tumors

Lung cancer, Sherlock Holmes and piano

/ Kevin McCormack / 1 Comment

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Image of lung cancer

When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.

A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”

They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.

Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.

So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.

“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.

With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.

UCLA Conducts CAR-T Cell Clinical Trial for Patients with Recurring and Non-Responsive Cancers

/ Yimy Villa / Leave a comment
Dr. Sarah Larson (left) and Dr. Yvonne Chen (right)

There have been many advances made towards the treatment of various cancers, such as deadly forms of leukemia and lymphoma, that were once considered a death sentence and thought to be incurable. Unfortunately, there are still people who do not respond to treatment or eventually relapse and see the cancer return. However, researchers at UCLA are attempting to fine-tune some of these approaches to help people with these recurring and non-treatment responding cancers.

Diagram describing CAR-T cell therapy

Dr. Sarah Larson and Dr. Yvonne Chen at UCLA are conducting a clinical trial that involves genetically-modifying a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells. The T-cells are modified with a protein called a chimeric antigen receptor (CAR), which identifies and destroys the cancer by detecting a specific protein, referred to as an antigen, on the cancer cells. These genetically modified T-cells are referred to as CAR-T cells and are re-introduced back into the patient as part of the therapy.

Previous CAR-T cells developed can only recognize one specific protein. For example, one FDA-approved CAR-T cell therapy is able to recognize a protein called CD19, which is found in B-cell lymphoma and leukemia. However, over time, the cancer cells can lose the CD19 antigen, making the CAR-T cell ineffective and can result in a reoccurrence of the cancer.

In a news release by UCLA, Dr. Larson describes the limitations of this design:

“One of the reasons CAR T cell therapy can stop working in patients is because the cancer cells escape from therapy by losing the antigen CD19, which is what the CAR T cells are engineered to target.”

But Dr. Larson and Dr. Chen are using a CAR-T cell that is able to recognize not one by two proteins simultaneously. In addition to recognizing CD19, their CAR-T cell is also able to recognize a protein called CD20, which is also found in B-cell lymphoma and leukemia. This is called a bispecific CAR-T cell because of it’s ability to identify two protein targets simultaneously.

In the same UCLA news release, Dr. Larson hopes that this approach will be more effective:

“One way to keep the CAR T cells working is to have more than one antigen to target. So by using both CD19 and CD20, the thought is that it will be more effective and prevent the loss of the antigen, which is known as antigen escape, one of the common mechanisms of resistance.”

Before the clinical trial, Dr. Chen and her team at UCLA conducted preclinical studies that showed how using bispecific CAR-T cells provided a much better defense compared to single target CAR-T cells against tumors in mice.

In the same UCLA news release, Dr. Chen elaborate on the results of her preclinical studies:

“Based on these results, we’re quite optimistic that the bispecific CAR can achieve therapeutic improvement over the single-input CD19 CAR that’s currently available.”

This first-in-humans study will evaluate the therapy in patients with non-Hodgkin’s B-cell lymphoma or chronic lymphocytic leukemia that has come back or has not responded to treatment. The goal is to determine a safe therapeutic dose.

Stem Cell Stories that Caught our Eye: Multiple Sclerosis, Parkinson’s and Reducing the Risk of Causing Tumors

/ Don Gibbons / Leave a comment

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Cell therapy for Parkinson’s advancing to the clinic. A decade-long moratorium on the transplant of fetal nerve tissue into Parkinson’s patient will end in two months when the first patients in a large global trial will receive the cells. BioScience Technology did a detailed overview on the causes for the moratorium and the optimism about the time being right to try again. The publication also talks about what most people in the field believe will be the long-term solution: moving from scarce fetal tissue to nerve cells grown from readily available embryonic stem cells. The author’s jumping off point was a pair of presentations at the International Society for Stem Cell Research in June, which we wrote about at the time. But the BioScience piece provides more background on the mixed results of earlier studies and references to recent journal publications showing long term—as much as 20 year—benefit for some of those patients.

It goes on to describe multiple reasons why, once the benefit is confirmed with fetal cells, moving to stem cells might be the better way to go. Not only are they more readily available, they can be purified in the lab as they are matured into the desired type of early-stage nerve cell. Researchers believe that some of the side effects seen in the early fetal trials stemmed from the transplants containing a second type of cell that caused jerking movements known as dyskinesias. One stem cell trial is expected to start in 2017, which we discussed in June.

Immunity persists through a special set of stem cells. Our immune system involves so many players and so much cell-to-cell interaction that there are significant gaps in our understanding of how it all works. One of those is how we can have long-term immunity to certain pathogens. The T-cells responsible for destroying invading bugs remember encountering specific ones, but they only live for a few years, generally estimated at five to 15. The blood-forming stem cells that are capable of generating all our immune cells would not have memory of specific invaders so could not be responsible for the long term immunity.

