title: Extended survival of glioblastoma patients after chemoprotective HSC gene therapy.
abstract: Chemotherapy with alkylating agents for treating malignant disease results in myelosuppression that can significantly limit dose escalation and potential clinical efficacy. Gene therapy using mutant methylguanine methyltransferase (P140K) gene-modified hematopoietic stem and progenitor cells may circumvent this problem by abrogating the toxic effects of chemotherapy on hematopoietic cells. However, this approach has not been evaluated clinically. Here, we show efficient polyclonal engraftment of autologous P140K-modified hematopoietic stem and progenitor cells in three patients with glioblastoma. Increases in P140K-modified cells after transplant indicate selection of gene-modified hematopoietic repopulating cells. Longitudinal retroviral integration site (RIS) analysis identified more than 12,000 unique RISs in the three glioblastoma patients, with multiple clones present in the peripheral blood of each patient throughout multiple chemotherapy cycles. To assess safety, we monitored RIS distribution over the course of chemotherapy treatments. Two patients exhibited emergence of prominent clones harboring RISs associated with the intronic coding region of PRDM16 (PR domain-containing 16) or the 3' untranslated region of HMGA2 (high-mobility group A2) genes with no adverse clinical outcomes. All three patients surpassed the median survival for glioblastoma patients with poor prognosis, with one patient alive and progression-free more than 2 years after diagnosis. Thus, transplanted P140K-expressing hematopoietic stem and progenitor cells are chemoprotective, potentially maximizing the drug dose that can be administered.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Adair
authors.forename: Brian C
authors.initials: BC
authors.lastname: Beard
authors.forename: Grant D
authors.initials: GD
authors.lastname: Trobridge
authors.forename: Tobias
authors.initials: T
authors.lastname: Neff
authors.forename: Jason K
authors.initials: JK
authors.lastname: Rockhill
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Silbergeld
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Mrugala
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D018572:Disease-Free Survival; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics; D057170:Translational Research, Biomedical; D019172:Transplantation Conditioning; D025521:Tumor Suppressor Proteins / Q000235:genetics; D016662:Virus Integration
chemical_list: D018906:Antineoplastic Agents, Alkylating; D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes