The 2018 Nobel Prize in Physiology or Medicine has had a very concrete, clinical application. Cancer patients around the world have been treated with James Allison’s and Tasuku Honjo’s immune checkpoint therapy, and during the Nobel week in December some of those patients gathered at the Grand Hotel in Stockholm to honor the two Laureates and show their gratitude. The most rewarding part of their research, both Laureates stated, as these patient’s cancers, if not treated with immunotherapy, would have taken their lives.
The activation of the immune system
Cancer diseases are characterized by uncontrolled proliferation of abnormal cells with the capacity for spread to healthy organs and tissues. Important progress has been made but advanced cancer remains difficult to treat and the need for better treatments is huge.
At the beginning of the 20th century the idea that activation of the immune system could be a strategy for attacking tumor cells emerged. Fundamental mechanisms regulating immunity were uncovered and it was shown how the immune system can recognize cancer cells. Scientists have also shown that T-cells (a type of white blood cells and key players in immune defense) have receptors that bind to structures recognized as non-self.
Such interactions trigger the immune system to engage in defense, while additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Other proteins that function as brakes on the T-cells and inhibit immune activation have also been identified, and the balance between accelerators and brakes has been proven to be essential for tight control and a functioning immune system.
Disengaging the T-cell brake
In the 1990s James P. Allison at the University of California, Berkeley, studied this very thing. He was investigating the T-cell protein CTLA-4 and he observed that it functioned as a brake on T-cells. He had already developed an antibody that could bind to CTLA-4 and block its function and now he wanted to see if this blockade could disengage the T-cell brake and unleash the immune system to attack cancer cells.
The first experiment was performed and the results were amazing. Mice with cancer were cured through treatment with the antibody that inhibited the brake and unlocked anti-tumor T-cell activity. Allison and his co-workers developed this strategy into a therapy for humans and in 2010 a clinical study showed striking effects in patients with advanced melanoma. Actually, in several patients all signs of remaining cancer disappeared.