Toca 511 plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 18; no. 10; pp. 1390 - 1401
• Main Authors: Yagiz, Kader, Huang, Tiffany T, Lopez Espinoza, Fernando, Mendoza, Daniel, Ibañez, Carlos E, Gruber, Harry E, Jolly, Douglas J, Robbins, Joan M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.10.2016
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Basic and Translational Investigation; Brain Neoplasms - pathology; Cytosine Deaminase - administration & dosage; Cytosine Deaminase - genetics; Disease Models, Animal; Female; Flucytosine - administration & dosage; Genetic Therapy - methods; Genetic Vectors; Glioblastoma - pathology; Immunohistochemistry; Immunotherapy - methods; Lomustine - administration & dosage; Male; Mice; Rats; Rats, Inbred F344; Retroviridae; high-grade gliomas; Toca 511; lomustine (CCNU); 5-FC; immunotherapy
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/now089

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. 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. 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. 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.