PHILADELPHIA INTERNATIONAL MEDICINE NEWS BUREAU
Contact: Leonard N. Karp
lkarp@philadelphiamedicine.com
215-735-3989
For Immediate Release:
In this month’s issue:
1. Research at The Children's Hospital of Philadelphia Can Open Door to Prenatal Treatment of Genetic Diseases
2. Fox Chase Cancer Center Looks to the Sea to Develop Future Cancer Treatment
3. Temple University Hospital Team Treats Cervical Cancer While Preserving Ability to Give Birth
Research at The Children's Hospital of Philadelphia Can Open Door to Prenatal Treatment of Genetic Diseases
Philadelphia - In a finding that could open the door to future treatments for many genetic diseases such as sickle cell anemia and muscular dystrophy, researchers have produced high levels of transplanted, healthy stem cells in mice, while sharply reducing a hazardous side effect of cell and organ transplants called graft-versus-host disease.
By combining prenatal transplants of blood-forming stem cells with manipulations of blood cells after birth, researchers at The Children's Hospital of Philadelphia achieved immune tolerance in mice, allowing donor cells to multiply without toxic side effects. The Children's Hospital of Philadelphia is a member of Philadelphia International Medicine.
The finding could greatly broaden the use of cell and organ transplants for genetic diseases detected before birth, such as leukemia, sickle cell disease, muscular dystrophy, and some kidney and liver disorders.
"Recent developments in genetic knowledge and technology are converging to make it likely that within a decade, nearly all human genetic diseases will be diagnosed before birth," said Alan W. Flake, MD, director of the Children's Institute for Surgical Science at The Children's Hospital of Philadelphia, and senior author of both articles. "Our research may greatly expand our ability to use prenatal interventions to help the body safely tolerate treatments for genetic diseases."
Flake's team used a prenatal procedure called in utero hematopoietic stem cell transplantation (IUHSCT). Hematopoietic stem cells develop into red blood cells, white blood cells and a variety of immune cells. The stem cells used in these studies were taken from the bone marrow of adult mice, not from human embryos.
As a disease treatment, prenatal stem cell transplants have faced a major barrier in that they have been unable to achieve high levels of engraftment -- the number of donor stem cells usually does not grow large enough to overcome the effect of diseased cells. An exception to this limitation is diseases in which donor cells have a normal advantage over the transplant recipient's cells. For instance, Flake was able to cure a child of a rare immune disease, X-linked severe combined immunodeficiency disorder (X-SCID), by using a prenatal stem cell transplant in 1996 that rebuilt his immune system.
Flake's current studies potentially extend prenatal stem cell transplants to a broader range of diseases, by manipulating conditions to create a competitive advantage for donor cells over host cells. The IUHSCT procedure first makes the recipient's immune system tolerant of low levels of donor cells, and then a second, nontoxic procedure after birth provides a competitive advantage for the transplanted donor cells, allowing them to multiply.
"Performing the stem cell transplant prenatally relies on features of the fetal immune system that are more receptive to transplantation," said Flake. "For instance, the immaturity of the fetal immune system makes it less able to mount an immune response against the transplanted cells." Paradoxically, the technique also relies on a strength of the fetal immune system: its healthy thymus, a gland that declines in function after puberty.
The fetal thymus produces T-regulatory cells, which help to reduce graft-versus-host disease. In that disease, a life-threatening complication of cell and organ transplants, donor cells attack the patient's tissues.
The second, postnatal step of the treatment compromises host blood cells and allows the donor cells to engraft themselves in the recipient's bone marrow and bloodstream. Because the prenatal transplant has made the host animal tolerant of donor cells, the postnatal procedure can be less toxic than conventional treatments that use harsh chemotherapy drugs or high-dose radiation to wipe out the hosts existing immune system.
In one study, Flake used donor lymphocyte infusion (DLI) as the postnatal treatment. Currently used against some leukemias, DLI supplies lymphocytes, donated immune cells that weaken or kill host blood cells. In the other study, the postnatal treatment was low-dose full-body irradiation followed by bone marrow transplantation. Graft-versus-host disease was minimal in the DLI study, killing only one mouse out of 56, and did not occur at all in the other study.
