title: Complete regression of large solid tumors using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy.
abstract: Combining chemotherapy and immunotherapy is problematic because chemotherapy can ablate the immune responses initiated by modulators of the immune system. We hypothesized that protection of immunocompetent cells from the toxic effects of chemotherapy, using drug resistance gene therapy strategies, would allow the combined use of chemotherapy and immunotherapy. In wild-type mice, the antitumor effectiveness of an immunotherapy regimen employing an agonistic anti-CD137 antibody is diminished with escalating doses of the antifolate trimetrexate (TMTX). Using retroviral gene transfer of a mutant form of dihydrofolate reductase (L22Y-DHFR), hematopoietic stem cells were genetically engineered to withstand the toxic effects of TMTX. Mice transplanted with L22Y-DHFR-modified bone marrow were then challenged with AG104 sarcoma cells and treated with TMTX only, anti-CD137 only, or a combination of chemotherapy and immunotherapy. Although tumor burden was transiently decreased during TMTX administration, no mice treated with TMTX alone survived the tumor challenge, whereas approximately 40% of transplanted mice treated with anti-CD137 alone survived. However, 100% of mice survived with complete tumor regression after transplantation with L22Y-DHFR-transduced bone marrow followed by combined treatment with TMTX and anti-CD137. In addition, adoptive transfer of splenocytes from cured mice extended the survival of tumor- bearing animals by approximately 3 weeks compared with controls. Therefore, protection of the hematopoietic system can allow for the combined administration of chemotherapy and immunotherapy, which results in complete tumor clearance.
authors.affiliation: Division of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, Emory University School of Medicine, AFLAC Cancer Center and Blood Disorders Services, Atlanta, GA 30322, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Becker
authors.initials: B
authors.lastname: Hewes
authors.forename: Bagirath
authors.initials: B
authors.lastname: Gangadharan
authors.forename: David R
authors.initials: DR
authors.lastname: Archer
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: H Trent
authors.initials: HT
authors.lastname: Spencer
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy / Q000379:methods; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D017354:Point Mutation; D017475:Receptors, Nerve Growth Factor / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D012509:Sarcoma / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000276:immunology; D014184:Transplantation, Homologous; D016597:Trimetrexate / Q000494:pharmacology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D013762:Tetrahydrofolate Dehydrogenase; D016597:Trimetrexate