title: Redirected tumor-specific allogeneic T cells for universal treatment of cancer.
abstract: Adoptive cell transfer of allogeneic tumor-specific T cells could potentially be used as a universal treatment for cancer. We present a novel approach for adoptive immunotherapy using fully MHC-mismatched allogeneic T cells redirected with tumor-specific, non-MHC-restricted antibody-based chimeric antigen receptor (T-bodies) in the absence of GVHD. Mice bearing systemic metastatic disease were lymphodepleted by irradiation and treated with Her2/neu re-directed T cells. Lymphodepletion created a 'therapeutic window', which allowed the allo-T-bodies to attack the tumor before their rejection. A single split dose administration of allogeneic T-bodies extended the survival of tumor-bearing mice similarly to syngeneic T-bodies, and to a significantly greater extent than nonspecific allogeneic T cells. Blocking egress of lymphocytes from lymphoid organs using the sphingosine-1-phosphate agonist, FTY720, extended the persistence of allogeneic T cells such that allogeneic T-bodies provided superior therapeutic benefit relative to syngeneic ones, and dramatically extended the median survival time of the treated mice for more than a year. Therefore, we suggest that ex-vivo generated MHC-mismatched T-bodies can be used universally for off-the-shelf cancer immunotherapy and that their graft-versus-host reactivity can be safely harnessed to potentiate adoptive cell therapy.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Marcus
authors.forename: Tova
authors.initials: T
authors.lastname: Waks
authors.forename: Zelig
authors.initials: Z
authors.lastname: Eshhar
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D002469:Cell Separation; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011409:Propylene Glycols / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D000951:Antigens, Neoplasm; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine