Person:

Wheeler, Lee Adam

The continued spread of HIV underscores the need to interrupt transmission. One attractive strategy is a topical microbicide. Sexual transmission of herpes simplex virus type 2 (HSV-2) in mice can be inhibited by intravaginal small inhibitory RNA (siRNA) application. To overcome the challenges of using siRNAs to knock down gene expression in immune cells susceptible to HIV infection, we used chimeric RNAs composed of an aptamer fused to an siRNA for targeted gene knockdown in cells bearing an aptamer-binding receptor. Here, we showed that CD4 aptamer-siRNA chimeras (CD4-AsiCs) specifically suppress gene expression in CD4+ T cells and macrophages in vitro, in polarized cervicovaginal tissue explants, and in both the genital and rectal tracts of humanized mice. CD4-AsiCs do not activate lymphocytes or stimulate innate immunity, provide durable target gene silencing for up to three weeks in vitro, and maintain effectiveness in a hydroxyethyl cellulose (HEC) gel formulation. CD4-AsiCs that knock down HIV genes and/or CCR5 inhibited HIV infection in vitro and in cervicovaginal explants. When applied intravaginally to humanized mice, CD4-AsiCs provided durable protection against transmission of the virus. Thus, CD4-AsiCs could be used as the active ingredient of a microbicide to prevent the sexual transmission of HIV.

The global impact of sexually transmitted infections (STIs) is significant. The sexual transmission of viruses such as herpes simplex virus type-2 (HSV-2) and the human immunodeficiency virus type-1 (HIV-1), has been especially difficult to control. To date, no effective vaccines have been developed to prevent the transmission of these STIs. Although antiretroviral drugs have been remarkably successful in treating the symptoms associated with these viral infections, the feasibility of their widespread use for prevention purposes may be more limited. Microbicides might provide an attractive alternative option to reduce their spread. In particular, topically applied small inhibitory RNAs (siRNAs) have been shown to not only block transmission of viral STIs to mucosal tissues both in vitro and in vivo, but also confer durable knockdown of target gene expression, thereby circumventing the need to apply a microbicide around the time of sexual encounter, when compliance is mostly difficult. Despite numerous clinical trials currently testing the efficacy of siRNA-based therapeutics, they have yet to be approved for use in the treatment of viral STIs. While several obstacles to their successful implementation in the clinic still exist, promising preclinical studies suggest that siRNAs are a viable modality for the future prevention and treatment of HSV and HIV.

Purpose: The prognosis for malignant gliomas is poor, and overall survival remains less than 15 months despite improved diagnostic and treatment techniques, underscoring the need for novel therapeutic options. This multicenter, single-arm Phase Ib/II trial was conducted to assess the safety and efficacy of AdV-TK, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, in patients newly diagnosed with high grade glioma.

Patients & Methods: Patients were recruited between 2005 and 2010 at four clinical sites. In addition to the standard of care (SOC), which included surgery, adjuvant XRT + temozolomide (TMZ), AdV-TK was administered to the tumor bed at the time of resection followed by valacyclovir prodrug. A total of 48 patients completed therapy per protocol, and were stratified based on extent of resection (total vs. subtotal) and pathological diagnosis (GBM vs. AA/AO). Data from 134 matched patients, who underwent similar SOC at a fifth clinical site during the same time period, were used for descriptive comparison.

Results: There were no dose-limiting toxicities or significant adverse events considered related to AdV-TK. Median overall survival (OS) was 17.05 months, with 67% and 35% at 1- and 2- years respectively. Median OS for patients with total resection was 25 months, compared with 13.5 months for patients with subtotal resection. This difference was more pronounced in patients with a pathological diagnosis of GBM (25.05 vs. 10.6 months). In the comparison group median OS was 13.5 months, with 57% and 22% at 1- and 2- years respectively. Median OS for those with total resection was 16.9 months and 12.47 months for subtotal resection. Progression free survival (PFS) was also improved in the AdV-TK group (8.3 vs. 6.43 months).

Conclusions: Results from this multicenter Phase Ib/II trial demonstrate that AdV-TK plus valacyclovir can be safely delivered at the time of surgical resection without added toxicity to patients with newly diagnosed high grade glioma. The median OS and the 1- and 2-year survival rates of AdV-TK study patients compare favorably to historical reports and a matched comparison set. Survival outcomes are significantly better in patients having undergone total resections versus subtotal resections. These data strongly support launching a statistically powered randomized clinical study of AdV-TK for the treatment of high grade glioma.