Significant synergy exists between CV706, a PSA-selective, replication-competent adenovirus and radiation in the treatment of human prostate cancer

Significant synergy exists between CV706, a PSA-selective, replication-competent adenovirus and radiation in the treatment of human prostate cancer

Proceedings of the 43rd Annual ASTRO Meeting Risk Group Low Intermediate High 205 115 % Positive Biopsies Number SVI ECE with – margin ECE wi...

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Proceedings of the 43rd Annual ASTRO Meeting

Risk Group Low Intermediate

High

205

115

% Positive Biopsies

Number

SVI

ECE with – margin

ECE with ⫹ margin

bNED @ 5 years

ⱕ50% ⬎50% ⱕ17% ⬎17%-34% ⬎34%-50% ⬎50% ⱕ50% ⬎50%

903 97 163 203 150 162 230 191

2% 5% 3% 3% 9% 17% 9% 36%

11% 29% 14% 16% 24% 36% 24% 39%

7% 11% 9% 9% 13% 20% 19% 19%

93% 52% 90% 83% 54% 19% 58% 12%

Significant Synergy Exists Between CV706, a PSA-Selective, Replication-Competent Adenovirus and Radiation in the Treatment of Human Prostate Cancer

T.L. DeWeese1, Y. Chen2, S. Scott1, J. Stephens1, D. Henderson2, D.C. Yu2 1 Oncology, Johns Hopkins Oncology Center, Baltimore, MD, 2Calydon, Sunnyvale, CA Purpose: To determine the anti-tumor activity in vitro and in vivo of CV706, a PSA-selective, replication-competent, cytolytic adenovirus combined with radiation in the treatment of the human prostate cancer (PCa) cell line, LNCaP, and to determine if synergy exists between the two treatments. Materials and Methods: CV706 was constructed by deleting E3 from an Ad5 adenovirus and adding a minimal promoter-enhancer construct of the human PSA gene 5’ of E1A resulting in regulation of E1A expression and, thus, regulated replication. The LNCaP cell line was used for all in vitro and in vivo analyses. MTT assays were performed to determine cell viability following treatment with CV706 alone, radiation alone and a combination of CV706 and radiation at 5, 10 and 20 Gy. Isobolograms were constructed. One-step growth curves were obtained after infection of monolayers with CV706 ⫹/- radiation. Virus yield was then determined by plaque assay. For the in vivo studies, xenografts were established subcutaneously in nude mice and were treated with a single, intratumoral injection of PBS alone, a single, intratumoral injection of CV706 alone, 10 Gy radiation alone or a single, intratumoral injection of CV706 ⫹ 10 Gy. Differences in relative tumor volumes between groups were compared at 6 weeks following treatment. Results: Addition of radiation to CV706 resulted in a synergistic increase in cytotoxicity in LNCaP cells compared to CV706 alone or radiation alone, with a reduction in cell viability by a factor of 7 (combined data points fell to the left of the envelope of additivity). Moreover, this combination also significantly increased viral burst size. Treatment of LNCaP xenografts with this combination therapy resulted in a statistically-significant decrease in relative tumor volume compared to virus alone or radiation alone (p ⬍ 0.01). This translated into a 6.7 fold greater inhibition of tumor growth over that expected if the treatments were additive. Conclusion: These data demonstrate that CV706 enhances the in vitro and in vivo radiation response of human PCa cells. It also supports the concept that radiation can actually augment, not inhibit adenoviral replication, which may be the mechanism by which the synergistic effects are elicited. These data, together with our previous Phase I/II clinical data with CV706, support our clinical translation of CV706 in combination with radiation in the treatment of localized PCa. Supported by NIH S.P.O.R.E. in Prostate Cancer

206

The Role of p53 in Radiation Therapy Outcomes for Prostate Cancer -- Early Stage Disease

M.A. Ritter, K.W. Gilchrist, R.J. Chappell, B.M. Verhoven Human Oncology, University of Wisconsin, Madison, WI Purpose: Some prostate cancers may have molecular alterations that render them less responsive to radiation therapy and that, if identified prior to treatment, might allow improved treatment optimization. This study investigated whether one such potential molecular determinant, p53, could predict long-term radiation therapy outcome in a restricted group of early stage prostate cancer patients treated uniformly with radiation alone. Materials and Methods: This study included 60 patients previously treated with radiotherapy for early stage, favorable-tointermediate risk prostate cancer. These patients were selected for relatively low pretreatment PSAs (less than 18 ng/ml) and Gleason scores (less than 7) to increase the likelihood of localized disease, a necessary condition if the efficacy of localized radiation therapy was to be examined. The status of p53 was immunohistochemically assessed in paraffin-embedded, pre-treatment biopsy specimens along with appropriate controls. This marker was selected based upon a usable prevalence in early stage prostate cancer and its potential linkage with radiation response via cell cycle, DNA repair and cell death pathways. Correlation between p53 and clinical outcome was analyzed in univariate and multivariate fashion, including conventional prognosticators such as stage, grade and PSA. Freedom from biochemical failure was determined using ASTRO criteria. Limitations of prior studies were potentially avoided by requiring adequate post-treatment follow-up (minimum of 5 years), pretreatment PSA and Gleason scores that suggested localized disease, and uniformity of treatment. Results: The total group of 60 favorable-to-intermediate risk patients demonstrated a biochemical failure rate of 35% at 5 years (Figure 1). Forty percent (40%) of all specimens had a greater than 10% labeling index for p53, and actuarial biochemical control was found to strongly and independently correlate with p53 status. Patients whose pre-treatment tumor biopsies demonstrated a greater than 10% p53 labeling index had a significantly higher PSA failure rate (p ⬍ 10 - 5 ) than did those with lower labeling indices (Figure 2). In contrast, p53 status did not correlate with pretreatment PSA, grade or tumor stage. Similarly, pre-treatment PSA (log rank 0.22), Gleason score (log rank 0.93) and T stage (log rank 0.15) were not prognostic for outcome in this favorable group of patients. Conclusion: 1) p53 status in pre-treatment biopsies strongly predicted for long-term biochemical control after radiation therapy in favorable-to-intermediate risk prostate cancer patients.