Reengineered Monoclonal Antibodies Step Up to the Plate in Cancer Studies... Miami Medical School Leads the Way in Assisting Haitians While Training Family Medicine Residents... Miscellanea Medica
LIKE SPORTS FANS habitually disappointed when their team falters after a promising early season, researchers working on monoclonal antibody (Mab)-targeted cancer therapies are no strangers to initial enthusiasm followed by dashed hopes.
While Mabs found a ready place as diagnostic tools within a decade after investigators discovered how to mass-produce identical antibodies using mouse cells, efforts to develop Mab-based treatments were considerably less successful.
"Difficulties were underestimated, the time line was unrealistic, and the claims were overstated," said Lloyd J. Old, MD, director of the Cancer Research Institute's (CRI) scientific advisory council and the Ludwig Institute for Cancer Research, New York, NY.
Now, with a better understanding of some of the pitfalls in bringing these Mabs into the human arena and the development of new generations of reengineered Mabs entering the clinic, some researchers at a CRI-sponsored conference in New York City expressed cautious optimism that the approach will soon result in a therapeutic home run or two.
A 1995 survey by the Pharmaceutical Research and Manufacturers of America found that 69 Mabs were being tested in clinical trials for a variety of disorders, from arthritis to multiple sclerosis, with most aimed at various malignancies.
It's easy to see why researchers found Mabs' potential for treatment so alluring: These proteins seemed to provide a way to fashion therapeutic "magic bullets" that would selectively target cancer cells and spare healthy tissue. This targeting hinges on the ability of such a Mab to recognize certain antigenic proteins on the tumor cell surface that are either missing or present in fewer numbers on normal cells.
However, earlier work was hampered by some technical difficulties. One important problem stemmed from the fact that when mouse Mabs are injected into a person, the human immune system responds by producing human antibodies that attack the mouse Mabs, reducing or blocking their antitumor activity.
As a result of this human antibody to mouse antibody (HAMA) phenomenon, repeat doses of the mouse Mab generally pack much less of a punch than the first one.
"There is nothing more critical to the future success of antibody-based therapies than the ability to re-treat," said Old.
Researchers are overcoming the problem of HAMA by constructing part-human, part-mouse "chimeric" Mabs and mostly human "humanized" Mabs, some of which are already in clinical trials. Other investigators are developing fully human Mabs by introducing human immunoglobulin genes into mice engineered to lack functional mouse immunoglobulin genes, reported Aya Jakobovitz, MD, of Cell Genesys Inc, a biotechnology company based in Foster City, Calif.
In addition to making the Mabs more human friendly, researchers have been tinkering with different methods for delivering a fatal blow to malignant cells. So far, noted Old, most efforts have focused on a few strategies. These include using Mabs that recruit some of the immune system's own cell-killing weapons or using Mabs as guided missiles to deliver deadly payloads, such as radioisotopes or toxins.
Radiolabeled Mabs show real promise in treating hematologic malignancies. In one study reported at the conference, Oliver W. Press, MD, of the University of Washington School of Medicine, Seattle, described work in which patients with relapsed non-Hodgkin's lymphoma (a group that typically has a poor prognosis) were treated with high doses of a Mab (anti-B1, a Mab that reacts with a B-cell surface antigen, CD20) linked to iodine-131. Because the dose used is sufficient to destroy the bone marrow, the patient's own stem cells, previously collected from the patient's marrow or peripheral blood, are reinfused after the Mab treatment to reconstitute the hematopoietic system.
"Using this rather radical approach, one can obtain a high tumor response rate," noted Press. About 85% of the study patients had complete responses to the treatment, and another 10% had partial responses. Reasoning that combination therapy might produce even better results, he and his colleagues are now conducting a phase II study that will examine how patients given the radiolabeled Mab plus chemotherapy fare.
Another group led by Mark S. Kaminski, MD, of the University of Michigan Medical Center, Ann Arbor, reported encouraging results from studies of patients with refractory low-grade and intermediate-grade non-Hodgkin's lymphoma who were also treated with the anti-B1 radiolabeled Mab.
