Doctors used to target cancers only with scalpels, toxic chemicals and radiation. Recently, a new therapy has been emerging. It instead allows the body’s immune system to take out cancer cells. Two men who did the pivotal work that made such an immune therapy for cancer possible were today awarded the Nobel Prize in physiology or medicine.
James P. Allison, 70, works at the MD Anderson Cancer Center in Houston, Texas. He will share this year’s award with Tasuku Honjo, 76, of Kyoto University in Japan. At a ceremony in December, the two will equally share the prize of 9 million kronor. That’s equal to a little more than $1 million.
Discoveries by these men “have added a new pillar in cancer therapy,” says Klas Kärre. This immunologist works at the Karolinska Institute in Stockholm, Sweden. He also is a member of the Nobel committee that awarded today’s prize. Immune therapy against cancer is “a new principle,” he observes. Other therapies — such as surgery, radiation and chemotherapy — targeted tumor cells. The new strategy instead revs up a patient’s own immune system. It gives cellular players in that immune system permission to attack the cancer.
The basic discoveries by Allison and Honjo represent a new “landmark in the fight against cancer,” Kärre said as he announced today’s award.
CTLA-4 is the name of a protein on the surface of immune cells, known as T cells. Allison discovered that this protein holds T cells back from attacking cancer cells. You might think of it as acting like the brake on a car. Allison’s lab worked to release that brake. To do it, they developed an antibody against the protein. And that, his team showed, allows T cells to kill tumor cells.
In a series of experiments, Allison and his colleagues used this immune therapy in mice with cancer. The treatment actually cured the rodents or shrank their tumors.
The technique has worked especially well against a type of human skin cancer known as melanoma. In 2011, the U.S. Food and Drug Administration, or FDA, approved a drug to treat that type of cancer. Known as ipilimumab (Ih-pih-LIH-myoo-mab), it is sold under the brand name Yervoy. More recently, it also has been approved to treat colorectal cancer and a type of kidney cancer known as renal (REE-nul) cell carcinoma (Kar-sih-NO-muh).
But this therapy can sometimes have bad side effects. In some people, taking the brake off of the T cells allowed them to inappropriately attack healthy tissues. What’s more, some cancers don’t respond to this kind of immune brake-release therapy. Among them, notes Allison, are pancreatic cancer and glioblastoma. That second one is a type of brain cancer.
Honjo discovered the body also produces a second type of natural brake on T-cell action. It’s known as PD-1. And using antibodies to knock out this brake seems to work even better than Yervoy against cancer cells that have begun to spread throughout the body. This spreading disease is known as metastasis (Meh-TAS-tuh-sis). Until scientists learned how to take the PD-1 brake off of T cells, this spreading cancer could not be cured. In 2012, the FDA approved the first antibody to release the PD-1 brake on T cells.
Now there are several antibodies against both PD-1 and its partner protein PD-L1. FDA has approved their use against melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers and Hodgkin lymphoma . Like the drugs that release the CTLA-4 brake, PD-1 antibodies have side effects. Still, they are generally milder than those due to the CTLA-4 brake release.
Reacting to the Nobel announcement
Norman “Ned” Sharpless directs the National Cancer Institute in Bethesda, Md. The new brake-release drugs are known as “immune checkpoint” therapies. And they have been a boon for cancer patients, he says.
“We’re not curing everybody,” he notes. “But in some cancers, 20 to 30 percent of patients will have substantial benefit.” Before, he notes, “We had nothing for those people.”
Physiology (Fiz-ee-OL-oh-gee) is the science of how the body works. Medicine is the field of fighting disease. Beyond their work in cancer, Allison and Honjo have contributed greatly to physiology, says Sharpless. In this case, they helped provide a better understanding of how the immune system works. The Nobel selection committee chose to honor the men’s work in cancer treatment, or medicine. However, he argues, they “also deserve lifetime achievement awards for their contributions to science.”
“I did not get into these studies to try to cure cancer,” he explained. “I got in to them because I wanted to know how T cells worked.” That type of work is known as basic research. Other approaches to treating cancer, such as with vaccines, hadn’t been as successful. Perhaps, Allison now says, that’s because “people started with insufficient knowledge.”
Honjo also pointed to the value of basic research here. PD-1’s discovery in 1992 “was purely a matter of basic scientific research,” Honjo said at a news conference today. But then it led to actual treatments. In time, he notes, his patients began to tell him: “This treatment has improved my condition and given me strength again. And it is all thanks to you.” With such comments, Honjo says, “I really began to understand the meaning of what my work had accomplished.”
Allison learned of the prize from his son. He had called his dad in his hotel room in New York City where Allison is attending a conference on cancer research. Soon, friends were calling and coming to Allison’s hotel room to celebrate. “We had a little party in the room this morning,” he said during a news conference.
Allison gave a shout-out to cancer patients. “We’re making progress,” he said. He wants to increase the number of them who can be helped by immunotherapy. “We know how to do it, we’ve just go to learn to do it better.” And one way may be to use it along with other therapies, such as radiation or chemotherapy.
