Addy's cells continue to advance DIPG research

SEATTLE, WASH. – After their daughter Addy was diagnosed with an inoperable brain tumor called Diffuse Intrinsic Pontine Glioma (DIPG) in June 2017, Addy's parents Jen and Treay Trevino of Seeley Lake agreed to donate cells from Addy's initial tumor biopsy. Addy's cells were the first treatment naïve, cells that have not been altered by radiation or chemotherapy, to grow in the lab at the Fred Hutchinson Research Center in Seattle, Wash. Now Addy's cells are being used to study immunotherapy treatment for children with DIPG and her cells are helping prepare for a clinical trial for DIPG patients this year.

Seattle's Children's Hospital Pediatric Neuro-oncologist and Addy's doctor Nicholas Vitanza said being able to grow DIPG cells in the lab has only been possible in the last seven years. He said there are about 30 DIPG cell lines that are regularly used in research and none of those are treatment naïve.

"The first question is will the cells grow," said Vitanza. "And then will they continue to grow after six months."

Before Vitanza came to Seattle Children's Hospital, there was not a program to study DIPG tissue in the lab. Just two years later, Addy is one of three DIPG patients who donated treatment naïve cells that have grown in Jim Olson's lab at the Fred Hutchinson Cancer Research Center where Vitanza is the Affiliate Investigator.

"In Addy's case we learned a lot in the beginning and it helped hone our technique on how we will do these for future patients," said Vitanza. "These are new contributions to the research."

The majority of the first 50 mice they put Addy's cells in, developed the DIPG tumor. Vitanza said this is helpful and unique because it allows them to continue to reproduce Addy's cells and use them for different studies.

One of these studies led by Vitanza is trying to understand why Panobinostat, an epigenetic drug, has been shown by other scientists to be beneficial to treat DIPG.

Vitanza's research team has been treating Addy's cells with Panobinostat and then doing a series of genetic and protein sequencing studies to find out how that drug is killing the cells.

"This is tens of thousands of dollars of sequencing that will take months to get the results thanks to Addy's cells," said Vitanza who is hopeful that this will help scientists find other drugs like it and see if it's beneficial to combine medications.

Second, Addy's treatment naïve cells have been given radiation in the lab to study the change that radiation causes. Radiation is currently the most effective way to slow down the progression of the terminal tumor.

Vitanza explained that most of the children that get treated for DIPG are in smaller institutions where they don't have the ability to do a biopsy. When these patients are looking for clinical trials and other treatment options, it is after they have received radiation.

"By studying what radiation does to the cells, we can have a better idea of what treatments work best before or after radiation," said Vitanza. "Thanks to Addy's cells we've already identified one drug that may be beneficial to children with DIPG."

Vitanza said that at incredibly low doses, this new drug is able to kill DIPG cells in a dish. Now they are looking to see if it is effective in animal models.

Vitanza said Addy's cells are also contributing to scientists' understanding of the immune function and will hopefully lead to immunotherapy trials for DIPG patients this year at Seattle Children's Hospital.

Seattle Children's Hospital doctors and researchers are developing chimeric antigen receptor (CAR) T cell immunotherapies to treat children and young adults with recurrent or refractory cancers who are not likely to survive with standard treatments. Through cellular engineering, scientists enable the body's own immune system to heal itself – without the harsh and often lifelong side effects of chemotherapy and radiation.

First a blood sample is drawn from the patient. T cells, white blood cells in the immune system that fight infection, are removed from the blood sample and then genetically modified. The changed T cells are grown into millions of new cells that are then given back to the patient through an intravenous infusion.

The change tells the T cells to make a place on their surface (a receptor) that acts like Velcro. This receptor allows the T cells to recognize and bind to a target on the cancer cells. When they bind, the T cells can attack the cancer cells as if they were fighting an infection. The change made to the T cells also "tags" the cells so the research team can track them in the body. The hope is that the changed cells will immediately start finding and destroying the cancer cells in the patient's body.

While DIPG is not currently included in the FDA-authorized clinical testing CAR T-cell therapies, Addy's cells are helping prepare for a third clinical trial of CAR T cells targeting B7-H3 which Vitanza believes is expressed on almost all DIPG tumors.

Vitanza and his team of scientists presented research that includes Addy's cells at the International Symposium on Pediatric Neuro-Oncology in Denver in 2018 and have been accepted to present at the Keystone Symposia on Epigenetics and Human Disease in March.

"Getting her results selected for those conferences, shows the value of what she has been able to teach us," said Vitanza. "She has already led to information we are sharing with the rest of the world."

Vitanza said that thanks to Addy's cells his lab was also awarded a New Investigator Grant for $125,000 per year for the next two years from the Michael Mosier Defeat DIPG Foundation and The ChadTough Foundation.

"A big part of our funding strategy is to increase the number of researchers dedicating their focus to DIPG," said Defeat DIPG co-founder Mark Mosier in a press release. "New investigator grants are directed toward individuals in their first independent faculty position or those who have never researched brain tumors, which means we're reaching a new group of scientists."

Vitanza also looks forward to his team submitting their first research publication that includes Addy's cell research later this year.

"We are excited that Addy's cells were able to grow and they were able to learn so much information from them," said Jen. "We are really excited that she can help. Although she wasn't able to help herself, we are looking forward to possibly helping thousands of others."

* * * * *

While the research with Addy's cells has allowed scientists to take great strides towards better treatment, Addy lost her life in October 2018. The Trevinos donated her brain to Vitanza's lab. While Vitanza said the donation will provide scientists with a lot of information in regards to DNA sequencing, he does not know yet if they are going to be able to grow the cells.

The Trevinos have started a DIPG awareness campaign using Addy's Cokens.

Addy always loved coins and tokens and she loved to collect them. When she turned two, she started to call them 'Cokens.' It didn't matter what it was - actual money, a token at an arcade, a little fake plastic one, or a coin for the carousel - to Addy, it was a Coken.

Addy's custom made wooden Cokens are available by sending a message to the Team Addy Boo's Facebook page. The Trevinos ask people to take a picture with Addy's Coken on different adventures and share it on social media with the hash tags #teamaddyboo and #addyscokens. Also post it to the Team Addy Boo Facebook page to continue to spread awareness.

"Just because I can't save my own child, doesn't mean that I can't spread awareness and advocate for other kids," said Jen.

Treay added in a text message, "I hope it becomes one of those things like, 'Oh, it's a DIPG tumor,' we give them this and it goes away."

For those that would like to financially contribute to DIPG research, the Trevinos recommend donating through the Pediatric Brian Tumor Research Fund online at pbtrf.org. Their main fundraising event is the Seattle Children's Run of Hope that raised $710,000 in 2018.

Vitanza said all of the funds raised from the Run of Hope go to support Seattle Children's brain tumor research and about a fifth of it goes to DIPG lab work. Donors can specify their donation go towards DIPG research. They can also leave a note in memory of Addy on the website.