Only about half of patients with intermediate-grade and high-grade lymphomas are curable, and no curative treatment of low-grade lymphomas is available, said Kaminski.
"Although patients with low-grade lymphoma respond initially to treatment, their inevitable course of disease is relapse," he noted. "They can respond to further chemotherapy, but the remission duration becomes shorter and shorter with each attempt."
Because the CD20 antigen is found on nearly all B-cell lymphomas and normal B cells, but not early progenitor B cells or fully mature antibody-secreting cells, the antigen is an especially promising target for Mab-targeted therapy.
"If you could wipe out all the cells in the body that express CD20, you'd be left with mature B cells, which make antibodies to protect host immunity, and very early cells, which can regenerate the more mature B cells ... which leaves a window with some blanks that can be filled in later," Kaminski said. Thus, patients could be treated with radiation doses high enough to kill the tumor cells without destroying the bone marrow or causing more than modest adverse effects.
A single treatment (based on the kinetics observed from a trace-labeled dose) produced a response in 22 of 28 patients with refractory B-cell lymphoma, 14 of whom had a complete response--an encouraging result in a group of patients who typically have a poor prognosis.
About 40% of the patients had longer durations of remission than they had with any previous chemotherapy regimen, and almost half of the complete responders continue to experience a complete remission nearly 21/2 years after treatment. Even though the anti-B1 is a murine Mab, fewer than 20% of patients develop HAMA, so many of those who relapse can be re-treated.
Future plans include phase II/III multicenter trials of the radiolabeled Mab as a treatment for patients with chemotherapy-refractory disease, as well as studies of the approach as an initial treatment.
Mabs that target an antigen called CD33 found on leukemic cells (but not on hematopoeitic stem cells) are showing promise in treating acute and chronic myelogenous leukemias, as a means of both reducing large burdens of leukemic cells and mopping up minimal residual disease, said David A. Scheinberg, MD, of Memorial Sloan-Kettering Cancer Center in New York, NY.
One study involved 27 patients with relapsed or refractory acute myologenous leukemia or accelerated/blastic chronic myelogenous leukemia--patients who typically do very poorly with bone marrow transplants. These patients (four of whom had relapsed after an earlier transplant) were treated with a radiolabeled mouse Mab called M195 or a humanized version, HuM195, before undergoing an allogeneic bone marrow transplant. All 27 patients engrafted and 26 achieved complete remission.
Of the 23 patients receiving their first bone marrow transplant, eight remain alive (and seven continue in unmaintained remission), with follow-up ranging from a few months to nearly 3 years. However, a randomized trial is needed to demonstrate whether such patients will fare better than patients who receive a bone marrow transplant without the Mab treatment, Scheimber said.
But so far, the evidence suggests that Mab therapy may provide a way to target greater numbers of malignant cells without adding additional toxicity. A phase II/III multicenter trial comparing the radiolabeled humanized Mab with conventional chemotherapy alone is now under way.
Even more challenging than inducing remission in patients with leukemia is preventing relapse resulting from malignant cells that elude treatment. The utility of using Mab therapy in this context was recently demonstrated in a prospective randomized trial that found that postoperative treatment with a Mab increased survival in patients with colon cancer who had minimal residual disease.
"Micrometastatic cells should be the most accessible target of all, and there is compelling logic to focus our efforts more on patients with minimal residual disease or on patients at high risk for tumor recurrence," said Old.
Scheinberg noted that he and his colleagues are currently exploring whether Mab therapy can safely reduce minimal disease and prolong remissions and survival in a subgroup of patients with acute promyelocytic leukemia. Because all neoplastic cells in such patients are characterized by a specific chromosomal translocation that rearranges the retinoic acid receptor, sensitive biochemical techniques that detect this rearrangment make it possible to monitor the presence of residual disease and evaluate responses to treatment.
