title: Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning.
abstract: Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4(+) and CD8(+) T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR(+) T cells. Importantly, IL-12-secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell-mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
authors.forename: Hollie J
authors.initials: HJ
authors.lastname: Pegram
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.forename: Erik G
authors.initials: EG
authors.lastname: Hayman
authors.forename: Gavin H
authors.initials: GH
authors.lastname: Imperato
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects; D018122:B7-1 Antigen / Q000235:genetics; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013945:Thymoma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D013953:Thymus Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D019172:Transplantation Conditioning; D014185:Transplantation, Isogeneic
chemical_list: D018941:Antigens, CD19; D018906:Antineoplastic Agents, Alkylating; D018122:B7-1 Antigen; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D003520:Cyclophosphamide