The procedures achieved complete or near-complete chimerism - meaning that all, or nearly all, of the animals blood cells were derived from the donor stem cells, even though the donor animals were not matched with the recipients. "This was the first time that complete chimerism was achieved across mismatched donors and recipients without using toxic therapy," said Flake. "If this strategy can be made to work in people, there are broad implications for treating human disease."
"This approach could potentially target any diseases that are now treatable with bone marrow transplants," adds Flake. "These include blood cell diseases such as leukemias, thalassemia and sickle cell disease, as well as many inherited immunodeficiency disorders."
Beyond that, he added, the technique might also treat muscular dystrophy, an incurable genetic disease that impairs muscle development. In previous research, Flake's team showed that stem cells transplanted in utero can develop into healthy muscle cells in mice with muscular dystrophy.
Organ transplant recipients might also benefit from the technique's ability to make a patient's immune system tolerant of the donated organ. "If prenatal screening predicts that a fetus would have kidney or liver failure, the prenatal stem cell transplant could prepare the immune system for a future transplant," says Flake. "A tolerized immune system would better accept an organ transplant from an unmatched donor."
Although prenatal screening is not yet widespread for many genetic diseases, he adds, currently emerging technologies will make it feasible to diagnose nearly all genetic diseases early in gestation within the next 10 years. "The combination of data from the Human Genome Project, improvements in molecular diagnoses, gene chip technology, and the ability to do molecular diagnoses of fetal cells or fetal DNA within the mothers blood, all support early gestational diagnosis of genetic disease," says Flake.
Flake cautions that the clinical applications may be years away, but based on these results, he will further investigate stem cell transplantation in mice and then in larger animals, with the goal of translating the approach to treatments for people.
Fox Chase Cancer Center Looks to the Sea to Develop Future Cancer Treatment
Cancer researchers around the world, including those at Fox Chase Cancer Center, a Philadelphia International Medicine hospital and research center, hope a drug made by a small sea creature can help treat cancer.
The agent is found in the tissues of a common ocean-dwelling animal called a sea squirt, or "Ecteinascidia turbinata," by its scientific name. One substance derived from it is called ET-743 (YondelisTM), studied clinically since the late 1990s.
ET-743 has been studied in European and American clinical trials for the treatment of soft-tissue sarcomas. Soft-tissue sarcomas are less common cancers affecting blood vessels, muscles, tendons and other connective tissues. Now, researchers at Fox Chase and elsewhere want to know if ET-743 will be effective in treating more common cancers, including advanced breast cancer.
"Breast cancer, when caught early, often can be successfully treated, but fewer treatment options exist for women whose cancer has spread," said Lori J. Goldstein, MD, director of the breast evaluation center at Fox Chase and principal investigator for the latest ET-743 study.
"Since the beginning of time, we have turned to nature to find medicinal agents. This time, we're looking to the sea with hopes that the sea squirt drug can help us treat advanced breast cancer."
Researchers have described a number of ways by which ET-743 might fight cancerous growth. Kathleen Scotto, PhD, a member of the Fox Chase Cancer Center pharmacology department, has spent several years researching the active mechanisms of ET-743.
"It is believed that ET-743 prevents cells from multiplying and selectively causes the cancer cell to die," explained Scotto. "How the drug accomplishes this is not yet clear, but we have shown that ET-743 is a novel and potent inhibitor of activation of a subset of genes that may be involved in the life and death decision made within a cell."
The safety of ET-743 has been tested in several Phase I clinical trials and additional studies continue. Roger B. Cohen, MD, director of Phase I clinical trials at Fox Chase, is conducting two Phase I clinical trials using ET-743 for solid tumors. Phase I studies are the first step in testing a new treatment where the drug is tested for safety. In addition, Goldstein is the principal investigator of a Phase II trial (third-line therapy) for breast cancer, the second step in the drug approval process. Phase II studies determine how well a drug works.
ET-743 is a powerful substance. Less than an ounce is enough to treat dozens of patients. Sea squirts grow abundantly in clusters in all the world's oceans, including the Mediterranean and Caribbean seas. The tube-like creatures can also be farmed. In Japan, sea squirts are considered a culinary delicacy.
Johnson & Johnson Pharmaceutical Research & Development, L.P., is sponsoring Fox Chase Cancer Center's Phase II clinical trial of the sea squirt drug for advanced breast cancer; however, it will take several years of human testing to obtain U.S. government approval.