Studies of small numbers of such patients treated with the mouse Mab radiolabeled with iodine-131 suggested that the treatment could prolong survival. Because HAMA prevents repeated dosing with the mouse Mab and iodine-131 causes nonspecific toxicity due to the radioisotope's long range of emission, the investigators collaborated with Protein Design Labs in Mountain View, Calif, to design a humanized version of the Mab.
Unlike the mouse Mab, the unlabeled humanized version is active without the additional punch (and toxicity) of the radioisotope, and repeated doses can be given without provoking a HAMA-type reaction. A multicenter phase III trial is now under way looking at the use of the Mab in patients older than 60 years with newly diagnosed acute myelogenous leukemia as an agent to eliminate minimal disease after induction of chemotherapy. Future trials with a Mab conjugated with a short-range alpha-particle-emitting radioisotope, which should be less toxic to normal "bystander" cells, are also in the works, he said.
John Mendelson, MD, and colleagues at Memorial Sloan-Kettering are exploring a novel combination therapy that involves coadmininstering chemotherapeutic agents with a Mab that blocks a cell-signaling pathway activated by epidermal growth factor (EGF).
Mabs that bind to the EGF receptor can inhibit proliferation of tumor cells in culture and prevent the growth of human tumors grafted onto immune-deficient mice, explained Mendelson. Although such tumors are often able to resist the EGF receptor blockade when they're already well established, animals treated concurrently with a chemotherapeutic agent like cisplatin and doxorubicin and anti-EGF receptor Mabs were cured of the malignancy.
Phase I clinical trials have shown that a single dose of a human chimeric Mab, C225, achieved serum levels high enough to saturate EGF receptors for a week, without causing any adverse effects or HAMA response against C225. Clinical trials with the anti-EGF chimeric Mab combined with cisplatin are now under way at Memorial Sloan-Kettering and other institutions. Additional studies with doxorubicin and C225 to treat prostate cancer and with taxol combined with the Mab in patients with breast cancer are planned.
Investigators have observed a similar synergistic effect against adenocarcinoma xenografts treated with a combination of cisplatin and a Mab against the HER2 receptor, and promising results have emerged from clinical trials in women with advanced breast cancer treated with a humanized Mab both alone and in combination.
Many other research groups are putting new spins on Mabs. Ira Pastan, MD, and colleagues at the National Cancer Institute in Bethesda, Md, have attached a mutant form of a bacterial toxin called Pseudomonas exotoxin A (lacking the portion that will allow it to bind to cells on its own) to a cancer-specific Mab, which showed antitumor activity in patients in a phase I clinical trial. A modified version, created with genetic engineering techniques to fuse a portion of the Mab to the mutant endotoxin, is even more active and less toxic.
Other candidates emerging from research laboratories include Mabs linked to T cells, aimed at increasing the killing power of Mabs by revving up the cellular arm of the immune system, and bispecific Mabs, in which portions of two antibodies are joined together with the aim of binding cancer cells with one arm of the Mab and cytotoxic cells with the other.
While investigators with long memories of the early hype and subsequent disappointments in Mab research are cautious about making predictions, the progress in recent years has left many with a renewed sense of optimism about the future of Mab-based therapies, said Sydney Welt, MD, of Memorial Sloan-Kettering Cancer Center and the Ludwig Institute for Cancer Research.
"The antibody approach is where the future is in oncology," he said.
--by Joan Stephenson, PhD
ALTHOUGH HAITI may be a land of frightful want, some who are interested in the field of family medicine see the country as a land of promise.
Among the first to recognize its potential is the University of Miami (Fla) School of Medicine, which has established a family practice residency rotation at Haiti's only teaching hospital, University Hospital in Port-au-Prince. Faculty members at the University of Miami School of Medicine are also helping Haiti's medical college set up its first family residency program, which they expect will be up and running in July 1996.
According to Arthur Fournier, MD, professor of family medicine and community health and associate dean for community health affairs at Miami, the school's Haitian Outreach Programs came about because his daughter carpools with the daughter of Bart Green, MD, chair of neurosurgery there.
