Recruiting Our Own “Natural Killers” To Fight Cancer

Image: Immune cell attacking cancer cell

There are natural killers in all of us—natural killer cells that is. A critical component of the innate immune system, “NK” cells are specialized white blood cells that are preprogrammed to kill virus-infected cells and tumors. But this ability is hindered in cancer patients, allowing malignant tumors to grow without resistance.

Investigators at Children’s Hospital Los Angeles (CHLA) are helping NK cells recognize, and destroy, their harmful targets in a new approach to cancer treatment. A type of immunotherapy, this technique is one of the ways the body’s own immune system can be harnessed to attack cancer cells. In recognition of the last day of Childhood Cancer Awareness Month, Araz Marachelian, MD, research faculty member of the Children’s Center for Cancer and Blood Diseases at CHLA, explains the impact of this new therapy:

What are the advantages of immunotherapy compared to traditional cancer treatments, such as chemotherapy and radiation?

The main advantage of immunotherapy when compared to traditional treatments is that it works hand-in-hand with the patient’s own immune system to help fight the cancer. The NK cells and other immune cells can be programed to be activated to the right target—the cancer cell. This approach has the potential to better prevent relapses, and it also may be less toxic than traditional chemotherapy and radiation.

There are currently several immunotherapy clinical trials going on here at CHLA. How can this same technique be used to treat different types of cancer?

The reason immunotherapy can be used to treat different kinds of cancers is because our immune system has a major role in interacting with the tumor cells, regardless of the type of tumor. We all have an immune system that we can hopefully learn to harness and work on our behalf to fight cancers. However, for each cancer, variations to the immunotherapy may need to be done to help recruit the right immune cells to do the job.

You are specifically working on immunotherapy in neuroblastoma. What sort of results have you seen so far?

Pediatric neuroblastoma has paved the way for immunotherapy. A recently completed trial showed that, in patients with a very common and most aggressive type of neuroblastoma, giving immunotherapy after completing all other therapy (chemotherapy and radiation) could help prevent relapses and increase long-term survival.

Now, we are working on making that immunotherapy even better by giving it with other drugs (think of them as “helper drugs”) that further recruit the right players of the immune system (the natural killer cells) and work even harder to eliminate the tumor. So far, in our NANT trial, we have seen exciting preliminary data that shows activation of the immune system with the helper drug in patients whose neuroblastoma has recurred. We are hoping to further study this in order to decide whether, in the future, all patients should be receiving this helper medication together with our standard immunotherapy.

What role does immunotherapy play in the future of cancer treatment and research?

Immunotherapy is absolutely the new frontier in cancer research, and it’s a frontier that is changing very rapidly. There are new immunotherapy agents being identified or being engineered to work on the cancer cells, which is very exciting. I think that, for all cancers, it is likely that some form of immunotherapy will become standard therapy in the not so distant future.

From Obese to Optimistic: How CHLA Volunteer Inspires Local Kids to Live Healthy

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Kyle Wong, age 47, is a health and wellness geek. He can talk for hours about nutritious foods and spends his weekends ziplining, hiking, boogie-boarding and “having as much fun as possible”.

Rewind to three years and 114 pounds ago, when Kyle was struggling to keep up with his own kids—let alone the dozen or so enrolled in the Kids N Fitness program, where he volunteers. Kyle had spent much of his adult life knowing he was overweight, but not knowing how to shed the excess pounds. He tried new exercise regimens and cutting calories with varying degrees of failure. He was resigned. Defeated.

But in 2009, a cascade of events changed Kyle’s outlook.

Read more about how Kyle’s own weight-loss struggles inspire healthy lifestyle changes in local kids.

Life After Sickle Cell Diagnosis

Twenty-five year old Brandon Smith doesn’t look chronically ill. After all, he’s 6’4,210 lbs., can bench 355 lbs., and describes some of his favorite activities as “hitting the gym and lifting weights.” But at two years old, Brandon was diagnosed with sickle cell disease by doctors at Children’s Hospital Los Angeles (CHLA).

An inherited condition, sickle cell disease is characterized by crescent-shaped red blood cells—instead of healthy, rounded discs. Because of their abnormal shape, the sickled cells cannot carry oxygen efficiently, leading to fatigue, dizziness and chronic pain. Patients with this disease also periodically experience “sickle cell crises” when the misshapen cells block blood flow to the organs and limbs. This can cause extreme pain and increase risk for strokes and organ damage.

“After my diagnosis, I was fine for a couple of years until I turned eight and had two minor strokes,” recalls Brandon. “I remember having to go to the bathroom and putting hot water on my hands because they wouldn’t stop shaking.”

Since then, Brandon returns to CHLA every three weeks for blood transfusions.

By the time he was a teenager, these routine pokes and prods turned his veins into scar tissue and a catheter had to be permanently inserted into his chest. Because of the risk of dislodging the catheter, Brandon was sidelined from playing his favorite sports, and he returned to his first love: XBOX.

