Frederick R. Applebaum, MD of Fred Hutchinson Cancer Center
The Forbeck Forum 2000 relates to the high dose drug therapy, treatment so toxic that it requires a bone marrow transplant to rescue the patient’s blood system. The graft of bone marrow can come from two sources. It is possible to harvest components of the blood system directly from the patient before therapy and give it back when treatment is completed. This is called autologous transplantation. The alternative (allogeneic transplantation) is to find an individual to make the donation of blood cells. This process has been difficult as finding an appropriate donor is not easy because tissues have to be matched with specific markers on the cell surface, otherwise rejection occurs. However, in the case of grafts of bone marrow cells it is now possible to undertake mis-matched grafts, making the procedure more useful. Allogeneic transplantation of bone marrow cells has some advantages. In some instances, cells in the graft can produce an immune response to attack the patient’s tumor cells. Unfortunately, this response can also affect normal tissues creating a very severe problem called graft versus host disease. In the past we have not been able to separate the anti tumor response from the cells that attach on the body, but now this situation is changing. It is likely that we will soon be able to manipulate allogeneic grafts to only kill the cancer cells, with an effectiveness which is greater than that achieved with drug therapy. This whole field is exploding as it now offers hope for the treatment of cancers which do not respond well to current therapies. Bringing together a group of scientists and clinicians to drive this process forward will be very exciting.
The Forum focused on the topic of allogenic stem cell transplantation. Participants included experts in stem cell biology, scientists interested in experimental models of transplantation and tumor immunology, clinical researchers, and population scientists. The general mood of the meeting was one of considerable excitement and optimism. The mood was created by the general agreement that for perhaps the first time we now have the necessary knowledge and most of the tools to harness the enormous power of the human immune system in the fight against cancer.
Irv Weisman opened the meeting with an outstanding talk about the nature of the hematopoietic stem cell. In addition to elucidating many principles about the behavior of the stem cell relevant to clinical transplantation, Irv presented some extraordinary information about how hematopoietic stem cells can actually transform into liver cells and about how neural stem cells might be used to treat devastating neurological diseases.
Peter Landsdorp continued the discussion on stem cells presenting new data about how stem cells age, how we can monitor their health, and how this information might impact both the safety of transplantation and predict for the development of hematologic malignancies.
Crystal Mackall presented data about how the stem cell goes about forming a new immune system and what might be done to assist this process, which is a central issue to the health of patients following transplantation. Following marrow transplantation, there is a powerful immunologic effect of the graft against the patient’s malignancy. However, this effect is often accompanied by the development of graft-versus-host disease which can be a serious or even lethal complication of transplantation.
Robert Korngold, Bruce Blazar, and Paul Martin each presented different experimental approaches to overcome the difficult problem of graft-versus-host disease. All three presented exciting and encouraging data that will need to be pursued in clinical trials.
Megan Sykes and Richard Champlin provided clinical data describing the process of non-ablative transplants, an approach that is revolutionizing the process of allogenic hematopoietic stem cell transplantation. Contrary to conventional wisdom, investigators have found that it is possible to achieve complete engraftment of donor marrow without first treating patients with extraordinarily high and dangerous doses of chemotherapy. By achieving grafts with relatively non-toxic specific immunosuppression, transplantation is finding a much wider audience, both in terms of the age and health of the patient as well as the variety of diseases under treatment.
Stan Riddell and Richard O’Reilly presented exciting new information on how one can isolate immune competent cells with activity restricted to tumor and how this extraordinarily promising method of treatment is now being used clinically. John Goldman and Guido Tricot outlined the major questions that need to be addressed in the application of transplantation to several specific diseases, including chronic myelogenous leukemia and multiple myeloma.
Mary Horowitz provided information about the still surprisingly limited access that patients have to transplantation, and outlined a number of barriers to the wider application of transplantation and to the performance of the clinical trials necessary to continue the progress we have made in this field.
In addition to these uniformly outstanding scientific presentations, the three Forbeck scholars, Philip Beckhove, Francesco Galini and Catherine Ju-Ying Wu gave talks that were at almost the same level as the senior scientists. Their level of enthusiasm and accomplishment were a pleasure to witness.
The participants were unanimous in their belief that it should be possible in the near future to isolate a relatively pure population of hematopoietic stem cells, to transfer them from a healthy donor to the patient, and to educate the immune system of the donor to attack and in many cases eradicate the patient’s malignancy. As demonstrated by the investigators at this forum, this can now be done in relevant animal models of human disease and all the tools are now available to apply these principles to patients.
The participants of the meeting also emphasized some of the barriers to the performance of such large cooperative studies. One such barrier id the lack of generally agreed upon endpoints for such trials. To this end, all participants were excited and gratified to learn of the Forbeck’s willingness to support a Forum to be co-chaired by Dr. Horowitz and Dr. Martin to define such endpoints. This news was a fitting ending to an exciting two days which began with the definition of the true stem cell and concluded with a discussion of how this technology can and should be used to the benefit of tens of thousands of individuals each year. All participants were deeply grateful to the Forbeck Foundation for allowing us to have these terrific several days.
Foundation Supports Follow Up Meeting
During the 2000 Forbeck Forum, the Foundation received a request from participant Dr. Mary Horowitz regarding the need for a meeting to deal with specific issues relating to Clinical Trials in Hematopoietic Stem Cell Transplantation. The Foundation agreed to fund a 1-day meeting in February, 2001 in Keystone, CO, tailgating to another meeting no bone marrow transplantation. Paul Martin, also a Forum 2000 participant, was a co-organizer of the meeting. (This is reported under the section ‘Focus Meetings’).
Frederick R. Applebaum, MD
Fred Hutchinson Cancer Center
Bart Barlogie, MD
University of Arkansas
Philipp Beckhove, MD, PhD
German Cancer Research Center
Bruce Blazar, MD
University of Minnesota
Richard Champlin, MD
MD Anderson Cancer Center
Francesco Galimi, MD, PhD
The Salk Institute
John Goldman, MD, FRCP
Imperial College School of Medicine
Mary M. Horowitz, MD
Medical College of Wisconsin
Robert Korngold, PhD
Jefferson Medical College
Peter Landsdorp, MD, PhD
The Terry Fox Laboratory
Crystal Mackall, MD
National Institutes of Health
Paul Martin, MD
Fred Hutchinson Cancer Research Center
Richrd J. O'Reilly, MD
Memorial Sloan-Kettering Cancer Center
Stanley Riddell, MD
Fred Hutchinson Cancer Research Center
Megan Sykes, MD
Massachusetts General Hospital
Guido Tricot, MD, PhD
University of Arkansas for Medical Science
Irv Weissman, MD
Catherine JuYing Wu, MD
Dana-Farber Cancer Institute