While Green had been interested in helping in Haiti for some time, the removal of Haiti's dictatorship by US-led forces in September 1994 inspired him to ask Fournier if he would like to join in the effort.
"I was very interested," Fournier says. "As associate dean for community health affairs at the medical school, my job is to set up teaching clinics in various communities around Miami. One of the communities I've been working with is `Little Haiti.' While working with these patients, I began to appreciate Haiti's unique language and culture. I also realized what a tremendous opportunity working in Haiti would be for our students to learn a lot of stuff they cannot learn easily elsewhere."
Last December, Fournier, Green, and about 23 other physicians and health professionals from the University of Miami visited Haiti, where they toured several hospitals and met with the country's medical school faculty and minister of health. "We came back very, very moved and committed to help," Fournier says. "The physicians in Haiti were functioning on a heroic level in the absence of any support. They were carrying the health care system on their backs. The University Hospital had no running water, it had no food service or pharmacy."
One of the first things the US physicians did was start an educational exchange program. Andre Vulcain, MD, a Haitian-American family resident at Miami, was the first to go to Haiti for a 4-week rotation in community medicine. The physicians also started to look around for unwanted hospital equipment and supplies to send to Haiti.
The country's health care system is in desperate need of the most basic medical equipment, such as patient beds, examination and delivery tables, operating room lights, and blood pressure cuffs. They were fortunate to find a system to get the supplies and equipment to Haiti: a former patient of Green's, who runs a shipping company, volunteered to ship the donated materials.
"Miami is an ideal US community to help, because of our large Haitian-American population and because of our large Haitian-American faculty," Green says. "The director of the University of Miami's Family Medicine Residency Program, Michel Dodard, [MD], is Haitian American. Ronald Joseph, [MD], another Haitian American, is director of the school's radiology residency program. They and several other Haitian-American faculty members have become deeply committed to the project."
Dodard, who came to the United States in 1975 after finishing 1 year of residency in internal medicine in Haiti, returned to his homeland for the first time in 1991. When he saw what had become of the University Hospital, he was "terribly shocked." Even though Haiti was always poor, its health care system was the one thing that managed to work, he says. Haiti's medical school provided free education. University Hospital worked much like an American teaching hospital. But decades of corrupt dictatorship and the international embargo broke everything. "The embargo didn't destroy the medical system," Dodard says. "It was just the coup de grace."
His visit in February 1995 has given him more hope. "The return of the elected government to Haiti has not fixed everything overnight. However, we're now dealing with officials who have at least some sense of responsibility to the people of Haiti."
Dodard says the devastation of the medical system may allow the creation of a new system built around generalists rather than specialists. "Haiti has the potential of becoming a model for building family medicine systems throughout the third world," he says. "The specialist model of medicine is totally inappropriate for most of the world. We are now questioning its appropriateness even for the United States."
Fournier says he and colleagues at Miami and in Haiti would like to encourage other medical schools to establish similar residency programs and academic exchanges. "I'd be happy to assist in facilitating communication and building networks," he says. "We have a long list of potential clinical training sites throughout Haiti. We also have connections with the Ministry of Health and nongovernmental organizations that run health care facilities, so we can help get people placed where they are most needed."
He invites medical school faculty interested in setting up an international health rotation in Haiti to call him at (305) 532-9358 or (305) 532-8711.
Fournier also has been working with US military medical personnel in Haiti and has nothing but praise for the help they have been giving the University Hospital (JAMA. 1995;274:1664-1666 and 1748-1750). Lester Martinez-Lopez, MD, a colonel and commander of the US Army's 86th Combat Support Hospital (whose task force just completed its tour of duty in Haiti), sent his physicians and nurses to work at University Hospital to teach and to learn. "Colonel Martinez deserves sainthood just for getting the water to flow again into the Haitian hospital," says Fournier. "That by itself was a miracle to rival Lourdes."
"If medical schools all throughout the United States send a couple of residents to Haiti like Miami is doing, and if medical schools and public health schools bring one or two Haitian students to the states for training in public health or health administration, that would make a huge difference," says Martinez-Lopez.
