Limits...
Maintaining therapeutic activity in the operating room: compatibility of a gamma-retroviral replicating vector with clinical materials and biofluids.

Burnett R, Ibañez CE, Pettersson PL, Chen CI, Parab S, Huang T, Robbins J, Bankiewicz K, Aghi M, Logg C, Kasahara N, Pertschuk D, Gruber HE, Jolly DJ - Mol Ther Methods Clin Dev (2014)

Bottom Line: We tested biocompatibility of Toca 511 with: delivery devices; MRI contrast agents, including ProHance supporting coinjection for real time MRI-guided intratumoral delivery; hemostatic agents; biofluids (blood and cerebrospinal fluid); potential adjuvants; and a needleless vial adapter that reduces risk of accidental needle sticks.Toca 511 is stable upon thawing at ambient temperature for at least 6 hours, allowing sufficient time for administration, and its viability is not reduced in the presence of: stainless steel and silica-based delivery devices; the potential MRI contrast agent, Feraheme; ProHance at several concentrations; the hemostatic agent SURGIFOAM; blood; cerebrospinal fluid; and the needleless vial adapter.Toca 511 is not compatible with the hemostatic agent SURGICEL or with extended exposures to titanium-based biopsy needles.

View Article: PubMed Central - PubMed

Affiliation: Tocagen Inc., Bunker Hill St. , San Diego, CA, USA.

ABSTRACT
Toca 511 is a novel retroviral replicating vector, encoding a modified yeast cytosine deaminase, administered to recurrent high grade glioma patients in Phase 1 trials by stereotactic, transcranial injection into the tumor or into the walls of the resection cavity. A key issue, with little published data, is vector biocompatibility with agents likely to be encountered in a neurosurgical setting. We tested biocompatibility of Toca 511 with: delivery devices; MRI contrast agents, including ProHance supporting coinjection for real time MRI-guided intratumoral delivery; hemostatic agents; biofluids (blood and cerebrospinal fluid); potential adjuvants; and a needleless vial adapter that reduces risk of accidental needle sticks. Toca 511 is stable upon thawing at ambient temperature for at least 6 hours, allowing sufficient time for administration, and its viability is not reduced in the presence of: stainless steel and silica-based delivery devices; the potential MRI contrast agent, Feraheme; ProHance at several concentrations; the hemostatic agent SURGIFOAM; blood; cerebrospinal fluid; and the needleless vial adapter. Toca 511 is not compatible with the hemostatic agent SURGICEL or with extended exposures to titanium-based biopsy needles.

No MeSH data available.


Related in: MedlinePlus

Compatibility assessments of Toca 511 with hemostatic agents. (a) pH indicator color changes from a 1 ml (1:200) dilution of Toca 511 with 1, 2, 4, 6, 8, or 10 squares (0.5 × 0.5 cm/sq) of SURGICEL or SURGIFOAM absorbable hemostatic agent. (b) pH measurements (Orion ROSS Micro pH Electrode (P/N 8220BNWP) of controls and the 2 hours, ambient temperature incubations (average of three determinations shown). (c) Transduction titer results from Toca 511/hemostat incubations. Twenty microliters of the incubation or the no-hemostat control was transferred to seeded host PC-3 cells for determination of proviral copy number after the initial round of infection (see materials and methods). Compatibility determinations (Table 3) were determined comparing incubation test articles to controls. SURGICEL became nonmeasurable for incubations greater than two squares. Gelfoam was tested for compatibility by combining saline-diluted (1:50) Toca 511 to 1, 2, 4, or 8 (0.5 × 0.5 cm) squares (6 and 10 square samples were not measured as with the other hemostatic agents) and incubated at ambient temperature for 2 hours.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4362351&req=5

fig3: Compatibility assessments of Toca 511 with hemostatic agents. (a) pH indicator color changes from a 1 ml (1:200) dilution of Toca 511 with 1, 2, 4, 6, 8, or 10 squares (0.5 × 0.5 cm/sq) of SURGICEL or SURGIFOAM absorbable hemostatic agent. (b) pH measurements (Orion ROSS Micro pH Electrode (P/N 8220BNWP) of controls and the 2 hours, ambient temperature incubations (average of three determinations shown). (c) Transduction titer results from Toca 511/hemostat incubations. Twenty microliters of the incubation or the no-hemostat control was transferred to seeded host PC-3 cells for determination of proviral copy number after the initial round of infection (see materials and methods). Compatibility determinations (Table 3) were determined comparing incubation test articles to controls. SURGICEL became nonmeasurable for incubations greater than two squares. Gelfoam was tested for compatibility by combining saline-diluted (1:50) Toca 511 to 1, 2, 4, or 8 (0.5 × 0.5 cm) squares (6 and 10 square samples were not measured as with the other hemostatic agents) and incubated at ambient temperature for 2 hours.

