In 1998, the Southern California Kaiser Permanente Medical Center moved its HCT program to City of Hope. The program is under the leadership of Neil Kogut, M.D., and Peter Falk, M.D. City of Hope has had a long relationship with Kaiser Permanente’s program and helped develop it many years ago. The merging of the two programs now allows Kaiser Permanente patients to receive therapy at City of Hope utilizing protocols developed in the City of Hope program by both City of Hope and Kaiser transplant physicians.
In 1998, in acknowledgment of the program’s basic and clinical research, including transplant studies for patients with myelodysplastic syndromes (MDS), the MDS Foundation recognized City of Hope as a Center of Excellence for MDS, one of only 34 hospitals worldwide to receive this designation.
City of Hope remains at the forefront of research and innovation, incorporating each new discovery into practical applications for the benefit of cancer patients worldwide. A major focus for researchers has been devising strategies to reduce the incidence of major transplant risks such as GVHD, infection and relapse, and they continually publish their results in prominent medical journals.
City of Hope also is renowned for developing innovative transplant regimens that have improved the cure rate for patients with acute myelogenous leukemia, acute lymphoblastic leukemia, Hodgkin’s lymphoma, lymphoma, multiple myeloma, myelodysplasia and other hematologic disorders, and solid tumors, leading to changes in the options available to patients with these disorders.
For more than two decades, City of Hope also has been at the forefront of CMV research. CMV is a relatively common herpes virus posing little risk to healthy adults. But for immunocompromised HCT patients, CMV infection can lead to fatal complications. Under the leadership of Schmidt and Zaia, the HCT Program became one of the first to develop a treatment for prevention of CMV infection after transplant. The treatment, results of which were published in the New England Journal of Medicine, has nearly eliminated the threat of CMV for HCT patients.
In 1998, three major grants, including one from the NCI’s new Rapid Access to Intervention Development Program, were awarded to City of Hope CMV researchers. Led by Don J. Diamond, Ph.D., director of the Laboratory of Vaccine Research, investigators are applying new insights into the molecular and immunologic aspects of CMV in their work to develop a preventive vaccine.
City of Hope investigators continue to explore new avenues for improving both the effectiveness of HCT and the long-term quality of life for HCT patients. More information on these innovative programs is available at the HCT Research Web site.
New Protocols in Transplants
City of Hope has actively developed and instituted new protocols for pretransplant conditioning which enable maximum effectiveness of the transplant, while reducing the necessity for debilitating doses of chemotherapy and radiation. This has opened the doors to multitudes of patients who were previously unable to undergo transplantation.
Traditionally, pretransplant protocols required high-dose chemotherapy and/or high-dose whole-body irradiation. For elderly patients or comorbid patients (patients with other diseases), this assault was simply more than they could handle and, as a result, such patients were often excluded from transplant.
In order to improve both the safety of transplant and its applicability to a larger number of patients, especially older patients with lymphoma, leukemia and myelodysplasia, the City of Hope Transplant Program developed an approach in 1998 based on the idea of a reduced intensity, or “mini,” transplant. These transplants rely less on the heavy doses of chemotherapy and radiation and more on the antitumor effects of the graft itself (known as a graft-versus-tumor effect). This novel approach has allowed for transplant of patients who are older, including patients in their 70s, who would previously not have been eligible for a transplant. These patients, with conditions such as leukemia, myeloma, lymphoma and myelodysplasia, have been significantly helped, even cured, by mini transplants
At the beginning of the transplant program in 1976, most transplant protocols included the use of high-dose total body irradiation. Under the direction of Andrew A. Raubitschek, M.D., chair of the Division of Cancer Immunotherapeutics and Tumor Immunology, City of Hope’s HCT Program has, over the years, developed novel ways of delivering radiation by utilizing radiolabeled monoclonal antibodies that target disease sites while minimizing damage to normal tissues. Trials led by Raubitschek, Auayporn Nademanee, M.D., Amrita Krishnan, M.D. have been performed primarily in certain patients with malignant lymphoma and have had excellent results. Studies, led by Anthony Stein, M.D., and Margaret O’Donnell, M.D, are now being extended to Hodgkin’s disease and acute myelogenous leukemia.
As T cells are an important component in the normal immune system and are specific for various infectious pathogens, Stephen J. Forman, M.D., Chair, Hematology & Hematopoietic Cell Transplantation, developed a novel approach to redirect T cells to recognize tumor cells. These T cells are derived from either a donor or the patient, genetically reprogrammed, grown to large numbers and reinfused in an effort to induce an antitumor immune response. Clinical trials, led by Forman, David DiGiusto, Ph.D., Eileen Smith, M.D. and Leslie Popplewell, M.D., have been developed for treatment of patients with lymphoma, certain kinds of leukemia, and some cancers of the brain and nervous system.
Application of HCT to Other Diseases
Although HCT has historically been used for treatment of hematologic cancers, and as salvage therapy for nonhematologic cancers, City of Hope physicians and researchers have made significant strides in applying HCT to the treatment of a wide variety of diseases.
