During the more than 40 years I’ve been a pharmacologist, I’ve answered a lot of questions. It’s the essence of what it means to be a scientist. Sometimes, however, I’m faced not with an experimental inquiry, but instead with a personal question from a friend, family member or coworker here at Charles River Laboratories who hopes that somehow my training will help clarify their options in the face of a cancer diagnosis.
Up until very recently, if it was melanoma we were talking about, my answer to someone asking about their options would be, “Unfortunately, there’s not much.” Melanoma is the most serious type of skin cancer. It spreads (and kills) rapidly. Traditionally the only treatments beyond surgery were very toxic options with low rates of success.
But thanks to advances in the field of “immunotherapy” — a treatment approach that seeks to harness the immune system to fight cancer — things have changed for the better. To truly appreciate what immunotherapy means for the treatment of melanoma (and eventually other cancers) it is useful to take a step back and look at the rationale and history of efforts in the field.
We’ve been artificially directing the immune system to kill things that shouldn’t be in the body since the advent of the vaccines in the 18th century. Usually these are directed against infectious agents like viruses and bacteria. A person is given a dead or weakened form of the infectious agent and this acts to rev up the immune system so that it will be poised to recognize the real thing should it come along.
About 40 years ago, a variation on this scheme was shown to be effective for cancer treatment. Infusion of Bacillus Calmette-Guerin (BCG), a weakened form of a bacterium related to the agent responsible for tuberculosis, into the bladder was found to trigger an immune response to bladder cancer. Why this works is still not well-understood, and efforts to replicate this type of cancer vaccination, with other bacteria or even pieces of or proteins from tumors, have not been very successful over the years.
A different type of cancer vaccine, one in which a patient’s immune cells are removed from his body, “trained” to recognize cancer cells in the lab, and then re-infused into the patient, was approved by the FDA in 2010 for the treatment of prostate cancer. This approach, however, must be personalized to each patient and there has been little effort to replicate it for other types of cancer due to commercialization issues.
Up until a few years ago, it would seem that the dream of immunotherapy might never come true. Part of the difficulty has been that the immune system is just so complicated. But thanks to advances in genomics and molecular biology, we have begun to understand more about specific immune mechanisms and, importantly, how we can exploit these mechanisms in order to treat cancer.
Key to recent progress has been the identification of individual receptors on immune cells and an understanding of how they help regulate what is and isn’t attacked in the body. We now know that cancer cells and the cells around them sometimes express proteins that bind these receptors and tell the immune system, “Everything is good. I’m supposed to be here.” So what if you could block that signal, releasing the brakes on a powerful, innate cancer-fighting force within the patient’s own body?
This isn’t just a theoretical possibility. Immunotherapy based on blocking inhibitory signals became a reality in 2011 with approval of medicine known as ipilimumab, which blocks a protein called CTLA-4, that significantly increased the median survival time for people with metastatic melanoma. Now many other similar medicines are in development. Just recently, a drug (nivolumab) that blocks a different protein that sends inhibitory signals to immune cells, PD-1, was combined with ipilimumab in patients with metastatic melanoma and shown to produce rapid and deep tumor shrinkage. These types of drugs and combinations are also being explored for other types of cancer.
It is extremely gratifying to see clinical achievements like these, to witness how our ever increasing understanding of biology is being translated into real-world outcomes. At Charles River, we’re doing our part through the work we do with sponsors who are developing new immunotherapies. We have the immune-competent animal models and other assays necessary to gather the preclinical data that allows potential new medicines to move into clinical testing.
But scientists like me are first and foremost people, and that’s why my excitement for immunotherapy goes beyond the technical. I have great hope for what the medicines already approved and those in development will mean for those who come to me with questions when faced with a cancer diagnosis. I hope this post gives them a glimpse into what is being made possible, and inspires and emboldens them to fight for their place in the immunotherapy revolution. The most important thing they can do is to keep asking their doctors, “What new medicines are available? Will they work for me?”