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

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

  • Neuro Oncol. 2016 Oct;18(10):1390-401. doi: 10.1093/neuonc/now089.
Kader Yagiz 1,  Tiffany T Huang 2,  Fernando Lopez Espinoza 2,  Daniel Mendoza 2,  Carlos E Ibañez 2,  Harry E Gruber 2,  Douglas J Jolly 2,  Joan M Robbins 2
Affiliations

Affiliations

  • 1 Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.) [email protected].
  • 2 Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
PMID: 27166379 DOI: 10.1093/neuonc/now089
Abstract

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.

Keywords

5-FC; Toca 511; high-grade gliomas; immunotherapy; lomustine (CCNU).

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