James P. Allison and Robert D. Schreiber
2017 Balzan Prize for Immunological Approaches in Cancer Therapy
Robert Schreiber is an exceptional scientist who originally focused his attention on elucidating the biochemistry and molecular cell biology of cytokines, and in particular the role of interferon-gamma in immune responses to cancer. He is particularly well known for his significant contributions to our understanding of the role of the immune system in destroying and shaping cancer.
Robert Schreiber and his colleagues used normal and genetically modified immunodeficient mice to demonstrate that the immune system could eliminate newly arising cancers or hold cancer cells in a state of immunemediated dormancy. They further showed that the immune system not only destroys spontaneous and carcinogen-induced primary tumors (immunosurveillance), but also sculpts the immunogenicity of tumor cells by selecting for the less immunogenic tumor cells that are most likely to survive in an immunocompetent host (immunoediting). Robert Schreiber’s work not only resolved a century-long argument over whether the immune system affects cancer development, but also formed the conceptual and experimental platform upon which today’s successful cancer immunotherapies have been built. His team subsequently uncovered the mechanisms underlying cancer immunoediting and demonstrated the importance of tumor-specific mutant neoantigens as targets of this process. Specifically, they showed that the tumor-specific mutated neoantigens (which are antigens present in and on tumor cells but not normal cells) are recognized by the immune system as foreign entities and are targeted for destruction by cytotoxic T-cells.
Recently, Schreiber pioneered the development of an immunogenomics approach that identifies sequences from the mutated cancer neoantigens that the immune system is most likely to recognize and that can lead to the development of potent cytotoxic T-cell-mediated tumor-eradicating immunity. Schreiber’s current efforts in his role as Founding Director of the Bursky Center for Hu- man Immunology and Immunotherapy Programs target the development of novel therapeutic neoantigen based cancer vaccines that may be more specific, more efficient and safer than current forms of cancer immunotherapy.
In short, Schreiber created the field of modern tumor immunology namely through his demonstration that tumors develop spontaneously in immunocompromised mice, and by proposing and later demonstrating the concept of immunoediting, in which tumor cells modulate their antigens to escape the immune attack. He unraveled its molecular genetic bases and the possibility to revert it by checkpoint blockade. These data changed the field.
Robert Schreiber has been recognized for his groundbreaking discoveries with numerous highly prestigious awards. These include his election to the American Academy of Arts and Sciences and the National Academy of Sciences of the United States, as well as his appointment to the Biden Blue Ribbon Panel on the Cancer Moonshot Program in 2016. In addition, he received the Coley Award for Distinguished Research in Basic and Tumor Immunology from the Cancer Research Institute, the Charles Rodolphe Brupbacher Prize for Cancer Research and the Lloyd J. Old Prize in Cancer Immunology from the American Association for Cancer Research.
James Allison characterized the protein structure of the T-cell receptor during his time as an Assistant Professor at the University of Texas Cancer Center, Science Park (Smithville), and after moving to the University of California (Berkeley), centered his interests on the interactions that take place between effector cytotoxic T-cells and the antigen presenting cells (APCs) that activate them. He discovered that CD28 is an important costimulatory molecule on the surface of T-cells that is required for their full activation. He later demonstrated that a T-cell transmembrane protein referred to as Cytotoxic T-Cell Associated Protein 4 (CTLA-4), disrupts T-cell coactivation and conveys an inhibitory signal to T-cells, preventing them from mounting a sustained response against the tumor cells. The ability to regulate T-cell activity as a consequence of these studies has allowed for remarkable advancements in the field. In 2004, Allison moved to the Memorial Sloan Kettering Cancer Research Center in New York City to participate in trials conducted in cancer patients with the aim of increasing the efficiency of the T-cell cytotoxic attacks on cancer cells by removing the inhibitory effect of the CTLA-4 brake through a monoclonal antibody directed against this protein.
The clinical trials were a superb success due to improved survival benefits among patients, in some cases including a durable regression of metastatic disease. It should be stressed that Allison was the first to apply this approach to humans at a time when the medical community questioned the feasibility and effectiveness of the strategy.The procedure was approved by the FDA in 2011. Initial studies were conducted in patients with melanoma but, since anti-CTLA-4 targets a T-cell specific molecule as opposed to a tumor-specific molecule, subsequent studies were also conducted with impressive beneficial results in patients with other tumor types including prostate, lung, ovarian and pancreatic cancer. Allison’s work with CTLA-4 opened an entirely new field termed “immune checkpoint therapy”.
Again, it should be stressed that without the energy and James Allison’s charisma, this anti-tumor strategy would not be where it is today, and it may well be that the strategy would never have been applied to patients. At present novel agents are being developed on a large scale in the community to block inhibitory checkpoints, such as the PD-1/PD-L1 system discovered by Honjo and Chen and colleagues. Moreover, they are found to bring efficient clinical benefits in patients. James Allison’s breakthrough in cancer immunology and immunotherapy has been recognized by numerous prestigious awards, namely the Lasker Clinical Medical Research Award in 2015. He is a member of the National Academy of Sciences of the United States and of the National Academy of Medicine and has just been elected to the American Academy of Arts and Sciences.