"Haiti's health problems are so overwhelming, we are not going to do much good coming down here just to provide care. That would hurt more than help the country. If Haitians become dependent on us for care, they will resent us when we leave. The best way we can help Haitians is by helping to train them so they can provide care for themselves."
A number of medical schools have begun to explore academic and clinical collaborations with their colleagues in Haiti. For example, faculty at Duke University School of Medicine, Durham, NC, are investigating a student exchange with Haiti's medical school, and faculty from Johns Hopkins School of Hygiene and Public Health, Baltimore, Md, have been collaborating with health professionals in Haiti to provide training in disease control and prevention and the delivery of preventive health care.
Now that Haiti's long reign of terror appears to be over, Fournier and Martinez-Lopez say they believe many other schools will take advantage of similar opportunities for helping and learning.
--by Andrew A. Skolnick
James A. Ferrendelli, MD, has been appointed chair, Department of Neurology, University of Texas, Houston, Medical School.
John V. Linberg, MD, has been named chair, Department of Ophthalmology, West Virginia University School of Medicine, Morgantown, and director, University Eye Center.
Robert W. McKenna, MD, University of Texas Southwestern Medical Center, Dallas, is president-elect, American Society of Clinical Pathologists.
T. Berry Brazelton, MD, Cambridge, Mass, has received the C. Everett Koop, MD, Health Advocate Award from the American Society for Health Care Marketing and Public Relations.
Raymond J. Mayewski, MD, has been appointed medical director of clinical services, University of Rochester (NY) Medical Center.
Leonard D. Hudson, MD, University of Washington School of Medicine, Seattle, is this year's recipient of the Forrest M. Bird, MD, Achievement Award, American Respiratory Care Foundation.
Robert D. Sparks, MD, has been appointed executive director and chief executive officer, CMA (California Medical Association) Foundation, San Francisco.
Ivo P. Janecka, MD, has been appointed director, Longwood Skull Base program, an interdisciplinary center of the otolaryngology, neurosurgery, and plastic surgery departments, Harvard Medical School, Boston, Mass. The treatment centers for adults and children include Children's, Brigham and Women's, and Beth Israel hospitals, Boston, and the program's focus is on tumors, trauma, and congenital deformities of the skull base.
Robert Mason, MD, has been named interim chair, Department of Thoracic and Cardiovascular Surgery, Loyola University Stritch School of Medicine, Maywood, Ill, succeeding Roque Pifarre, MD, who has become codirector of Loyola's Cardiovascular Institute. Mamdouh Bakhos, MD, has been appointed vice chair, and Bryan Foy, MD; John Grieco, MD; and Bradford Blakeman, MD, also have rejoined the department.
Fritz E. Dreifuss, MD, University of Virginia School of Medicine, Charlottesville, is the first American to receive the Ciba-Geigy/International League Against Epilepsy/International Bureau for Epilepsy Epileptology Prize.
Royce Moser, Jr, MD, Salt Lake City, Utah, former commander, School of Aerospace Medicine, Brooks Air Force Base, San Antonio, Tex, has become vice president for medical affairs, American College of Occupational and Environmental Medicine, in the Chicago, Ill, suburb of Arlington Heights. This is a part-time administrative position through a consultant agreement between the college and the University of Utah.
Ricardo Martinez, MD, administrator, says the National Highway Traffic Safety Administration (NHTSA) has prepared its first-ever draft Strategic Execution Plan for traffic safety until the turn of the century. Those wishing to comment or seeking additional information may contact Eleanor A. Hunter, Strategic Planning Division, NPP-11, NHTSA, 400 7th St SW, Washington, DC 25090; telephone (202) 366-2573; facsimile (202) 366-2559. The plan is available via World Wide Web at http://www.nhtsa.dot.gov.
A. James Hudspeth, MD, PhD, has joined the Rockefeller University (New York, NY) faculty as F. M. Kirby (Foundation) Professor.
