It began in a wine bar in San Francisco. A bustling after work crowd filled every bar stool, lounge chair and dimly lit corner. In a quiet space near the back of the bar, two men sat close together, hunched over a stack of cocktail napkins filled with tiny ballpoint pen doodles. They talked, ecstatic.
While the rest of the bar’s customers exchanged office gossip and weekend plans, Dr. Ira Mellman and Dr. Dan Chen discussed something far more scientific. They strategized their next move against a common enemy: cancer.
Cancer is caused by the abnormal reproduction or behaviour of cells. When cancer develops, old or damaged cells remain in the body while new cells form, which could result in abnormal growths called tumours. Cancer can start anywhere in the body and, as it progresses, can metastasize or spread to other parts of the body.
In 2015, the Canadian Cancer Society estimated that two in five Canadians will develop cancer in their lifetime, and one in four will die of cancer. Cancer accounts for almost 30 per cent of all deaths in Canada.
“It has been a dream for many years, but one we really didn’t know how to accomplish, to take a patient’s immune system and train it to identify and kill cancer cells.”
– Dr. Ira Mellman
Dr. Ira Mellman didn’t dream of becoming a cancer immunologist. The native New Yorker shipped off to Ohio’s Oberlin College to pursue a degree in music, but his first year biology class led him to shift his interests from harmonies to cell structures. After completing a doctorate and postdoctoral work, Mellman found himself at Yale enjoying a prestigious career as a medical faculty member, department chair and cancer centre director. But he wanted more.
For Mellman, the decision to leave a coveted academic post had less to do with career than with people – two of his children coped with inflammatory disease and each year he saw more friends succumbing to the ravages of cancer. He gave up his professor’s desk for the chance to rewrite cancer, to work on the cutting edge of cancer research at one of the world’s leading biotechnology companies.
“To see that it might be possible to apply what we have learned about the immune system to cancer, and then being presented the opportunity of moving to one of the best places to do drug discovery – I don’t know if it was a moral obligation, but it certainly was a motivating force for me.”
– Dr. Ira Mellman
The Challenge of Immunity
The immune system is trained to recognize the difference between what is foreign and what is normal in the body. When something foreign is detected, an immune response is triggered to protect the body from viruses, bacteria and micro-organisms.
About 99.9999 per cent of the time, the immune system does a remarkable job. That 0.0001 per cent when the immune system gets it wrong is usually cancer.
Cancer is a disease that is dependent entirely on its cells developing alterations and mutations from the body’s normal cells. These miniscule differences define cancer and allow it to grow incrementally, yet unrestrained.
The Bigger Picture
For decades, immunologists had demonstrated the capacity of the immune system to recognize and kill cancer cells in the laboratory. The problem was they couldn’t reliably translate those same results in patients.
Fortunately researchers made advances in understanding the underlying biology of the immune system, and honed in on a number of factors in the tumour microenvironment. One of those factors was the programmed death-1 pathway, or PD-1, which is normally involved in preventing tissue damage in cases of chronic inflammation. PD-1 was found to impair anti-tumour functionality. Meanwhile, an associated protein called PD-L1 was found to block the immune system’s ability to recognize cancer cells.
With these new bits of information trickling in, Mellman and Chen sought a way to understand and represent what happens when cancer and the immune system meet.
The process took about two years of research, developing new pipeline therapies and uncovering new facts about how the immune system works on a nearly daily basis.
Along the way, scientists across the globe continued their own research and uncovered new information about cancer and immunology, cell biology and clinical oncology.
