title: Treatment of a solid tumor using engineered drug-resistant immunocompetent cells and cytotoxic chemotherapy.
abstract: Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches.
authors.affiliation: Aflac Cancer Center and Blood Disorders Service, Division of Hematology/Oncology and Bone Marrow Transplantation, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Dasgupta
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Shields
authors.forename: H Trent
authors.initials: HT
authors.lastname: Spencer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D015254:DNA Modification Methylases / Q000096:biosynthesis / Q000235:genetics; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005818:Genetic Engineering; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D000077204:Temozolomide; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D016597:Trimetrexate / Q000008:administration & dosage; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D013762:Tetrahydrofolate Dehydrogenase; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D016597:Trimetrexate; D000077204:Temozolomide