Stephen Lagakos, PhD, is scientific director of the Harvard School of Public Health's new Center for Biostatistics in AIDS Research, Boston, Mass. The center encompasses the research activities of the AIDS Statistical and Data Analysis Center, which has been analyzing AIDS clinical trials in the United States for eight years.
John W. Sparks, MD, has been named chair, Department of Pediatrics, University of Texas, Houston, Medical School.
Chris Fletcher, MD, has been named corporate director, medical services, Corrections Corporation of America, Nashville, Tenn.
Norig Ellison, MD, University of Pennsylvania School of Medicine, Philadelphia, is the new president, American Society of Anesthesiologists.
Douglas E. Henley, MD, Fayetteville, NC, is the new president, American Academy of Family Physicians. Patrick B. Harr, MD, Maryville, Mo, is president-elect.
Emmett O. Templeton, MD, Baptist Medical
Center-Montclair, Birmingham, Ala, is chair, Board of Chancellors,
American College of Radiology. Ronald G. Evens, MD,
Washington University School of Medicine, St Louis, Mo, and member of
the John S. Greenspan, MD, PhD, University of
California, San Francisco; Shirley M. Tilghman, PhD,
Princeton (NJ) University; Cairns Aitken, MD, DPM, Royal
Infirmary of Edinburgh, Scotland, UK; and Mamphela A. Ramphele,
MbChB, PhD, University of Cape Town, South Africa, have been
elected foreign associates, Institute of Medicine, Washington, DC. This
category of membership, established 7 years ago, now totals 41
members.
Alan N. Houghton, MD, is the new program chair of
immunology, Sloan-Kettering Institute, New York, NY, where he also is
chief, Clinical Immunology Service, Memorial Sloan-Kettering Cancer
Center.
Hans von Leden, MD, Los Angeles, Calif, has received
the Distinguished Award for Humanitarian Efforts, American Academy of
Otolaryngology-Head and Neck Surgery Foundation.
Michael A. Lutarewych, MD, University of Minnesota
Medical School, Minnesota, and Daniel E. Nixon, DO, Medical
College of Virginia, Richmond, are recipients of the National
Foundation for Infectious Diseases-Astra Postdoctoral Fellowship in
Infectious Disease Training and Herpes Virus Research.
Dennis G. Egnatz, MD, has joined the Sara Lee
Corporation, Winston-Salem, NC, as director, corporate medical program,
succeeding Donald M. Hayes, MD, who is retiring.
William Bunney, Jr, MD, has been named to the Della
Martin Chair of Psychiatry, University of California, Irvine, College
of Medicine.
Steven A. Leibel, MD, Memorial Sloan-Kettering Cancer
Center, New York, is the new president, American Society for
Therapeutic Radiology and Oncology. Richard Hoppe, MD,
Stanford (Calif), is president-elect. Jay R. Harris, MD,
Harvard Medical School, is the new board chair.
Stephen K. Carter, MD, has been appointed senior vice
president, research and development, Boehringer Ingelheim
Pharmaceuticals, Inc, Ridgefield, Conn.
Peter S. Aronson, MD, and Robert S. Sherwin,
MD, have been appointed C. N. H. Long Professor(s) of Internal
Medicine, Yale University School of Medicine, New Haven, Conn.
C. McCollister Evarts, MD, Pennsylvania State
University College of Medicine, Hershey, has been named chair, Board of
Directors, Association of Academic Health Centers.
William J. Martone, MD, is the new senior executive
director, National Foundation for Infectious Diseases, Bethesda,
Md.
Patrick C. Walsh, MD, Johns Hopkins University
School of Medicine, Baltimore, Md, has received the Barringer Medal,
American Association of Genitourinary Surgeons, for his contributions
to the management of genitourinary cancer.
Hidesaburo Hanafusa, PhD, Rockefeller University, New
York, NY, has received Japan's Order of Culture for his cancer
research.
Editor's Note: Miscellanea Medica normally apppears in the Medical News & Perspectives
section several times each month. Items submitted for consideration should be directed to the
attention of Phil Gunby, director, Medical News & Humanities Division.