Biological therapies involve the use of living organisms, substances derived from living organisms or versions of such substances created in laboratories. There are a number of biological therapies for cancer:
|Biological Cancer Therapies||Benefit of Treatment||Possible Side Effects|
|Monoclonal Antibodies||Monoclonal antibodies (MAbs) help the immune system fight cancer. Different types of MAbs work in different ways: some “coat” cancer cells and trigger an immune response that destroys these cells while some bind to receptors on immune cells and prevent them from attacking the body’s own tissue, including cancer cells. Some MAbs interfere with proteins that stimulate tumour growth, some stimulate the activities of specific immune system components and some are attached to cancer-killing substances which are taken up by targeted cancer cells.||Nausea and vomiting, diarrhea, constipation, loss of appetite, change in weight, stomach or abdominal pain or tenderness, inflammation of the intestines, bloody or dark stool or urine, headache, dizziness, fainting, fatigue, chills, fever, cough, shortness of breath, infection of the nose, sinuses or throat, lung infection, urinary tract infection tiredness, joint and back pain, muscle aches and spasms, nosebleeds, skin redness or itchiness, severe skin reactions, swelling in the ankles, face, lips, mouth or throat, sepsis, bleeding or bruising, chest pains, fast or irregular heartbeat, hypertension, ulcers in the mouth, severe infusion reactions, bleeding or bruising easily, problems with the pancreas, changes in health test results (liver, kidney, blood and enzyme), change in mood or cognition, anxiety, change in vision, change in sex drive, irritability, kidney impairment, hormone problems, increase in blood sugar, liver failure or inflammation, perforation of the intestine, paralysis, immune disease, recurrence of hepatitis B.|
|Cytokines||Cytokines are signaling proteins produced by white blood cells that, among other functions, help regulate immune responses. There are two types of synthetic man-made cytokine treatments available: interferons and interleukins. Both can enhance the body’s immune response to kill cancer cells.||Severe allergic reactions, acute hypersensitivity, fever, fatigue, headache, muscle and joint pain, chills, severe cough, nausea, vomiting, diarrhea, constipation, severe stomach pain, blood or clots in stool, severe nosebleeds, waxy pallor, chest pains, breathing problems, rapid or irregular heartbeat, altered mental status, feelings of depression, hallucination, impaired consciousness, dizziness, convulsion, high blood sugar, lung or respiratory problems, kidney problems, diabetes, generalized edema, sepsis, shock, disorders of the metabolism and nutritional system, musculoskeletal system, nervous system, cardiovascular system and gastrointestinal system.|
Much research is being conducted in the field of biological cancer therapies and more treatments continue to be under investigation.
Then, in that San Francisco wine bar, Mellman and Chen began to pull everything together.
“When you think of a series of events happening from A to B to C, it’s generally linear. It became clear to Dan and me, however, that the interaction between cancer and the immune system was not linear at all. It was circular. The series of events form a loop that feeds back on itself.”
– Dr. Ira Mellman
Mellman says everything starts at the initial recognition event. In order for any kind of immune response to take place, the system has to be educated to identify the offending antigen, or foreign substance.
In cancer, a tumour becomes infiltrated with dendritic cells which accumulate all foreign substances that exist in the body and carry them to the lymph nodes. Dendritic cells are smart. Mellman likens them to Army generals who receive information and share that information with their troops in order to get the job done. When dendritic cells enter the lymph nodes, they encounter T cells that travel through the bloodstream, infiltrate a tumour and destroy cancer cells.
Once T cells kill the cancer, the process begins again. Dead cancer cells release antigens which dendritic cells carry off to lymph nodes to trigger the release of more T cells. The response iterates as the cycle turns each time.
|With immunotherapy, we want to trigger the cancer-immunity cycle – without harming healthy cells.|
|In Step 1, mutations in cancer cells cause the release of substances called “antigens”, or foreign substances, that show that cancer cells are different from normal cells. This allows the immune system to recognize them.|
|In Step 2, immune cells that specialize in finding antigens capture the released antigens and take them to T cells, located in the lymph nodes. Immunotherapy can boost immunity at this step and others.|
|In Step 3, T cells become ‘primed’ or ‘activated’ by these foreign antigens, which begins the immune response against cancer cells.|
|In Step 4, activated T cells travel through blood vessels towards the location of the tumor.|
|In Step 5, T cells reach the cancer cells and “infiltrate” the tumor in order to attack it.|
|In Step 6, T cells are able to recognize foreign cancer cells based on the antigens they released earlier.|
|In Step 7, T cells destroy cancer cells by activating a series of steps that lead to cell death. This is where some immunotherapies can affect PDL1 or PD1, enhancing immunity.|
“The wine bar was the final step,” Chen noted. “When we pulled everything together and drew the circles as they are now, Ira described it as ‘the cancer immunity cycle’ and I immediately said ‘that’s our name!’”
For Mellman and Chen, the conceptual breakthrough was in framing the biology as a tool they could use practically.
“In any one patient, the cycle can fail at any one of a number of points. And if we can figure out which is the failure point for any one patient, then we can figure out what it is we have to do for that patient,” Mellman explained. “Another step might become a failure point, but the process continues.”
“Dan has compared it to the gears of a bicycle,” Mellman added. “You don’t have to drive it yourself all the time; you just have to get it going. Once the gears and wheels start turning, the bicycle begins to move on its own.”