“Ever since I was little, I had to have the newest videogames and try to figure out every way to beat them.”

This passion prompted him to study graphic design and he hopes to create and design his own videogames in the future, along with accomplishing his main goal of becoming a bodybuilder.

In addition to videogames and weightlifting, Brandon enjoys watching anything sports-related and spending time with his family. As with everything else in his life, Brandon doesn’t hide behind his diagnosis; when he meets someone for the first time, he is sure to tell them that he has sickle cell disease.

“I don’t want to mask what’s happening with me internally. I don’t want to start hanging out with people and have something happen that I can’t be open about. Sometimes my mother will even tell me, ‘Ok Brandon, you should calm down and take care of yourself because you don’t want to get sick right now.’”

This loving and supportive network not only includes close family and friends, but his “CHLA-family” as well.

“I’ve known Brandon the entire 11 years I have worked at CHLA,” remarks Dawn Canada, LCSW. “He has turned his back on being a ‘victim,’ seeing little benefit in that, and has chosen instead to show that one can be victorious, despite having sickle cell disease. It’s no surprise that Brandon was recently recognized as a Sickle Cell Champion [by California Sickle Cell Resources], because he is a champion in every sense of the word and I am a better person for knowing him!”

With his infectiously positive attitude, Brandon is encouraged to set an example for other people with sickle cell disease. He knows just about everything there is to know about his condition and uses his experience to help his two younger brothers—who also have sickle cell disease—get through the tough times. Brandon actively shares his story on sickle cell support pages on Facebook, encourages other kids with the disease to follow him on Instagram and has donated his bone marrow for sickle cell disease research. He’s willing to do anything to help out now, knowing that his actions can shape the way this condition affects people in the future.

“Don’t get me wrong, sickle cell is a very serious disease, but I want to show other kids that you don’t have to let the disease control you—it’s a mind over matter situation. Try to go out and be active. Drink lots of water, stay calm and stay healthy. If you stand there and fight, you can overcome anything.”

How a Single, Genetic Change Causes Retinal Tumors in Young Children

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Top image: Cone precursor cells, the photoreceptor cells of the retina that detect color, are in green. The red identifies the Rb protein that is expressed in these cells. This protein is needed to suppress development of retinoblastoma.

Bottom image: Cones are again in green. However, in this image, the red coloring identifies the MYCN protein that is expressed at especially high levels in cones and promotes development of retinoblastoma when the Rb protein is lost.

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From their first smile to first day of school, every moment of a child’s young life is captured by their camera-toting parents. But these photographs not only serve as collateral for the troublesome teenage years; they can also be used to identify the most common childhood eye cancer, retinoblastoma. Usually affecting children aged one to two years, this retinal tumor causes the affected eye to glow white in response to a camera’s flash.

While retinoblastoma can be fatal or result in blindness when left untreated, it has also played a special role in understanding the mechanisms of cancer as a whole.

This is because retinoblastoma arises from the mutation of a single gene—the RB1 gene, demonstrating that some cells are only a step away from developing into cancer. (Other cancers, such as skin or breast cancer, arise from an often unpredictable combination of genetic and environmental factors.)

But why do mutations to the RB1 gene only cause tumors of the retina, and not of other cells like those of the iris or pupil?

David E. Cobrinik, MD, PhD, of The Vision Center at Children’s Hospital Los Angeles (CHLA), together with colleagues at Memorial Sloan-Kettering Cancer Center, has recently answered this long-standing question. This study could reveal new cellular signaling pathways that explain retinal and cancer development, and ultimately lead to the development of novel therapies for retinoblastoma. These results were published today in Nature.

In healthy individuals, the RB1 gene codes for a tumor suppressor protein, referred to as Rb, which prevents excessive cell growth. If both alleles of the RB1 gene are mutated early in life, the Rb protein is inactivated. This allows cells to rapidly multiply without resistance and develop into retinoblastoma tumors.

Cobrinik and colleagues discovered that retinoblastomas originate specifically in cone photoreceptor precursors. These are the immature photoreceptor cells in the retina that are responsible for color vision. The researchers also found that the cone precursors prominently express key, cancer-related proteins that enable proliferation and suppress apoptosis, or programmed cell death. This, in combination with the inactivated Rb protein, is sufficient to allow retinoblastomas to form.

“We showed that the cone precursors’ normal developmental program collaborates with RB1 mutations to deregulate cell growth,” said Cobrinik, who is also an associate professor of ophthalmology at the University of Southern California (USC) Eye Institute, Keck School of Medicine of USC. “In other words, loss of the RB1 gene results in abnormal proliferation because the cone precursors lack a self-monitoring ‘surveillance system’ – which would normally cause abnormally proliferating cells to undergo apoptosis. Instead, the cone precursors are able to divide uncontrollably and eventually become cancerous.”

To read more about this discovery, click here

Contact Children’s Hospital Los Angeles Research Communications
rescomm@chla.usc.edu or (323) 361-1812