Allison and Honjo will receive a medal and their prize money at a December 10 awards ceremony in Stockholm.
antibody Any of a large number of proteins that the body produces from B cells and releases into the blood supply as part of its immune response. The production of antibodies is triggered when the body encounters an antigen, some foreign material. Antibodies then lock onto antigens as a first step in disabling the germs or other foreign substances that were the source of those antigens.
bladder A flexible bag-like structure for holding liquids. (in biology) The organ that collects urine until it will be excreted.
cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.
chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.
chemotherapy A chemical treatment that’s most often used to kill cancer cells in the body. Chemotherapy can have many unpleasant side effects as it kills not only cancer cells but many healthy cells as well.
colleague Someone who works with another; a co-worker or team member.
field An area of study, as in: Her field of research was biology. Also a term to describe a real-world environment in which some research is conducted, such as at sea, in a forest, on a mountaintop or on a city street. It is the opposite of an artificial setting, such as a research laboratory.
Food and Drug Administration (or FDA) A part of the U.S. Department of Health and Human Services, FDA is charged with overseeing the safety of many products. For instance, it is responsible for making sure drugs are properly labeled, safe and effective; that cosmetics and food supplements are safe and properly labeled; and that tobacco products are regulated.
immune (adj.) Having to do with the immunity. (v.) Able to ward off a particular infection. Alternatively, this term can be used to mean an organism shows no impacts from exposure to a particular poison or process. More generally, the term may signal that something cannot be hurt by a particular drug, disease or chemical.
immune system The collection of cells and their responses that help the body fight off infections and deal with foreign substances that may provoke allergies.
kidney Each in a pair of organs in mammals that filters blood and produces urine.
lymphoma A type of cancer that begins in immune system cells.
melanoma A type of cancer that starts in pigment-making cells called melanocytes, usually in the skin.
metastasis The spread of cancer from one organ or body part to another, either due to growth and invasion of neighboring tissues or due to the spread of individual cancer cells to remote areas through the bloodstream or lymph system.
National Cancer Institute The largest of the 21 institutes making up the National Institutes of Health. With a staff of almost 4,000 people, NCI is based in Bethesda, Md. Its budget of almost $5 billion a year goes to support research — by its scientists and outside researchers — to better understand, diagnose and treat cancers.
Nobel prize A prestigious award named after Alfred Nobel. Best known as the inventor of dynamite, Nobel was a wealthy man when he died on December 10, 1896. In his will, Nobel left much of his fortune to create prizes to those who have done their best for humanity in the fields of physics, chemistry, physiology or medicine, literature and peace. Winners receive a medal and large cash award.
physiology The branch of biology that deals with the everyday functions of living organisms and how their parts function. Scientists who work in this field are known as physiologists.
protein A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.
radiation (in physics) One of the three major ways that energy is transferred. (The other two are conduction and convection.) In radiation, electromagnetic waves carry energy from one place to another. Unlike conduction and convection, which need material to help transfer the energy, radiation can transfer energy across empty space.
rodent A mammal of the order Rodentia, a group that includes mice, rats, squirrels, guinea pigs, hamsters and porcupines.
side effects Unintended problems or harm caused by a procedure or treatment.
strategy A thoughtful and clever plan for achieving some difficult or challenging goal.
T cells A family of white blood cells, also known as lymphocytes, that are primary actors in the immune system. They fight disease and can help the body deal with harmful substances.
therapy (adj. therapeutic) Treatment intended to relieve or heal a disorder.
tissue Made of cells, it is any of the distinct types of materials that make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues.
toxic Poisonous or able to harm or kill cells, tissues or whole organisms. The measure of risk posed by such a poison is its toxicity.
tumor A mass of cells characterized by atypical and often uncontrolled growth. Benign tumors will not spread; they just grow and cause problems if they press against or tighten around healthy tissue. Malignant tumors will ultimately shed cells that can seed the body with new tumors. Malignant tumors are also known as cancers.
Journal: M. F. Krummel and J. P. Allison. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. Journal of Experimental Medicine. Vol. 182, August 1, 1995, p. 459. doi: 10.1084/jem.182.2.459.
Journal: Y. Ishida et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. The EMBO Journal. Vol. 11, November 1992, p. 3887.
Journal: D. Leach, M. Krummel, J. Allison. Enhancement of antitumor immunity by CTLA-4 blockade. Science. Vol. 271, March 1996, p. 1734. DOI: 10.1126/science.271.5256.1734.
Journal: E. Kwon et al. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA. Vol. 94, July 22, 1997, p. 8099.
Journal: H. Nishimura et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. Vol. 11, August 1, 1999, p. 141. doi: 10.1016/S1074-7613(00)80089-8.
Journal: Freeman G. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. Journal of Experimental Medicine. Vol. 192, October 2, 2000, p. 1027. DOI: 10.1084/jem.192.7.1027.
Journal: F. Hodi et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA. Vol. 100, April 15, 2003, p. 4712. doi: 10.1073/pnas.0830997100.
Journal: Y. Iwai, S. Terawaki, T. Honjo. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. International Immunology. Vol. 17, February 1, 2005, p. 133. doi: 10.1093/intimm/dxh194.