Cancer cells: sneaky assassins, and finding ways to annihilate them

The 2018 Nobel Prize recognizes cancer immunotherapies researchers

Today, the Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo. “By stimulating the ability of our immune system to attack tumor cells, this year’s Nobel Prize laureates have established an entirely new principle for cancer therapy,” the Nobel Assembly of Karolinska Institute in Stockholm noted.

Anyone can get cancer at any age, although more than 90% of cancers are diagnosed in people 50 years and older. This is because the risk for cancer increases with age. Incidence rates also vary by gender, race, and ethnicity. Although there are fewer deaths from cancer in the last few decades thanks to the development of new therapies, projections from the American Cancer Society suggest that there will be almost three new cancer diagnoses every minute, in 2018.

From Cancer Statistics Center

The majority of cancers are much more complicated in origin than most other diseases, and each one can have a molecular signature unique to a patient. Consequently, treating cancers can be an extremely entangled process compared to treating most other diseases. For centuries, surgery was the only option as a treatment for cancers; after Marie and Pierre Curie’s discoveries at the end of the 19th century, radiation became the next form of treatment.

Mustard gas had been used widely by the Germans in the WWI, and was responsible for thousands of deaths. Its use was subsequently banned per the Geneva Protocol. However, with the start of WWII there were concerns that mustard gas might be used surreptitiously. Consequently, the US Department of Defense recruited two pharmacologists, Louis S. Goodman and Alfred Gilman, to study the effects of mustard gas, and to find antidotes for it. One of the compounds they synthesized involved replacing a sulfur atom with a nitrogen atom in mustard gas, resulting in the nitrogen mustard, mustine.

Mustard gas (left) and a nitrogen mustard — mustine (right)

When reviewing case histories of people who’d been exposed to mustard gas, Goodman and Gilman noticed one common thread — low numbers of lymphocytes. This led them to consider testing their new compound in mice who had lymphoma — a cancer in which lymphocytes change and grow out of control. With a successful outcome in animal studies, this first chemotherapeutic agent was then administered to a patient with lymphoma in August 1942. After initial success over a few months when the patient appeared to be in remission, he eventually succumbed to the disease. Still, the initial success led to modest hope about the potential of mustine to treat cancers.

On December 2, 1943 a German air raid over Italy destroyed a US cargo ship. The ship was carrying a secret cargo of mustard gas based bombs, and its explosion resulted in more than 1000 people being exposed to the toxic material. Those in the immediate vicinity died, others had very low lymphocyte counts. This prompted Goodman and Gilman to expand their work with cancer patients and their larger clinical trial could only be published at the end of the war, because of the high level of secrecy using mustine. The findings were also reported by The New York Times on October 6, 1946: “WAR GASES TRIED IN CANCER THERAPY; Army Branch Joins Research Groups in Study of Using Nitrogen Blister Chemicals”

It is worth noting that there were barely a few days between the publication of the results of this clinical trial, and news that Hermann Joseph Muller was awarded the Nobel Prize in Physiology or Medicine “for the discovery of the production of mutations by means of X-ray irradiation." In his Nobel lecture in December 1946, he said “[there is] we believe, no escape from the conclusion that there is no threshold dose, and that the individual mutations result from individual “hits”, producing genetic effects in their immediate neighborhood.” So that year, while we learnt from Muller’s work that there is no threshold dose for X-rays when it comes to causing mutations (some of which might result in cancers), we also gained a new tool to treat some cancers.

The National Cancer Institute lists more than 250 cancer drugs on its website — a few of these are targeted therapies. A targeted therapy is one that is designed to precisely “hit” only those cells that express the molecules that cause the cancer. In order to design a targeted therapy, a tremendous amount of research has to be done to understand the molecular mechanism that caused the cancer, and how the cancer cell survives and divides unceasingly. In the last two decades, due in large part to basic research funded by the National Institutes of Health, we now have access to targeted therapies to some cancers. The trailblazers were Herceptin, or trastuzumab, and Gleevec, or imatinib. In the US, Herceptin was approved for treatment of HER2+ breast cancers in 1998; Gleevec was approved for treating chronic myelogenous leukemia (CML) patients three years later.

A cell’s DNA might acquire mutations, some of which result in cancers, some of which become resistant to treatments. We’ve all heard of MRSA infections — those that are caused by staph bacteria that have become resistant to typical antibiotic treatments because of mutations in the staph DNA; tumor cells can similarly acquire a resistance to an ongoing therapy. Drug resistance can also occur because of other reasons, as shown below.

In some cases, tumors shrink significantly upon initial treatment with a targeted therapy, but the respite can be short-lived because the tumor develops resistance to the therapy. This can happen because the tumor exhibits a previously undetected mutation, which “outsmarts” the treatment program, resulting in the tumor growing again, and sometimes causing metastases in other organs.

This brings us to today’s news from Stockholm. A relatively new addition to the possibilities for treating cancers is immunotherapy. Dissecting mechanisms whereby T-cells don’t attack healthy tissue had already been useful in studying and developing treatments for autoimmune disorders. It was a system of “brakes” on the T-cells that protected healthy tissue from T-cell attack. Researchers exploited this system in developing inhibitors for those “brakes” so that in cancer patients, inhibition of the brakes can allow the immune system to attack and clear out cancer cells. This class of drugs is called “checkpoint inhibitors.”

Illustration courtesy Andy Brunning

The efficacy of checkpoint inhibitors can be improved by using them in conjunction with a personalized treatment that is called CAR-T therapy. Briefly, this involves collecting cells from the immune system — T-cells or T- lymphocytes— and engineering them in the lab to express a protein on their surface that can recognize a specific cancer cell type. These engineered cells called CAR-T cells, are introduced into the patient and circulate through the body looking for cancer cells. Once the CAR-T cells recognize cancer cells, the immune system goes into full gear and destroys the cancer. As of this writing, two CAR-T therapies have been approved by the FDA — one for acute lymphoblastic leukemia (ALL), the other for large-B-cell lymphomas. However, these are still early days of CAR-T therapies and researchers and clinicians are still working on minimizing collateral damage to the patient. Nevertheless, explorations on expanding this method to also treat other cancers, continue.

The principle of the CAR-T approach has been extended to natural killer (NK) cells, another type of immune cell. The first trials of CAR- NK cells started in China in 2016, in patients with several kinds of cancers — early results from one trial suggest the cells are safe. At MD Anderson, Katy Rezvani and colleagues are pitting CAR-NK cells against several varieties of lymphoma and leukemia. A European trial testing CAR-NK cells in patients with the brain cancer glioblastoma was launched this year. On the horizon — CAR-macrophages. If successful, this would be a major breakthrough in treating solid tumors because macrophages, another cell type in the immune system, patrol the body ready to clean up cellular debris, microbes, and even have the capacity to engulf and destroy cancer cells.

The future certainly looks promising for cancer treatments. Unfortunately, the cost of many of these treatments is prohibitive and can run well in excess of a million dollars. With insurance companies being slow to embrace these new treatments, patients and families are left struggling to make decisions that are often simply too difficult and clinical trials become attractive options.

Use this link if you want to look for clinical trials for various cancers - https://www.cancer.gov/about-cancer/treatment/clinical-trials/search

Deepti is a scientist & now, a research analyst at Yale University. She runs Tilde Cafe, a forum to demystify science & make it accessible (www.tildecafe.org)