5 research outputs found
RGD-A-<i>TNF</i> Dose Escalation Study: Patient Population and RGD-A-<i>TNF</i> Trafficking Data
<p>TU: transducing units; IF: immunoflourescent staining for presence of RGD-A-<i>TNF</i> in tumors; OCS: osteochondrosarcoma; PCT: plasma cell tumor; BCT: basal cell tumor; NST: nerve sheath tumor; STS: soft tissue sarcoma; OS: osteosarcoma; FS: fibrosarcoma; N.A.: not analyzed due to improper shipment.</p>*<p>Patient I.D.: dog is identified as participating in study 1 (dose escalation study), followed by patient number (i.e. patient 1.2 is dog 2 in study 1 and so on);</p>**<p>These two tumors originally diagnosed as soft tissue sarcomas were reclassified upon histopathologic review by a single pathologist (SN).</p
RGD-A-<i>TNF</i> trafficking resulted in selective tumor endothelial cell localization and TNF <i>α</i> expression.
<p>(A, B) RGD-A-<i>TNF</i> selectively targeted tumor-associated vasculature (arrows) and was absent from normal tissues at 4–6 hours (A) and at 4 days (B). Magnification, 400-fold; scale bar, 100 µM. Pre-treatment tumor biopsies, post-treatment tumor biopsies, and post-treatment normal tissues in dogs that received a single-dose of RGD-A-<i>TNF</i> double-stained with an anti-CD31 specific antibody plus an anti-bacteriophage specific antibody. Detection was performed with Alexa Fluor 488 (green, blood vessels), Alexa Fluor 594 (red, AAVP), and DAPI (blue, cell nuclei). (C) Pre-treatment tumor biopsies (day 0), post-treatment normal biopsies (day 4) and post-treatment tumor biopsies (day 4) were used for extraction of total RNA. RT-PCR was performed to measure transcript levels of human TNFα in quadruplicate. The Y-axis represents the relative TNFα expression levels in post-treatment normal biopsies and post-treatment tumor biopsies compared to pre-treatment tumor biopsies after normalization to GAPDH expression (Kruskal-Wallis Test, p = 0.0107). All data are presented as means±standard deviations. (D–F) Presence of RGD-A-<i>TNF</i> was evaluated in post-treatment (day 28) necropsy samples of tumor (D) and normal tissues (E, F). Tissues were stained for RGD-A-<i>TNF</i> as described earlier. RGD-A-<i>TNF</i> selectively targeted tumor-associated vasculature in post-treatment tumor samples (arrows). In contrast, the vector was not apparent in pre-treatment tumor samples or in post-treatment normal control necropsy samples (such as lung, liver, spleen or intestine) after serial administrations of RGD-A-<i>TNF</i>.</p
RGD-A-<i>TNF</i> administration resulted in objective tumor responses in dogs with spontaneous cancers.
<p>A large primary soft tissue sarcoma on the flank of Dog #2.11 is shown to feature the potential magnitude of the tumor response. Prior to therapy (day 0), the tumor measured 12.3 cm in longest diameter. At day 28, after 4 weekly infusions of RGD-A-<i>TNF</i>, the tumor measured 8.2 cm in longest diameter (a 33% regression) and a RECIST-based partial response (PR). At day 56, after a total of 8 weekly systemic infusions of RGD-A-<i>TNF</i>, the tumor measured 1.85 cm in longest diameter prior to resection. Therefore, this response equated to an 85% regression from baseline and a continued clinical PR. Upon surgical resection of the residual lesion, no viable tumor was found and a pathological complete response was determined.</p
RGD-A-<i>TNF</i> Multiple Dose Study: Patient Data and Tumor Responses
<p>FS: fibrosarcoma; OS: osteosarcoma; PNST: peripheral nerve sheath tumor (malignant); SCC: squamous cell carcinoma; S-C MS: subcutaneous myxosarcoma; MLT: multi-lobular tumor; Mel: LN mets: melanoma lymph node metastases; inc.: increase; dec.: decrease; PD: progressive disease; SD: stable disease (shown in yellow); PR: partial response (shown in green); Unevaluable: due to consent withdrawal by the owner, or death or euthanasia before completion of cycle 1</p>*<p>Patient I.D.: dog is identified as participating in study 2 (fixed multiple dose study), followed by patient number (i.e. patient 2.2 is dog 2 in study 2 and so on)</p><p>Cycle 1: dogs received 4 weekly doses of RGD-A-<i>TNF</i>; Cycle 2: dogs received additional 4 weekly doses of RGD-A-<i>TNF</i></p
Schema representing the schedule for the dose escalation phase of RGD-A-<i>TNF</i> evaluation in dogs with spontaneous cancers.
<p>(A) This study was structured as a dose-escalation using a modified Fibonacci design to govern dose escalation towards an MTD. (B) Three dogs were enrolled in the starting-dose cohort, and three dogs per cohort were enrolled there after for each of the five dose levels planned. Dogs were scheduled to receive RGD-A-<i>TNF</i> on day zero and to undergo definitive tumor resection 4 days later. This initial 4-day group was designed (i) to evaluate vector localization and TNFα expression within tumors and (ii) to verify that the tentative follow-up schedule of RGD-A-<i>TNF</i> administration at one-week dosing intervals was biologically appropriate. After a group of dogs (n = 18) were treated according to this schedule, an additional group was enrolled by equivalent inclusion criteria to receive RGD-A-<i>TNF</i> on the same day of definitive surgical resection. In this subset of dogs (n = 6), surgery was performed 4–6 hours post administration of RGD-A-<i>TNF,</i> this same-day experimental subset was designed to establish the acute selectivity of RGD-A-<i>TNF</i> trafficking and its tumor vascular localization.</p