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Clinical Trial
. 2010 Nov 1;16(21):5277-87.
doi: 10.1158/1078-0432.CCR-10-0791. Epub 2010 Oct 26.

A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases

Kristopher J Kimball  1 , Meredith A Preuss, Mack N Barnes, Minghui Wang, Gene P Siegal, Wen Wan, Huichien Kuo, Souheil Saddekni, Cecil R Stockard, William E Grizzle, Raymond D Harris, Rosemarie Aurigemma, David T Curiel, Ronald D Alvarez
Affiliations
Clinical Trial

A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases

Kristopher J Kimball et al. Clin Cancer Res. .

Abstract

Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5-Δ24-Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases.

Experimental design: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 10(9) to 1 × 10(12) viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response.

Results: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a >20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent.

Conclusions: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted.

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Figures

Figure 1
Figure 1. Quantification of Ad5-Δ24-RGD in ascites/peritoneal lavage samples (A) and immunohistochemical evidence of colocalization of Ad5-Δ24-RGD and ovarian cancer cells (B)
A. Using real time quantitative PCR, Ad5-Δ24-RGD copy numbers were quantified in each patient's lavage samples (in triplicate) on Day 0,3,7,14, and 28. B. Representative immunohistochemical stains of ascites from selected patients are depicted. All images are 40× magnification. The top panels depict localization of Tag-72, an antibody to a tumor associated glycoprotein known to be expressed by ovarian cancer cells. The second row depicts localization of anti-hexon antibody, an anti-adenovirus antibody. The bottom row shows a digital overlay of the two previous images. On day 0, green fluorescence demonstrates the presence of ovarian cancer cells while the anti-adenovirus staining panel demonstrates only background red fluorescence. Some red background fluorescence is present in adenovirus negative cells. Representative images shown after treatment contain cells that stain for both the tumor marker and adenovirus.
Figure 1
Figure 1. Quantification of Ad5-Δ24-RGD in ascites/peritoneal lavage samples (A) and immunohistochemical evidence of colocalization of Ad5-Δ24-RGD and ovarian cancer cells (B)
A. Using real time quantitative PCR, Ad5-Δ24-RGD copy numbers were quantified in each patient's lavage samples (in triplicate) on Day 0,3,7,14, and 28. B. Representative immunohistochemical stains of ascites from selected patients are depicted. All images are 40× magnification. The top panels depict localization of Tag-72, an antibody to a tumor associated glycoprotein known to be expressed by ovarian cancer cells. The second row depicts localization of anti-hexon antibody, an anti-adenovirus antibody. The bottom row shows a digital overlay of the two previous images. On day 0, green fluorescence demonstrates the presence of ovarian cancer cells while the anti-adenovirus staining panel demonstrates only background red fluorescence. Some red background fluorescence is present in adenovirus negative cells. Representative images shown after treatment contain cells that stain for both the tumor marker and adenovirus.
Figure 2
Figure 2. Quantification of Ad5-Δ24-RGD in Serum (A), Saliva (B) and Urine (C)
Using RT-PCR, Ad5-Δ24-RGD copy numbers were quantified in each patient's serum (A), saliva (B) and urine (C) samples on Day 0,3,7,14, and 28.
Figure 2
Figure 2. Quantification of Ad5-Δ24-RGD in Serum (A), Saliva (B) and Urine (C)
Using RT-PCR, Ad5-Δ24-RGD copy numbers were quantified in each patient's serum (A), saliva (B) and urine (C) samples on Day 0,3,7,14, and 28.
Figure 2
Figure 2. Quantification of Ad5-Δ24-RGD in Serum (A), Saliva (B) and Urine (C)
Using RT-PCR, Ad5-Δ24-RGD copy numbers were quantified in each patient's serum (A), saliva (B) and urine (C) samples on Day 0,3,7,14, and 28.
Figure 3
Figure 3. Assessment of anti-adenoviral neutralizing antibody (Nabs) response in serum (A) and ascites (B)
Assessment of induced anti-adenovirus Nabs response after treatment was carried by exposing a nonreplicative luciferase expressing virus, Ad5-RGD-Luc1, to either patient serum (A) or ascites (B) prior to infection of SKOV3.ip1 cells. Following neutralization in respective samples, Ad5-RGD-Luc1 transduction efficacy was determined by a luciferase assay. Each treatment cohort's mean response is documented here in addition to a negative control represented by No Sera or No Ascites.
Figure 3
Figure 3. Assessment of anti-adenoviral neutralizing antibody (Nabs) response in serum (A) and ascites (B)
Assessment of induced anti-adenovirus Nabs response after treatment was carried by exposing a nonreplicative luciferase expressing virus, Ad5-RGD-Luc1, to either patient serum (A) or ascites (B) prior to infection of SKOV3.ip1 cells. Following neutralization in respective samples, Ad5-RGD-Luc1 transduction efficacy was determined by a luciferase assay. Each treatment cohort's mean response is documented here in addition to a negative control represented by No Sera or No Ascites.
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