Their work helped identify proteins on certain immune cells that act as brakes, opening the door to a new class of cancer drugs
Two scientists from different parts of the globe were awarded the Nobel Prize for Medicine and Physiology today for showing how different strategies inhibiting the brakes on the immune system can be used in the treatment of cancer.
James Allison, Chair of Immunology and Executive Director of the Immunotherapy Platform at the University of Texas MD Anderson Cancer Center, and Tasuku Honjo, a professor at Kyoto University in Japan, independently discovered proteins on certain immune cells that act as brakes. (In Allison’s case the protein was CTLA-4 and in Honjo’s case it was PD-1.) They proved in parallel that if you could release the brakes temporarily on these proteins, the immune system would be able to fight cancer more aggressively. These discoveries became the basis for a new class of cancer drugs known as immune checkpoint inhibitors that fundamentally changed the outcome for certain groups of patients with advanced cancer and transformed the field of oncology.
What is perhaps more remarkable, though, is that this notion of using the immune system to fight cancer had been floating around for decades. More than 50 years ago, Lewis Thomas and Nobel laureate Frank Macfarlane Burnet suggested that T-cells were the pivotal sentinel in the immune system’s response to cancer. At the time, such theories were considered highly controversial.
The actual genesis of cancer immunotherapy went back even further to the late 19th century, Dr. William Coley, also known as the Father of Immunology, noticed that the tumors of some patients disappeared following high fevers from an unrelated infection. On the basis of these observations, Coley treated his first patient with streptococcal organisms and noted a shrinkage of a malignant tumor. Over the next 40 years he injected more than 1,000 cancer patients with bacteria or bacterial products, reporting excellent results. Most of the treated patients had inoperable sarcomas, with the bacterial toxin achieving a cure rate of over 10%.
Of the two immune checkpoint targeting antibody therapeutics activating the patients’ T cell immune response, PD-1 has been more effective, spawning several blockbuster drugs against lung cancer and melanoma. New clinical studies indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated in patients with melanoma.
“Given the perhaps unprecedented research activities in the immune checkpoint field, it is likely that there will be major developments regarding this therapy at all levels, The Nobel Committee noted. “Their findings have conferred great benefit on mankind; they add a new pillar to the existing cancer treatments.”
Indeed, Julia Schueler PhD, Research Director of Charles River’s Discovery Oncology site in Freiburg, thinks checkpoint inhibitors are just the start of the revolution. “The arena of cancer immunology is evolving tremendously and is rapidly moving towards innovative therapeutic strategies translating into tangible benefit for cancer patients,” she said. “Besides the checkpoint inhibitors, other promising approaches are currently in clinical testing, including adoptive cell transfer, cancer vaccines, and therapeutic monoclonal antibodies targeting subsets of immune regulatory cells.”
At the same time, the advent of these novel therapies has triggered a need for pre-clinical in vitro and in vivo models to investigate the efficacy and mode of action of these drugs, and a growing demand for translational approaches to help identify the best compounds.
“Furthermore these pathway-specific drugs add a new level of complexity to the in vitro lot release of such drugs for testing laboratories,” says Ulrike Herbrand PhD, Scientific Supervisor for R&D at Charles River’s Biopharmaceutical site in Erkrath, Germany. “In contrast to the earliest anticancer therapeutic monoclonal antibodies (mAbs), these newer mAbs interfere with the adaptive immune system and can activate both innate and adaptive immune responses. The mechanisms of action of such drugs are highly specific and need to be reflected to ensure safety and efficacy for patients.”
“With the advent of these new therapeutic approaches there will be a growing demand for novel tools to stratify patients, Schueler added. “These biomarkers will not be limited to somatic genomic aberrations, but will also include subtyping of immune effector cells, patterns of immune cell infiltration, and quantification of immune cells as response markers to monitor therapy success,” says Schueler. “Concomitantly, the challenge is to “bridge” between these new established pre-clinical models, and the real clinical situation. There will also be a growing demand for translational approaches, where analysis workflows in the drug development process need to be co-developed with biomarkers in clinical cancer research.”