Now, an international team from Germany and from the Hutchison Center in Washington has isolated a subset of so-called “memory T-cells” that have stem cell properties. They can renew themselves and they can generate diverse offspring cells. Researchers have assumed cells like this must exist, but could not confirm it until they had some of the latest gee-wiz technologies that allow us to study single cells over time. ScienceDaily carried a story derived from a press release from the university in Munich and it discusses the long-term potential benefits from this finding, most notably for immune therapies in cancer. The team published their work in the journal Immunity.

Method may reduce the risk of stem cells causing tumors. When teams think about transplanting cells derived from pluripotent stem cells, either embryonic or iPS cells, they have to be concerned about causing tumors. While they will have tried to mature all the cells into a specific desired adult tissue, there may be a few pluripotent stem cells still in the mix that can cause tumors. A team at the Mayo Clinic seems to have developed a way to prevent any remaining stem cells in transplants derived from iPS cells from forming tumors. They treated the cells with a drug that blocks an enzyme needed for the stem cells to proliferate. Bio-Medicine ran a press release from the journal that published the finding, Stem Cells and Development. Unfortunately, that release lacks sufficient detail to know exactly what they did and its full impact. But it is nice to know that someone is developing some options of ways to begin to address this potential roadblock.

Multiple sclerosis just got easier to study. While we often talk about the power of iPS type stem cells to model disease, we probably devote too few electrons to the fact that the process is not easy and often takes a very long time. Taking a skin sample from a patient, reprogramming it to be an iPS cell, and then maturing those into the adult tissue that can mimic the disease in a dish takes months. It varies a bit depending on the type of adult tissue you want, but the nerve tissue that can mimic multiple sclerosis (MS) takes more than six months to create. So a team at the New York Stem Cell Foundation has been working on ways to speed up that process for MS. They now report that they have cut the time in half. This should make it much easier for more teams to jump into the effort of looking for cures for the disease. ScienceCodex ran the foundations press release.

Unique Cellular Signal Directs Cells to Gobble Up Toxic Waste; Could Serve as New Weapon to Fight Disease

/ cirmweb / Leave a comment

White blood cells have a lot of work to do. They are our body’s main defense against foreign invaders—and are quite adept at it. Tasked with cleanup duty, they target and destroy cells that have been infected with bacteria, viruses or other harmful, disease-causing pathogens.

But as good as they are at their job—they aren’t perfect. Sometimes they need a little help. This is where modern medicine steps in to help the body fight disease.

A healthy cell (green) that has recognized and engulfed dying cells (purple) is shown. [Credit: Toru Komatsu/University of Tokyo]

A healthy cell (green) that has recognized and engulfed dying cells (purple) is shown. [Credit: Toru Komatsu/University of Tokyo]

But what if we could reprogram human cells, and supercharge them—so that they are then able to do the job that as of right now, only the most advanced drugs could accomplish. This is the hope of scientists from Johns Hopkins University, who today report that they are on the path towards doing just that.

Published online in the journal Science Signaling, Dr. Takanari Inoue and his team at Hopkins—along with his collaborators at the University of Tokyo—have together pioneered an innovative way to transform cells not normally involved in fighting disease into a new, cellular line of defense.

This discovery could potentially alter how our bodies combat some of humankind’s most relentless diseases—including pathogens that are skilled at evading white blood cells, or even cancer cells that can grow out of control and lead to dangerous tumors.

As Inoue explained in today’s news release:

“Our goal is to build artificial cells reprogramed to eat up dangerous junk in the body, which could be anything from bacteria to…the body’s own rogue cancer cells. By figuring out how to get normally inert cells to recognize and engulf dying cells, we’ve taken an important first step in that direction.”

A class of white blood cells called macrophages normally target and destroy dangerous cellular ‘junk’ via a process called phagocytosis. Phagocytosis is a fundamental but complex cellular process, so Inoue and his team broke it down step by step. In this way, they hoped to find out the bare minimum process needed, in order to give cells the power of phagocytosis.

The team started with a type of laboratory grown cell called HeLa. The first step was to tweak HeLa cells so that they could target and attach to dying cells. The second step was to destroy those dying cells.

The first step was accomplished simply by modifying a particular protein that sits on the surface of HeLa cells so that damaged or dying cells would be attracted to them. By making this modification, up to six dying cells locked onto each HeLa cell.

Next, the team switched on a gene in the HeLa called Rac. Previous research by other teams had found that turning on Rac causes a cell to engulf whatever is attached to it. In this case, activating Rac spurred the HeLa cells to swallow up the dying cells already attached to its surface. In effect, they had changed the cells’ job description—allowing them to mimic the phagocytosis process normally reserved for certain white blood cells.

As Inoue elaborated:

“We’ve shown it’s possible to endow ordinary cells with the power to do something unique: take on the role of a specialized macrophage.”

These results, while encouraging, are still preliminary. For example, even though the HeLa cells engulfed the dying cells, they likely weren’t destroyed. This next step in phagocytosis will be critical if the researchers are to further develop the idea of modifying the body’s own cells to combat disease.