Temple University Hospital Team Treats Cervical Cancer While Preserving Ability to Give Birth
A unique, multidisciplinary approach to the evaluation and management of patients with gynecologic cancer makes it possible for Temple University Hospital physicians to effectively treat patients with cervical cancer and, in many cases, preserve the patient's ability to have children. Temple University Hospital is a Philadelphia International Medicine member.
"In early cervical cancer cases, we can effectively treat the patient while preserving the uterus," says Enrique Hernandez, MD, director of Temple's Division of Gynecologic Oncology. "More than 50 percent of these patients will still be able to conceive and deliver a healthy baby after being cured of their cancer."
The gynecologic oncology team includes gynecologic and radiation oncologists, oncology nurses and pharmacists, gynecologic pathologists, a nutritionist and social workers. Because of their expertise, the team is able to evaluate patients accurately and offer a full range of treatment options, from the most conservative to the most aggressive.
"Our approach allows us to tailor treatment to meet each patient's individual needs. We are both exacting and appropriately aggressive," says Hernandez.
This individualized approach greatly benefits patients undergoing treatment for early-stage cervical cancer, beginning with careful review of the pathology specimen by the physician members of the team.
Ting Shen, MD, of Temple's Department of Pathology and Laboratory Medicine, has special training and expertise in gynecologic pathology. Additionally, Hernandez has a special interest in gynecologic pathology and is the editor of the textbook Clinical Gynecologic Pathology.
"This initial review determines if a patient with this type of cancer, who wants to preserve fertility, can be successfully treated without removing the uterus," says Hernandez. "In some cases, performing a cervical conization is adequate therapy. While this is a common procedure, determining who is a candidate for this conservative approach requires unique expertise in gynecologic pathology and gynecologic oncology."
In other cases of early-stage cervical cancer, a more aggressive approach is needed and a radical cervicectomy is called for. In this unique procedure, the cervix is removed but the body of the uterus is preserved. This allows for future pregnancies, which are carried to term in more than 50 percent of cases.
Radical cervicectomy is performed at only a few specialized centers in the United States. Karen Houck, MD, from Temple's Division of Gynecologic Oncology, has experience performing this procedure using a standard abdominal approach. "After removing the cancer and being certain that the edges of the excision are free of cancer, the body of the uterus is attached to the vagina," explains Houck. "A suture is loosely tied around the lower aspect of the uterus to prevent it from opening when the woman becomes pregnant."
The Division of Gynecologic Oncology at Temple participates in the NCI-funded Gynecologic Oncology Group (GOG). This cooperative clinical trials group provides cutting-edge investigational therapies to women with gynecologic cancers. In addition to the chemotherapy regimens provided through GOG protocols, patients also can be treated with new drugs being tested under strict guidelines by the pharmaceutical industry. One such on-going clinical trial utilizes standard chemotherapy with or without interferon for the treatment of advanced ovarian cancer. It is hoped that the immune system modulator interferon will improve the results seen with intensive chemotherapy.
Hernandez was recently appointed chairperson of the Department of Obstetrics, Gynecology and Reproductive Sciences.
Hernandez did his residency and fellowship training at Johns Hopkins, and he is board certified in gynecologic oncology. He is a nationally recognized expert in gynecologic oncology, and has served as the Director of the Division of Gynecologic Oncology since his arrival at Temple in 1998.
Hernandez has been very active in clinical practice. His research focus is primarily in clinicopathologic issues in cervical and endometrial cancer. His teaching excellence has been recognized through his receipt of the Association of Professors in Obstetrics and Gynecology Teaching Award and the Award for Excellence in Teaching by the Council on Resident Education in Obstetrics and Gynecology.
Philadelphia International Medicine is an organization that provides medical and patient support services to international patients. It also provides continuing medical education and health care training and education to international physicians, administrators and other practitioners. As the international department of several Philadelphia-area hospitals, international patients gain access to physicians and hospitals rated among the best in the world through one telephone call to PIM. You can reach PIM by calling 1-215-735-3575; fax, 1-215-790-1267; or e-mail, physicians@philadelphiamedicine.com. You can find out more about PIM through its Website at www.philadelphiamedicine.com.