Drew Pardol, MD, Ph.D., Johns Hopkins University, Baltimore, MD
Jack Bennink, MD, National Institutes of Health, Bethesda, MD
Martin Cheever, MD, University of Washington, Seattle, WA
Victor Engelhard, Ph.D., University of Virginia, Charlottesville, VA
Alan Houghton, MD, Memorial Sloan-Kettering Cancer Center, New York, NY
David Lo, MD, Ph.D., Scripps Research Foundation, La Jolla, CA
Richard Mulligan, Ph.D., Massachusetts Institute of Technology, Cambridge, MA
Stanley Riddell, MD, Fred Hutchison Cancer Research Center, Seattle, WA
Walter Storkus, Ph.D., University of Pittsburgh, Pittsburgh, PA
Suzanne Topalian, MD, National Cancer Institute, Bethesda, MD
Benoit Van den Eynde, Ludwig Institute for Cancer Research, Bruxelles, Belgium
Jonathan Yewdell, MD, National Institutes of Health, Bethesda, MD
Layout and Goals
- Immune Regulation
- Antigen Presentation and the Characterization of Tumor Specific Antigens
- Antigen-Based Vaccine Strategies
- The Transition from Animal Models to Clinical Protocols
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.