The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation”. Their pioneering work on the CTLA4 and PD1 immune checkpoints revealed that these pathways act as so-called ‘brakes’ on the immune system, and showed that inhibition of these checkpoint pathways allows T cells to more effectively eradicate cancer cells. This research laid the foundation for the clinical development of immune checkpoint inhibitors, which have dramatically improved outcomes for many people with cancer.
Attempts to rid people of their cancer burden date back to 1600 B.C. when the disease was first recognized. But the idea of using a patient’s own immune system to eliminate aggressive cancers is more recent. James P. Allison and Tasuku Honjo’s discoveries have led to new medicines that activate the immune system and drive it to fight cancers. These therapies can defeat even the deadliest malignancies. Allison and Honjo have revolutionized our understanding of how the immune system recognizes tumor cells and have created a paradigm shift in clinical oncology that will likely alter how we treat cancer for the foreseeable future.
To date, our best tools for treating aggressive cancers that have spread beyond the range of curative surgery have been radiation therapy and systemic chemotherapy agents. For the most part these treatments kill rapidly dividing tumor cells by damaging their DNA or disrupting other essential cellular processes. This has led to most of the significant treatment advances we have achieved in terms of long-term survival in patients with advanced cancers. To understand the significance of Allison and Honjo’s discoveries, one must appreciate researchers have been trying to rally a powerful immune response against tumor cells for the past century. Prior to Allison and Honjo’s work, researchers believed that aggressive cancers grew unchecked because the immune response was too weak. The consensus was that if one could stimulate the immune system, it would respond and destroy the invasive tumor cells. Allison and Honjo, however, made a critical leap when they characterized two very important and potent pathways – called “immune checkpoints” – that can shut down the immune response. These pathways inhibit T cells – white blood cells that are charged with destroying virus-infected cells and tumor cells – and prevent them from “seeing” and attacking the tumor. Allison and Honjo identified and characterized two different proteins, called CTLA-4 and PD-1, respectively, that sit on the surface of T-cells. When these proteins interact with matching proteins on tumor cells or other immune cells – the way a key fits a lock – the T-cells fall into “sleep mode” and don’t attack the tumor. In many patients with cancer, these CTLA-4 and PD-1 pathways shut down anti-tumor immune activity. Without immune surveillance, the tumors grow and spread. This meant that our early attempts to activate the immune system were like trying to drive a car with the brake pedal pressed to the floor. No matter how we tried, or stepped on the gas, the brakes thwarted any progress. But Allison and Honjo’s research led to the development of a new type of drug: monoclonal antibodies that block the regulatory pathways controlled by CTLA-4 and PD-1. These drugs, called immune checkpoint inhibitors, basically attach to the CTLA-4 and PD-1 proteins and prevent them from switching off the T-cells. These new antibody-drugs have led to dramatic tumor regressions. The results are so impressive that the FDA has approved their use for a variety of advanced cancers such as: metastatic melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancers, and other tumors.