The age-old challenge faced by every cancer researcher is one of simple precision: how to selectively target and kill cancerous cells, while causing the minimal amount of collateral damage to healthy cells, the innocent bystanders in this cellular battle.
Several years ago, scientists at the Hutchinson Center helped to pioneer one elegant approach to the problem. In radioimmunotherapy, antibodies, a natural component of the immune system with the ability to recognize and attack cancer cells, are loaded with radioactive molecules. The antibody transports the source of radiation to the tumor sites, where the targeted cells are confronted with a molecular one-two punch: Antibody binding initiates the process of cell death, while the radioactive atom delivers deadly radiation to the cancerous cells.
The pioneering work of Drs. Fred Appelbaum and Oliver Press, among others, established the Center as an international leader in this field. As it evolves, the next generation of medical researchers, including Dr. John Pagel, step up to the task of making radiolabel therapy safer and more effective for leukemia and lymphoma patients.
Recently awarded a faculty position in the Clinical Research Division, Pagel began his research career at the Center under Press' supervision.
"John joined my laboratory in July 2000 and since that time has impressed everyone in our group with his tremendous energy, determination, unparalleled industry, superlative laboratory skills, intelligence and his dedicated approach to translational research," Press said.
Pagel now leads the leukemia studies of radioimmunotherapy at the Center as the principal investigator of several human clinical trials. Last year, he was the recipient of prestigious Career Development awards from the Lymphoma Research Foundation and Damon Runyon Cancer Research Foundation, which will fund his research to develop and improve various types of antibody therapy in the treatment of non-Hodgkin's lymphomas and acute leukemias.
Pretargeting reduces 'friendly fire'
The success of radioimmunotherapy as a cure for bloodborne cancers like leukemia and certain lymphomas is limited by one main problem. After the radioactive antibody is injected into the patient's bloodstream, it can take many hours for the protein to achieve maximal localization at targeted cancer sites. Up until that point, the radioactive antibody meanders throughout the body, emitting radiation in an indiscriminate way. Healthy tissues and organs are exposed to lethal beta particles intended for the tumor cells, and this sort of "friendly fire" causes grave side effects. To overcome this problem, Pagel and collaborators have developed a method called "pretargeting." Using animals for preliminary tests, Pagel has separated the delivery of the antibody from the delivery of the radiation with a multi-stage approach. First, the cold antibody, without its radioactive label, is injected into the animal, where it gradually localizes to the specific sites of cancer. The radioactive molecules are introduced later and, through a molecular engineering trick, are able to specifically bind to the antibodies.
In preclinical animal studies, Pagel and his group have demonstrated a level of radiolabel selectivity for tumor sites that is at least 10- to 50-fold higher than existing radioimmunotherapy procedures. "We hope, in the relatively near future, to translate that success directly into human clinical trials," Pagel said.
If that works, the therapeutic benefit of radioimmunotherapy might be radically increased. "The idea is that if we can improve the targeting specificity of the absorbed radiation delivered directly to the tumor sites, we will be able to allow for the safe escalation of the therapeutic dose since we are not increasing nonspecific toxicities," he said. Higher levels of radiation should reduce relapse rates, a frequent and tragic occurrence in non-Hodgkin's lymphomas and acute leukemias.
Antibody therapy without radioactivity
There are ways to enhance the usefulness of antibody therapy without resorting to the extremes of radioactivity, which can be expensive, time-consuming and inconvenient for the patient. For example, Pagel is pursuing research with nonradioactive chemical partners to antibodies.
In the past, researchers have combined antibody therapy with classical chemotherapy agents to achieve a synergistic effect in tumor killing. While this supplemental chemotherapy can markedly improve survival rates, it also burdens a patient with the infamous side effects associated with chemotherapy, as healthy tissues and cells are poisoned as well.
Pagel is exploring the idea that certain nontoxic substances may augment the anti-cancer actions of antibodies in the same way. In close collaboration with Center scientists Dr. Ajay Gopal, Press and others, Pagel has recently published two studies of low-toxicity, synergistic partners for antibody therapy, using both human and mouse cells to model non-Hodgkin's lymphomas. For example, Pagel and Gopal found that a synthetic derivative of vitamin A, fenretinide, amplifies the therapeutic actions of rituximab, the first FDA-approved antibody treatment and a very common treatment for B-cell lymphomas.
In mice with established lymphoma tumors, the fenretinide-rituximab combination proved significantly more powerful than rituximab alone, and human trials are to begin in the near future. Pagel points out that the most exciting aspect of this variety of antibody therapy is its lack of toxicity, thereby making it suitable for long-term, maintenance treatment of patients in danger of relapsing, such as patients with indolent lymphomas or older lymphoma patients who may not be able to tolerate traditional chemotherapy.
Following their footsteps
Pagel says he chose to come to the Center specifically with the goal of conducting translational research in the tradition of his mentors, Appelbaum and Press. Translational medicine, or "bench-to-bedside" research, is the direct application of basic laboratory sciences to the clinical practice of treating individual patients. The gap, between molecular models and test tube experiments all the way to treatment options presented to cancer patient, is tremendous.
According to frequent collaborator Gopal, Pagel certainly has the ability to bridge these distances. "John is the one of the few young 'triple threat' academicians," Gopal said. "He is an expert clinician, a skilled bench and clinical investigator and a superb teacher."
In turn, Pagel relies on support of the entire Center research community, past and present. "The Center is one of the very few places in the country, quite possibly in the world, where such multidisciplinary and collaborative research could be done."
While the laboratory research constitutes most of his work, Pagel's role as a physician, on the stem-cell transplant team and in his own lymphoma and leukemia clinic at the Seattle Cancer Care Alliance, provides the rewards of patient contact. He describes the intimacy of patient-clinician relations with reverence.
"Working with leukemia and lymphoma patients, I have the unique opportunity to help every single person, patient and family member, whom I come in contact with, to improve or impact their life in some way, however small."
It's an honor and a privilege, he says, to be allowed so close to patients as they and their families navigate such a delicate stage of life. In this way, Pagel can witness the translation of all his laboratory studies — mouse models, response rates, apoptosis induction, radioisotope distributions — into the health and well-being of each individual patient.