Led by Zaia, now chair of the Division of Virology, and John J. Rossi, Ph.D., chair of the Division of Molecular Biology, City of Hope’s HCT program has long studied the concept of genetically modifying blood cells to be resistant to HIV infection. This led to the first clinical trials of gene-modified stem cells for the treatment of HIV patients who also have malignant lymphoma and Hodgkin’s disease resulting from their HIV infection. The results of concurrent transplant studies, begun by Arturo Molina, M.D., and now led by Krishnan, have been excellent, and patients with HIV infection who developed lymphoma are enjoying long remissions without complications or underlying infection. This experience is now the basis for new trials focusing on curing the lymphoma and modifying the transplanted stem cells so they are persistently resistant to the virus.
HCT results in the replacement of a patient’s immune system with that of a healthy donor. With this in mind, investigators in the HCT program, led by Harry Openshaw, M.D., are exploring the use of both autologous and allogeneic transplantation in the treatment of patients with scleroderma, multiple sclerosis and lupus since 1999. With support from the National Institutes of Health and the Bernie Marcus Foundation, and in collaboration with investigators at Stanford University, clinical trials now have been developed for all of those diseases, with the hope of inducing a graft-versus-autoimmunity effect that could cure the patient of autoimmune disease.
Recognizing the importance of maintaining contact with all transplant patients, City of Hope’s Transplant Program established a formal Long-term Follow-up Program in 1998 under the direction of Smita Bhatia, M.D., chair of the Division of Population Sciences. The program, which follows all patients who have received a transplant at City of Hope, helps maintain communication between patients, families and physicians. It also conducts long-term outcomes research to increase awareness of the kinds of problems, both physical and psychological, which some patients face after transplant, so they can receive continuing advice, information and care.
NCI Grant Renewal
In April 2000, City of Hope’s Clinical and Translational Research Program once again was recognized when the NCI acknowledged the importance of the basic and clinical research conducted by its HCT Program by awarding City of Hope a five-year, $15 million grant. This new grant represented continuous funding for the HCT Program by the NCI since 1981.
Similar to other projects in the program, the grant drew upon the talent and research expertise of a number of different laboratories and disciplines within City of Hope and included national collaborations with other HCT centers.
In 2004, the City of Hope Hematologic Neoplasia Program was awarded a SPORE (Specialized Program of Research Excellence) grant to further its work in utilizing transplant and nontransplant approaches for the treatment of malignant lymphoma and Hodgkin’s lymphoma. This grant, under the direction of Forman and Raubitschek, has four projects focusing on different aspects of lymphoma. These include the development of radioimmunotherapy for the treatment of Hodgkin’s disease, the development of immunofusion molecules for the treatment of lymphoma, the development of genetically modified T cells to treat lymphoma, and studies to understand how patients exposed to cancer chemotherapeutic agents can develop myelodysplasia and leukemia (secondary malignancies). This SPORE is one of only three SPORE awards in the United States and builds upon the expertise in the transplant and cancer immunotherapy programs here at City of Hope.
New Research Initiatives
In 2005, under the direction of Mark Kirschbaum, M.D., City of Hope’s Hematologic Malignancy Program developed a new program to conduct phase I and phase II trials of novel agents designed to improve treatments for lymphoma, myeloma, myelodysplasia and leukemia. These studies, which allow patients to be treated for their diseases with the newest agents, are generally sponsored by the NCI and often are in collaboration with other institutions.
In 2006, in recognition of the importance of studies of leukemia and stem cell biology in the development of curative therapies for treatment of leukemia and other stem cell disorders, Ravi Bhatia, M.D., was named the director of the Department of Hematopoietic Stem Cell and Leukemia Research and associate director of the Hematological Malignancies Program at City of Hope.
In April 2006, the NCI again recognized the HCT Program, awarding City of Hope a five-year, $15.2 million grant to develop innovative therapies for people battling leukemia, lymphoma and other cancers. This was the 25th consecutive year that City of Hope received funding for the program.
The grant supports three projects within the HCT Program:
- Exploring the potential of radioimmunotherapy in treating leukemia and lymphoma. Investigators: Raubitschek, Nademanee, Stein, Krishnan and O’Donnell
- Treating acute lymphoblastic leukemia and reducing chances of relapse after HCT by using a donor’s genetically modified T-cells targeted against the CD-19 antigen. Investigators: Forman
- Testing the efficacy of a CMV vaccine. Physicians will give the vaccine to stem cell donors so that, when their marrow is transplanted into the recipient, it is already boosted to fight CMV. Investigators: Diamond and Zaia
The NCI grant supports continuing research aimed at improving the outcome for patients undergoing either autologous or allogeneic HCT for hematologic malignancy. The grant also allows researchers at City of Hope to develop laboratory-based clinical studies to extend the boundaries of HCT into new areas. These studies include the development of therapies incorporating the emerging sciences of gene transfer, molecular biology, radioimmunotherapy, cellular immunotherapy and genetics into allogeneic and autologous transplant.
The program has continued to expand laboratory-based research in order to understand the nature of malignancy and improve the effectiveness of transplantation. This includes the establishment of laboratories focused on the development of antigen-specific T cell therapy, stem cell biology, and stem cell development and expansion.
Reviewing the accomplishments of the past years, it is evident the enormous potential for HCT continues to unfold. New studies in molecular biology, immunology, stem cell biology and genetics are emerging, and there can be no doubt that HCT and other areas of applied research will transform the way medicine is delivered during the next century.