Dr. Press's ongoing work to enhance the effectiveness and reduce the side effects of treatments for lymphoma has led to significant developments in the areas of radioimmunotherapy (RIT). Rather than irradiating a patient's whole body, RIT involves targeting the delivery of radiation by attaching a radioactive molecule to antibodies that can specifically bind to cancer cells. Dr. Press and others have been developing a promising approach that builds on RIT called pretargeted radioimmunotherapy (PRIT) in which the antibody and the radioactive molecule are administered sequentially. Using PRIT, radiation can be targeted even more specifically to the cancer cells, reducing exposure to healthy tissues.
To further refine these strategies, Dr. Press and his colleagues compared three different radiolabeled antibody compounds, both alone and in combination, in models of human lymphoma. It was the first head-to-head comparison of these compounds in PRIT and the first study to evaluate the use of the three compounds in combination.
The study confirmed that PRIT offers advantages over RIT by reducing the amount of radiation to which healthy organs are exposed and, consequently, the severity of harmful side effects. Surprisingly, they found that using all three compounds together did not deliver more radiation to the tumor site. Instead, their results suggest that the best outcomes may be achieved by first characterizing the patient's cancer cells and using that information to determine which radiolabeled antibody would be most effective. This tailored approach to treatment could help improve cure rates and reduce the chances of recurrence.
Non-Hodgkin's lymphoma (NHL) is diagnosed in nearly 60,000 individuals each year in the United States. More than half of those diagnosed are over 60 years old, and these patients are typically least physically able to cope with the side effects of treatments such as blood stem-cell transplantation. This year, Dr. Press and his colleagues set out to determine whether a modified pre-transplant regimen involving targeted radioimmunotherapy, followed by the blood stem-cell transplant, would be a viable option for these patients. They recently published results from a clinical trial of their approach in patients with B-cell NHL that had relapsed or was not responding to therapy.
The investigators found that RIT using [131I]Tositumomab, which targets CD20-producing lymphoma cells, followed by blood stem-cell transplant is safe and effective and causes less severe side effects compared to standard pre-transplant conditioning regimens. Their results suggest that the new approach may be as safe and effective in older adults as it has been in other patient populations, such as younger patients and patients who had not already been through as many rounds of treatment. Researchers will next compare this approach directly against the current standard of care for older adults with relapsed NHL to determine when and if it should replace existing methods.
The radioactive compounds currently used in RIT for lymphoma are called beta-emitters because of the type of radiation they generate. Although they have produced favorable results in patients, there are disadvantages. In particular, the radiation can affect a relatively large area around the cancer cells being targeted, causing damage to other healthy tissues nearby. The beta-emitting compounds can also fail to produce enough energy to kill every cancer cell, which can lead to disease relapse.
In collaboration with colleagues in Norway, Dr. Press has been investigating the potential of radioactive compounds called alpha-emitters. Because they deliver a more powerful burst of radiation to an area only a few cells wide, alpha-emitters could make RIT more effective with fewer or less-severe side effects. Using alpha-emitters could also revolutionize treatment by making it available to patients in an outpatient setting rather than in select hospitals specially equipped to handle and administer beta-emitting compounds.
The research team compared an alpha-emitting compound called Thorium 227 (227Th)-rituximab, which targets CD20-producing lymphoma cells, with a standard beta-emitting anti-CD20 compound called ZevalinŽ. They found the 227Th-rituximab was significantly more effective at killing individual cancer cells as well as larger tumors in mice than the standard beta-compound. Their results also suggest the physical and chemical properties of the alpha-emitting compound would make it suitable for use in an outpatient setting. This study provides critical early evidence that 227Th-based compounds could offer a promising new approach to treating B-cell lymphomas and, potentially, a variety of other cancers.
In addition to radioimmunotherapy, Dr. Press has been investigating ways to modify a patient's own T lymphocytes (a type of immune cell) to fight lymphoma. The modification involves inserting a gene that enables the T-cells to produce a molecule on their surface that helps the cells seek out and destroy CD20-producing lymphoma cells. Although initial work proved promising, the researchers needed to overcome three major barriers before human clinical trials would be feasible.
This year, Dr. Press and his colleagues did just that. They developed a way to make the modified cells produce more of the surface molecules, which enhances the cells' ability to target the cancer cells. They also designed techniques to more rapidly and efficiently generate the large number of cells they would need for treating patients, and they found a way to keep the cells alive and circulating in the patient for longer, which should improve the effectiveness of the treatment.
Their painstaking work to develop these methods led to a prestigious grant from the Lymphoma Research Foundation. The three-year project, which just began, will allow the researchers to test the safety and efficacy of their techniques, refine them in pre-clinical studies and complete a phase I clinical trial in patients with advanced mantle cell lymphoma, a B-cell lymphoma that leads to about 3,000 to 4,000 NHL cases per year in the United States.
Dr. Press remains the co-chair of the National Cancer Institute’s Lymphoma Steering Committee, helping to select the most promising new approaches in lymphoma treatment for testing in national phase 3 clinical trials. He is also co-chair of the University of Washington Nanotechnology Training Program and co-director of the Center for Intracellular Delivery of Biologics. Through these interdisciplinary collaborations, Dr. Press can leverage his experience with targeted cancer therapies to aid in the development of the next generation of medical breakthroughs.
Dr. Press's work illustrates how studies of cancer at the molecular level can lead to more effective, less arduous therapies. In the process of refining these innovative approaches, Dr. Press shares his expertise with the many graduate students and postdoctoral fellows in his laboratory. As one of the busiest mentors at the Center, he helps train the next generation of leaders in lymphoma research and treatment.
Under Dr. Press's guidance, his postdoctoral fellows have all obtained grant support. Since these talented young investigators are often responsible for the preliminary research that leads to major grant awards, support of their work can jumpstart their careers and spur substantial additional funding.