Thermal Dosimetry | Human Clinical Trials | Tumor Physiology | Novel Drug & Immunogene
    Therapy | Specific Research Projects

Specific Research Projects

Project 1: Human Clinical Trials

Leonard Prosnitz, MD, Project Leader
Ellen Jones, MD, PhD, Investigator

This project has four specific aims, all of which emphasize highly innovative applications of hyperthermia. Specific Aim 1 focuses on continuation of our efforts to improve thermal dosimetry. We have completed a thermal dose escalation trial in superficial tumors. We are testing non-invasive thermometry in patients with soft tissue sarcomas of the extremities:

We are also studying the use of computer modeling to improve power deposition to deep seated tumors. Specific Aim 2 emphasizes phase III testing of hyperthermia combined with radiation and/or chemotherapy where the diseases being treated are potentially curable and the quality of treatment is tightly controlled. Novel approaches to drug delivery combined with hyperthermia are tested in Specific Aim 3, which includes use of vascular targeting drugs plus carboplatin plus hyperthermia for ovarian cancer and liposomally encapsulated doxorubicin plus hyperthermia for breast cancer. Physiologic studies of perfusion, oxygenation, oxygen consumption and metabolism will be measured to determine whether these parameters carry prognostic significance in Specific Aim 4.

A liposome is a fat-coated vesicle that is 50 times smaller than a red blood cell. It can be loaded with several types of chemotherapeutic drugs to very high concentrations. The liposomes can then be administered to patients through an intravenous catheter. Clinical trials in this program currently focus on liposomal formulations that contain the highly active cancer drug, doxorubicin. Figure is courtesy of Dr. Needham.

Hyperthermia treatment selectively increases pore sizes in tumor vessels. These pores are conduits for liposomes to escape the vessels and enter the tumor tissue. Hyperthermia does not cause this effect in normal tissues, thereby leading to preferential targeting of liposomes to the tumor. Hyperthermia can selectively increase the amount of drug delivered to a tumor by at least 5-fold compared to giving drug in its free state, and a factor of at least 2 over what can be achieved by giving liposomes without heating. This type of formulation is being tested in Human clinical trials in Project 1.

The Duke Program is also investigating a novel temperature sensitive liposome formulation. When this formulation reaches a critical temperature of 39.5-40°C (103-104°F), the liposome coating becomes unstable and drug is rapidly released in a "burst-like" manner. This method increases tumor-specific selective drug delivery by a factor of 5 over using heat with non-thermally sensitive liposomes and a factor of nearly 30 over what can be achieved with free drug. In pre-clinical models, this increased drug accumulation leads to significantly better antitumor effect. This type of formulation is being tested in Pet canine trials currently (Project 2) and will be expanded to include human trials within the next year (Project 1).

 

Project 2: New Hyperthermia Applications in Canine and Feline Tumors

Mark W. Dewhirst, DVM, PhD, Project Leader
Donald Thrall, DVM, PhD, Investigator
Susan M. LaRue, DVM, PhD, Investigator

The objective of Specific Aim 1 is completed. This was a trial investigating whether prospective control of thermal dose is correlated with treatment outcome in dogs with soft tissue sarcomas treated with thermoradiotherapy. Specific Aims 2 and 3 focus on phase I and II testing of a novel thermosensitive doxorubicin containing liposome formulation, initially developed by Duke faculty. Tumor control associated with this liposome is far superior to other available formulations in a human tumor xenograft model. This formulation will be tested in phase I/II studies in dogs with soft tissue sarcomas. Specific Aim 4 will focus on a second novel technology, which utilizes the HSP70 promoter to signal transcription of the powerful immunomodulatory cytokine, IL-12. Again, pre-clinical data show striking anti-tumor effects with this approach. This treatment will be tested in combination with radiation therapy in phase I/II studies of cats with vaccine associated soft tissue sarcomas.

Project 3: Delivery of Liposomal Drugs and Gene Therapy with Heat

Mark W. Dewhirst, DVM, PhD, Project Leader

This project interdigitates with projects 1 and 2. It asks important questions about how to optimize the implementation of new therapies being tested in those two projects. The emphasis in Specific Aim 1 is to test the effect of hyperthermia on liposomal uptake, intratumoral drug levels and plasma pharmacokinetics. In Specific Aim 2 the ability of MR perfusion measurements to predict the efficiency of liposome delivery to tumors with hyperthermia will be evaluated. Specific Aim 3 asks whether tumor pH is a predictor of treatment outcome in liposome-hyperthermia trials. Specific Aim 4 explores the efficiency of a heat inducible immunogene therapy approach in inducing IL-12 and its downstream effector cytokine, interferon gamma. Intratumoral and systemic levels of the cytokines will be assessed before and after treatment. The overall emphasis of this project is on the quantitative measurement of delivery of these novel therapeutics to tumors.

Project 4: Non-invasive Thermometry

Thaddeus Samulski, PhD, Project Leader

The goal of this project is to use magnetic resonance imaging (MRI) in a clinical trial to control and monitor temperatures achieved in tumors during hyperthermia. We have preliminary data from human patients attesting to the feasibility of this approach. The thermal, spatial and temporal resolution achieved with MRI measurements are generally in the range of 0.5-1.0°C, 0.5-1.0 cc voxel size, with 6-20 second measurement acquisition time. These resolution ranges imply that MRI can play an important role as a non-invasive tool in the development and application of thermal therapies. The hypothesis of the study is that magnetic resonance imaging can be used to control the energy absorption rate distribution (ARD) and monitor temperatures during thermal therapeutic procedures involving large tumor volumes. In a collaborative effort with Project 1 the following specific aims will be implemented:

• Develop robust MR thermal imaging techniques for in vivo applications.
• Develop MRI based feedback control algorithms for the ARD.
• Demonstrate ARD control and temperature monitoring in patients having tumors of the lower extremity based on temperature data acquired with MR chemical shift and/or effective diffusion constant images.
• Demonstrate ARD control and temperature monitoring in patients having tumors in the lower abdomen and pelvis with temperature resolution of 0.75-1.25°C in 1 cc voxels.

Click to play movie

Example of non-invasive temperature measurements made during treatment in a patient with a soft tissue sarcoma of the lower leg (arrows). The colors indicate the temperatures reached during this part of the treatment, which range from 95-109°F (35-42.7°C). The circular structures at the 9 and 11 o=clock positions represent bones (fibula and tibia) of the lower leg. The accompanying movie shows measurements taken at several time points during a one-hour hyperthermia treatment of this patient. The time points are indicated in the lower left-hand corner of the image. The heated zone shifts from one part of the tumor to another as the operator changes the settings on the hyperthermia device. This illustrates how non-invasive temperature measurements can be used to adjust power during therapy, thereby increasing heating in the tumor bearing region. Successful implementation of this technology will greatly enhance the ability to more precisely treat tumors with hyperthermia. NOTE: The jumpiness of the movie is not related to patient movement during treatment. It has to do with image processing.