Toca 511 plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models
Autor: | Fernando Lopez Espinoza, Kader Yagiz, Joan M. Robbins, Douglas J. Jolly, Tiffany T. Huang, Carlos E. Ibanez, Daniel Mendoza, Harry E. Gruber |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
Male
Cancer Research medicine.medical_treatment Cell Genetic Vectors Flucytosine Pharmacology Cytosine Deaminase 03 medical and health sciences Mice 0302 clinical medicine Basic and Translational Investigation Lomustine Glioma Antineoplastic Combined Chemotherapy Protocols medicine Splenocyte Animals business.industry Brain Neoplasms Cytosine deaminase Immunotherapy Genetic Therapy medicine.disease Immunohistochemistry Rats Inbred F344 Rats Disease Models Animal medicine.anatomical_structure Retroviridae Oncology 030220 oncology & carcinogenesis Toxicity Female Neurology (clinical) business Glioblastoma 030217 neurology & neurosurgery medicine.drug |
Popis: | BACKGROUND Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, used in combination with 5-fluorocytosine (5-FC) kills tumor by local production of 5-fluorouracil (5-FU), inducing local and systemic immunotherapeutic response resulting in long-term survival after cessation of 5-FC. Toca 511 and Toca FC (oral extended-release 5-FC) are under investigation in patients with recurrent high-grade glioma. Lomustine is a treatment option for patients with high-grade glioma. METHODS We investigated the effects of lomustine combined with Toca 511 + 5-FC in syngeneic orthotopic glioma models. Safety and survival were evaluated in immune-competent rat F98 and mouse Tu-2449 models comparing Toca 511 + 5-FC to lomustine + 5-FC or the combination of Toca 511 + 5-FC + lomustine. After intracranial implantation of tumor, Toca 511 was delivered transcranially followed by cycles of intraperitoneal 5-FC with or without lomustine at the first or fourth cycle. RESULTS Coadministration of 5-FC with lomustine was well tolerated. In F98, combination Toca 511 + 5-FC and lomustine increased median survival, but "cures" were not achieved. In Tu-2449, combination Toca 511 + 5-FC and lomustine increased median survival and resulted in high numbers of cure. Rejection of tumor rechallenge occurred after treatment with Toca 511 + 5-FC or combined with lomustine, but not with lomustine + 5-FC. Mixed lymphocyte-tumor cell reactions using splenocytes from cured animals showed robust killing of target cells in an effector:target ratio-dependent manner with Toca 511 + 5-FC and Toca 511 + 5-FC + lomustine day 10. CONCLUSION The combination of Toca 511 + 5-FC and lomustine shows promising efficacy with no additive toxicity in murine glioma models. Immunotherapeutic responses resulting in long-term survival were preserved despite lomustine-related myelosuppression. |
Databáze: | OpenAIRE |
Externí odkaz: |