Mentions: Toca 511 was assessed for stability in the presence of SURGICEL sterile absorbable hemostat, SURGIFOAM absorbable gelatin sponge, and Gelfoam (absorbable gelatin sponge). These hemostatic agents are often used in a surgical setting to control bleeding after tumor resection. The hemostatic agents were cut into approx. 0.5 × 0.5 cm squares (1–10 squares of SURGICEL or SURGIFOAM, and up to eight squares for Gelfoam) and incubated for 2 hours at ambient temperature with 1 ml of a 1:200 (1:50 for the Gelfoam samples) media dilution of Toca 511. SURGICEL and SURGIFOAM assessments were made by either adding the cut squares directly to the diluted vector or presoaking the squares in sterile saline prior to transferring to the diluted vector (data for the saline-soaked samples not shown; compatibility results were equivalent to the directly added samples). During the incubation with SURGICEL, a color change in the dilution media (from the phenol red, see Figure 3a) as a function of the number of squares present during the incubation, indicative of a lower pH. SURGIFOAM did not significantly change the media color. The extent of the pH change was confirmed by direct measurement (Figure 3b). The pH dropped from 7.78 for the media-diluted vector alone to 3.17 when incubated with SURGICEL (10 squares), while it only dropped to 7.19 when incubated with SURGIFOAM (10 squares) and 5.81 while incubated with Gelfoam (8 squares). For SURGICEL, titer determination of the samples revealed a sharp drop in transduction titers that was dependent on the total surface area of the SURGICEL squares incubated with the vector (Figure 3c; Table 3). Incubations with Gelfoam indicate compatibility with the smallest surface area exposure (1 square), but decreasing compatibility as a function of surface area of the agent. By contrast, incubations with the SURGIFOAM had a minimum impact on pH and measured no impact on transduction titers indicating good compatibility.


Maintaining therapeutic activity in the operating room: compatibility of a gamma-retroviral replicating vector with clinical materials and biofluids.

Burnett R, Ibañez CE, Pettersson PL, Chen CI, Parab S, Huang T, Robbins J, Bankiewicz K, Aghi M, Logg C, Kasahara N, Pertschuk D, Gruber HE, Jolly DJ - Mol Ther Methods Clin Dev (2014)

Compatibility assessments of Toca 511 with hemostatic agents. (a) pH indicator color changes from a 1 ml (1:200) dilution of Toca 511 with 1, 2, 4, 6, 8, or 10 squares (0.5 × 0.5 cm/sq) of SURGICEL or SURGIFOAM absorbable hemostatic agent. (b) pH measurements (Orion ROSS Micro pH Electrode (P/N 8220BNWP) of controls and the 2 hours, ambient temperature incubations (average of three determinations shown). (c) Transduction titer results from Toca 511/hemostat incubations. Twenty microliters of the incubation or the no-hemostat control was transferred to seeded host PC-3 cells for determination of proviral copy number after the initial round of infection (see materials and methods). Compatibility determinations (Table 3) were determined comparing incubation test articles to controls. SURGICEL became nonmeasurable for incubations greater than two squares. Gelfoam was tested for compatibility by combining saline-diluted (1:50) Toca 511 to 1, 2, 4, or 8 (0.5 × 0.5 cm) squares (6 and 10 square samples were not measured as with the other hemostatic agents) and incubated at ambient temperature for 2 hours.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362351&req=5

