Second-Generation Replication-Competent Oncolytic Adenovirus Armed with Improved Suicide Genes and ADP Gene Demonstrates Greater Efficacy without Increased Toxicity

Abstract

Replication-competent adenovirus-mediated suicide gene therapy has proven to be safe in humans when delivered intraprostatically. Although signs of efficacy are emerging, it is likely that further improvements will be needed before this technology will have widespread applicability in the clinic. Toward this end, we have developed a second-generation, replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-ADP) containing an improved yeast cytosine deaminase (yCD)/mutant(SR39) herpes simplex virus thymidine kinase fusion (yCD/mutTK(SR39)) gene and the adenovirus death protein (ADP) gene. Relative to the first-generation Ad5-CD/TKrep adenovirus, Ad5-yCD/mutTK(SR39)rep-ADP demonstrated greater tumor cell kill in vitro and significantly greater tumor control in preclinical models of human cancer. Quantification of transgene volume following direct injection of fadenovirus into human tumor xenografts and the naïve canine prostate demonstrated that ADP enhanced adenoviral spread in vivo. Toxicology studies were performed to determine whether the improved yCD/mutTK(SR39) fusion and ADP genes increased toxicity. Intraprostatic injection of Ad5-yCD/mutTK(SR39)rep-ADP did not result in significantly increased toxicity relative to the parental Ad5-CD/TKrep adenovirus, the latter of which has proven to be safe in two Phase I prostate cancer clinical trials. Together, these results provide the scientific basis for evaluating the safety and efficacy of the second-generation Ad5-yCD/mutTK(SR39)rep-ADP adenovirus in humans.

Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus

“…It was shown previously that antitumor activity of replication-competent Ad vectors was improved by overexpression of ADP (E3-11.6K) due to enhanced vector spread both in cell culture and in vivo after direct i.t. injections (28)(29)(30). For studying the anticancer activity of systemically delivered Ad, we constructed a nonattenuated oncolytic Ad5 that overexpresses ADP.…”

“…Work has been done to increase oncolytic potency of the vectors by arming them with therapeutic genes and has produced promising results (30,(37)(38)(39)(40)(41). However, most of the preclinical and clinical studies with oncolytic Ad have been performed by direct i.t.…”

Quantifying the Activity of Adenoviral E1A CR2 Deletion Mutants Using Renilla Luciferase Bioluminescence and 3′-Deoxy-3′-[18F]Fluorothymidine Positron Emission Tomography Imaging

“…Although dlCR2 Ren lacks E3 11.6 (ADP), this should not have any effect on intracellular replication, as ADP only affects final cell lysis (20). A reduction in replication has been noted in other vectors with transgenes adjacent to E1 (21) and attempts to augment viral potency by inserting transgenes, such as mda-7, into the E1 and/or E3 regions have met with varying degrees of success (22)(23)(24). However, dlCR2 Ren may be able to kill cells at a lower intracellular copy number so that a At all time points after virus injection, light emission in dlCR2 Ren-treated animals exceeded that in Ad LM-X-and dl922-947-treated animals (P = 0.04 to <0.0001; one-tailed t test).…”

Trial Watch—Oncolytic viruses and cancer therapy

“…in combination with cisplatin-based chemoradiation 188,189 (NCT01584284). 190 Moreover, (1) G207 (a conditionally replicating HSV-1 strain) 191 has been tested in combination with radiation therapy in nine patients with progressive, recurrent glioblastoma (NCT00157703); 192 (2) the therapeutic profile of NTX-010 (a native, replication-competent variant of the Seneca Valley picornavirus, also known as SVV-001) 193 in combination with metronomic cyclophosphamide has been assessed in 22 children with neuroendocrine tumors (NCT01048892); 194 (3) Ad5-yCD/mutTKSR39rep-ADP (a replication competent adenoviral strain endowed with superior oncolytic potential) 195 has been tested in combination with intensity modulated radiation therapy 196,197 in 44 prostate carcinoma patients; 198 (4) the clinical activity of HF10 (a replicative HSV-1 strain) 199 has been investigated in 17 subjects with advanced malignancies, who received HF10 intratumorally as standalone immunotherapeutic intervention; 200 (5) MV-NIS (a strain of oncolytic measles virus encoding the human thyroidal sodium iodide symporter), 201,202 has been tested as standalone immunotherapeutic intervention in two myeloma patients; 203 (6) the safety and efficacy of OBP-301 (an oncolytic adenovirus engineered to selectively target telomerase reverse transcriptase (TERT)-overexpressing cells, also known as telomelysin) 204 has been assessed in six elderly subjects with esophageal carcinoma, who received OBP-301 i.t. in combination with radiation therapy (UMIN000010158); 205 and (7) the clinical profile of an oncolytic variant Western Reserve vaccinia virus artificially endowed with improved specificity 206 has been evaluated in 16 individuals with advanced solid malignancies, who were treated with oncolytic virothapy i.t.…”