Abstract
Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma (www.clinicaltrials.gov NCT01156584).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 145-159 |
| Number of pages | 15 |
| Journal | Neuro-Oncology |
| Volume | 14 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2012 |
| Externally published | Yes |
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Keywords
- 5-fluorocyosine
- brain cancer
- cytosine deaminase
- gene therapy
- glioblastoma multiforme
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Clinical Neurology
Cite this
Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. / Ostertag, Derek; Amundson, Karin K.; Espinoza, Fernando Lopez; Martin, Bryan; Buckley, Taylor; Da Silva, Ana Paula Galvão; Lin, Amy H.; Valenta, David T.; Perez, Omar D.; Ibañez, Carlos E.; Chen, Ching I.; Pettersson, Pär L.; Burnett, Ryan; Daublebsky, Veronika; Hlavaty, Juraj; Gunzburg, Walter; Kasahara, Noriyuki; Gruber, Harry E.; Jolly, Douglas J.; Robbins, Joan M.
In: Neuro-Oncology, Vol. 14, No. 2, 02.2012, p. 145-159.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector
AU - Ostertag, Derek
AU - Amundson, Karin K.
AU - Espinoza, Fernando Lopez
AU - Martin, Bryan
AU - Buckley, Taylor
AU - Da Silva, Ana Paula Galvão
AU - Lin, Amy H.
AU - Valenta, David T.
AU - Perez, Omar D.
AU - Ibañez, Carlos E.
AU - Chen, Ching I.
AU - Pettersson, Pär L.
AU - Burnett, Ryan
AU - Daublebsky, Veronika
AU - Hlavaty, Juraj
AU - Gunzburg, Walter
AU - Kasahara, Noriyuki
AU - Gruber, Harry E.
AU - Jolly, Douglas J.
AU - Robbins, Joan M.
PY - 2012/2
Y1 - 2012/2
N2 - Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma (www.clinicaltrials.gov NCT01156584).
AB - Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma (www.clinicaltrials.gov NCT01156584).
KW - 5-fluorocyosine
KW - brain cancer
KW - cytosine deaminase
KW - gene therapy
KW - glioblastoma multiforme
UR - http://www.scopus.com/inward/record.url?scp=84857569415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857569415&partnerID=8YFLogxK
U2 - 10.1093/neuonc/nor199
DO - 10.1093/neuonc/nor199
M3 - Article
C2 - 22070930
AN - SCOPUS:84857569415
VL - 14
SP - 145
EP - 159
JO - Neuro-Oncology
JF - Neuro-Oncology
SN - 1522-8517
IS - 2
ER -