Drew Pardoll, MD, PhD of Johns Hopkins University
The eighth Annual Forbeck Forum covered one of the most exciting new topics to emerge in cancer therapy. Basic immunologists as well as cancer immunologists and cancer gene therapists were brought together to develop new concepts in engineering the immune system to react against cancer antigens. It is now known that cancer cells, because of genetic changes that occur during the process of cancer development, contain a number of new proteins, both on their cell surface and inside their cells that distinguish them from the normal cells from which they arose. If it were possible to train the immune system to recognize these cancer antigens as something foreign and unwanted in the body then an individual’s own immune system could be used to turn against and attack their cancer cells.
In the past, immunotherapy strategies for cancer have involved the use of tumor vaccines that have shown some promise but not significant effectiveness. Over the last 5-10 years there has been a tremendous amount of information learned about the molecules that control immune responses. Furthermore, we now understand how one of the most potent cells in the immune system – the T cell – recognizes its antigen. Also, new techniques have been developed to efficiently transfer genes into cells, allowing scientists to molecularly engineer these cells to behave differently."
In the initial scientific session of the meeting, John Yewdell described experiments to delineate how the cell produces pieces of antigens and combines them internally with molecules entitled MHC proteins that act as a molecular conveyor belt to bring these antigens to the surface of the cell. Once at the surface of the cell, they can be recognized by T cells. David Lo described animal models of autoimmune disease and discussed how the inappropriate immune responses, leveled against self- antigens that cause diabetes, teach us how one could potentially modify immune responses as therapeutic agents against cancer cells.
In the second scientific session, four scientists, Suzanne Topalian, Walter Storkus, Benoit van den Eynde and Victor Englehard, described their attempts to actually identify the specific modules in tumors that represent tumor specific antigens. The genetic analysis described by Dr. van den Eynde has indeed led to the identification of the first human melanoma specific antigen recognized by T cells. The general consensus of this session was that additional technological advances would be required to routinely identify antigens expressed by many different human tumors.
The third session described various cell based strategies to utilize the principles of regulation of the immune system in order to activate or augment immune responses against tumor cells. Dr. Martin Cheevers described the evidence that T lymphocytes can recognize portions of oncogenes, the cellular gene products which actually cause the uncontrolled proliferation of cells that define the cancer phenotype. Jack Bennick then described the use of a modified small pox virus as a vaccine strategy to enhance immune responses as well as to test whether cancer cells are suitable targets for activated T lymphocytes. Dr. Drew Pardoll described a gene therapy approach for cancer that use defective viruses to introduce genes into tumor cells that encode the growth and activating factors for the immune responses that under certain circumstances are capable of curing animals of distant deposits of tumors.
The final session described the development of clinical protocols for human cancer based on many principles and vaccine strategies outlined in the earlier sessions of the meeting. Dr. Stan Riddell described immunotherapy for bone marrow transplant patients with cytomegalovirus infections using clones of T cell specific for the cytomegalovirus antigens. He described that this represented a model approach for the use of genetically engineered anti-cancer T cells for adoptive immunotherapy. He also described the use of genetically engineered T cells against the AIDS virus – a clinical protocol which is currently being initiated. Alan Hougton described a number of human melanoma vaccine approaches that use either intact genetically modified cancer cells, or purified human melanoma antigens. Elizabeth Jaffee described the development of clinical trials to use genetically engineered tumor cells for the treatment of metastatic renal cancer.
A number of lively discussions ensued which delineated many of the issues involved in the translation of basic science discoveries to the development of human clinical protocols that will eventually result in meaningful therapies for patients with cancer.
Dr. Pardoll summarized the meeting with a hypothetical scenario of a patient coming to the hospital with cancer in the year 20XX in which a standard laboratory test would be sent off to identify which of a hundred potential tumor antigens this particular patient’s cancer expressed and then the use of a combination of two or three off the shelf vaccine immunization gene therapy strategies that would ultimately result in the cure of this patient’s cancer.
While it is quite clear that such a dream-like scenario is still many decades in the future, it is equally clear that the advances in our understanding of how the immune system is regulated and the ability to use molecular genetics to design human gene therapy approaches makes such hypothetical scenario a reasonable goal to guide future investigation rather than pure fantasy."
Quotes from Participants
“I thoroughly enjoyed my interactions with the participants … and felt a real sense of accomplishment at the conclusion. [The] Foundation is performing an excellent service that I hope will continue, and might serve as a model for the development of scientific conferences sponsored by other groups” -- Victor H. Engelhard, Ph.D., University of Virginia
“It is rare that scientists can meet together under circumstances so conducive to a free exchange of ideas … My sense is that the Foundation has been extraordinarily productive over the years and will continue to provide a unique forum to encourage scientific progress against cancer and other diseases”. -- Suzanne L. Topalian, MD, National Cancer Institute
“It was unusually productive for me … I had already learned a lot from discussions well before the first scientific session … I hope that my contributions will be of some value to the other members of the Forum, but I can say that my discussions with them have already helped me gain some new perspectives even in my own work on autoimmune disease. If in the future I begin a serious program on research in tumor immunity, I will have the Foundation to thank.” -- David Lo, MD, Ph.D., The Scripps Research Institute
“The greatest benefit I got from the Forum is the personal contact with other scientists working in fields related to my research. Although I previously met some of them, it was at very big meetings, with hundreds to thousands of people, without any opportunity for discussion and exchange of ideas that was provided at the Forbeck meeting. This was an invaluable help for me, because now I feel free to contact these colleagues whenever I need their help … proceed with these Forums which are very useful because they are so different, and in many aspects, more productive than classical meetings.” -- Benoit Van den Eyde, MD, Ludwig Institute for Cancer Research, Bruxelles, Belgium
“… a unique and informative conference on cancer. It truly was the best scientific meeting I have been to. I fell that this meeting has resulted in many potential collaborations in the near future … I particularly found the organization of the Forum to be a very useful one … encourages greater discussion and exchange of ideas. In fact, this format helps to enhance the freedom of exchange of data that is usually missing from national meetings.” -- Elizabeth Jaffee, MD, Johns Hopkins Oncology Center
Jack Bennink, MD
National Institutes of Health
Martin Cheever, MD
University of Washington
Victor Engelhard, PhD
University of Virginia
Alan Houghton, MD
Memorial Sloan Kettering Cancer Center
David Lo, MD, PhD
Scripps Research Foundation
Richard Mulligan, PhD
Massachusetts Institute of Technology
Drew Pardol, MD, PhD
Johns Hopkins Medicine
Gregory Plautz, MD
Cleveland Clinic Foundation
Stanley Riddell, MD
Fred Hutchinson Cancer Research Center
Walter Storkus, PhD
University of Pittsburgh
Suzanne Topalian, MD
National Cancer Institute
Benoit Van den Eynde
Ludwig Institute for Cancer Research
Jonathan Yewdell, MD
National Institutes of Health