherein the peripheral blood cell composition is a whole blood product or an apheresis product. 
     
     
         152 . The allogenic lymphocyte composition for use according to  claim 149 , wherein the nanoparticles further comprise a cytokine, wherein the cytokine is an interleukin and is selected from the group consisting of IL-2, IL-7, IL-12, and IL-15; or the cytokine is an interferon and is selected from the group consisting of interferon gamma, interferon beta, interferon alpha, interferon, tau, interferon omega, and consensus interferon.