Anthony T Power

VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

Ideally, an oncolytic virus will replicate preferentially in malignant cells, have the ability to treat disseminated metastases, and ultimately be cleared by the patient. Here we present evidence that the attenuated vesicular stomatitis strains, AV1 and AV2, embody all of these traits. We uncover the mechanism by which these mutants are selectively attenuated in interferon-responsive cells while remaining highly lytic in 80% of human tumor cell lines tested. AV1 and AV2 were tested in a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer. While highly attenuated for growth in normal mice, both AV1 and AV2 effected complete and durable cures in the majority of treated animals when delivered systemically.

Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy

Live cells offer unique advantages as vehicles for systemic oncolytic virus (OV) delivery. Recent studies from our laboratory and others have shown that virus-infected cells can serve as Trojan horse vehicles to evade antiviral mechanisms encountered in the bloodstream, prevent uptake by off-target tissues and act as microscale factories to produce OV upon arrival in tumor beds. However to be employed effectively, OV-infected cells are best viewed as dynamic biological systems rather than static therapeutic agents. The time-dependent processes of infection and in vivo cell trafficking will inevitably vary depending on which particular OV is being delivered, as well as the type of carrier cells (CC) employed. Understanding these parameters with respect to each unique CC/OV combination will therefore be required in order to effectively evaluate and harness their potential in preclinical study. In the following review, we discuss how early studies of OV delivery led us to investigate the use of cell carriers in our laboratory, and the approaches we are currently undertaking to compare the dynamics of different CC/OV systems. On the basis of these studies and others it is apparent that the success of any cell-based system for OV delivery rests upon the coordinated timing of three sequential phases—(1) ex vivo loading, (2) stealth delivery and (3) virus production at the tumor site. While at the current time, the timing of these processes are coupled to the natural cycle of infection and in vivo trafficking properties innate to each cell virus system, a quantitative delineation of their dynamics will lay the foundation for engineering CC/OV biotherapeutic systems that can be clinically deployed in a highly directed and controlled manner.

Diffusion properties of conventional and calcium-sensitive MRI contrast agents in the rat cerebral cortex

Calcium-sensitive MRI contrast agents can only yield quantitative results if the agent concentration in the tissue is known. The agent concentration could be determined by diffusion modeling, if relevant parameters were available. We have established an MRI-based method capable of determining diffusion properties of conventional and calcium-sensitive agents. Simulations and experiments demonstrate that the method is applicable both for conventional contrast agents with a fixed relaxivity value and for calcium-sensitive contrast agents. The full pharmacokinetic time-course of gadolinium concentration estimates was observed by MRI before, during and after intracerebral administration of the agent, and the effective diffusion coefficient D* was determined by voxel-wise fitting of the solution to the diffusion equation. The method yielded whole brain coverage with a high spatial and temporal sampling. The use of two types of MRI sequences for sampling of the diffusion time courses was investigated: Look-Locker-based quantitative T(1) mapping, and T(1) -weighted MRI. The observation times of the proposed MRI method is long (up to 20 h) and consequently the diffusion distances covered are also long (2-4 mm). Despite this difference, the D* values in vivo were in agreement with previous findings using optical measurement techniques, based on observation times of a few minutes. The effective diffusion coefficient determined for the calcium-sensitive contrast agents may be used to determine local tissue concentrations and to design infusion protocols that maintain the agent concentration at a steady state, thereby enabling quantitative sensing of the local calcium concentration.