fig3: Compatibility assessments of Toca 511 with hemostatic agents. (a) pH indicator color changes from a 1 ml (1:200) dilution of Toca 511 with 1, 2, 4, 6, 8, or 10 squares (0.5 × 0.5 cm/sq) of SURGICEL or SURGIFOAM absorbable hemostatic agent. (b) pH measurements (Orion ROSS Micro pH Electrode (P/N 8220BNWP) of controls and the 2 hours, ambient temperature incubations (average of three determinations shown). (c) Transduction titer results from Toca 511/hemostat incubations. Twenty microliters of the incubation or the no-hemostat control was transferred to seeded host PC-3 cells for determination of proviral copy number after the initial round of infection (see materials and methods). Compatibility determinations (Table 3) were determined comparing incubation test articles to controls. SURGICEL became nonmeasurable for incubations greater than two squares. Gelfoam was tested for compatibility by combining saline-diluted (1:50) Toca 511 to 1, 2, 4, or 8 (0.5 × 0.5 cm) squares (6 and 10 square samples were not measured as with the other hemostatic agents) and incubated at ambient temperature for 2 hours.
Mentions: Toca 511 was assessed for stability in the presence of SURGICEL sterile absorbable hemostat, SURGIFOAM absorbable gelatin sponge, and Gelfoam (absorbable gelatin sponge). These hemostatic agents are often used in a surgical setting to control bleeding after tumor resection. The hemostatic agents were cut into approx. 0.5 × 0.5 cm squares (1–10 squares of SURGICEL or SURGIFOAM, and up to eight squares for Gelfoam) and incubated for 2 hours at ambient temperature with 1 ml of a 1:200 (1:50 for the Gelfoam samples) media dilution of Toca 511. SURGICEL and SURGIFOAM assessments were made by either adding the cut squares directly to the diluted vector or presoaking the squares in sterile saline prior to transferring to the diluted vector (data for the saline-soaked samples not shown; compatibility results were equivalent to the directly added samples). During the incubation with SURGICEL, a color change in the dilution media (from the phenol red, see Figure 3a) as a function of the number of squares present during the incubation, indicative of a lower pH. SURGIFOAM did not significantly change the media color. The extent of the pH change was confirmed by direct measurement (Figure 3b). The pH dropped from 7.78 for the media-diluted vector alone to 3.17 when incubated with SURGICEL (10 squares), while it only dropped to 7.19 when incubated with SURGIFOAM (10 squares) and 5.81 while incubated with Gelfoam (8 squares). For SURGICEL, titer determination of the samples revealed a sharp drop in transduction titers that was dependent on the total surface area of the SURGICEL squares incubated with the vector (Figure 3c; Table 3). Incubations with Gelfoam indicate compatibility with the smallest surface area exposure (1 square), but decreasing compatibility as a function of surface area of the agent. By contrast, incubations with the SURGIFOAM had a minimum impact on pH and measured no impact on transduction titers indicating good compatibility.

Bottom Line: We tested biocompatibility of Toca 511 with: delivery devices; MRI contrast agents, including ProHance supporting coinjection for real time MRI-guided intratumoral delivery; hemostatic agents; biofluids (blood and cerebrospinal fluid); potential adjuvants; and a needleless vial adapter that reduces risk of accidental needle sticks.Toca 511 is stable upon thawing at ambient temperature for at least 6 hours, allowing sufficient time for administration, and its viability is not reduced in the presence of: stainless steel and silica-based delivery devices; the potential MRI contrast agent, Feraheme; ProHance at several concentrations; the hemostatic agent SURGIFOAM; blood; cerebrospinal fluid; and the needleless vial adapter.Toca 511 is not compatible with the hemostatic agent SURGICEL or with extended exposures to titanium-based biopsy needles.

View Article: PubMed Central - PubMed

Affiliation: Tocagen Inc., Bunker Hill St. , San Diego, CA, USA.

ABSTRACT
Toca 511 is a novel retroviral replicating vector, encoding a modified yeast cytosine deaminase, administered to recurrent high grade glioma patients in Phase 1 trials by stereotactic, transcranial injection into the tumor or into the walls of the resection cavity. A key issue, with little published data, is vector biocompatibility with agents likely to be encountered in a neurosurgical setting. We tested biocompatibility of Toca 511 with: delivery devices; MRI contrast agents, including ProHance supporting coinjection for real time MRI-guided intratumoral delivery; hemostatic agents; biofluids (blood and cerebrospinal fluid); potential adjuvants; and a needleless vial adapter that reduces risk of accidental needle sticks. Toca 511 is stable upon thawing at ambient temperature for at least 6 hours, allowing sufficient time for administration, and its viability is not reduced in the presence of: stainless steel and silica-based delivery devices; the potential MRI contrast agent, Feraheme; ProHance at several concentrations; the hemostatic agent SURGIFOAM; blood; cerebrospinal fluid; and the needleless vial adapter. Toca 511 is not compatible with the hemostatic agent SURGICEL or with extended exposures to titanium-based biopsy needles.

No MeSH data available.


Related in: MedlinePlus