Cookies for Kids' Cancer Funds Support Rapid Discovery of New Therapies

What comes from a “Box of Hope?” Inside you will find three kinds of scrumptious cookies, but what you are truly unwrapping is the potential for pediatric cancer researchers to advance novel treatments to clinical trial as quickly as possible.

Cookies for Kids’ Cancer, a nonprofit foundation dedicated to pediatric cancer research, uses the proceeds from its cookie sales and other fundraising events to provide grants to support the work of scientists at five of the nation’s leading pediatric cancer centers. The Children’s Hospital of Philadelphia has received continuous funding since the Cookies for Kids’ Cancer foundation was established in 2008. Most recently, two CHOP teams received a total of $200,000 in grants to focus on pediatric neuroblastoma and acute myeloid leukemia (AML) research.

John Maris, MD, a CHOP pediatric oncologist and the Giulio D’Angio Chair in Neuroblastoma Research, met the Cookies for Kids’ Cancer founders, Gretchen and Larry Witt, when their son, Liam, was at CHOP to receive treatment for neuroblastoma. An aggressive cancer of the peripheral nervous system that usually appears as a solid tumor in the chest or abdomen, neuroblastoma accounts for 7 percent of all childhood cancers, but it causes 15 percent of all childhood cancer deaths.

“The family saw early on that for children who have relapsed or refractory types of cancers there was a huge gap in funding,” Dr. Maris said. “There were not enough effective treatments, and the key to changing that was research.”

In the first Cookies for Kids’ Cancer bake sale, Gretchen baked and sold 96,000 cookies with the help of 250 volunteers, raising more than $400,000 for research. Since 2008, the foundation has supported four dozen childhood cancer research grants that have led to nine new treatments being tested in clinical trials.

“The foundation is unique in that it will only fund research projects where there is a tangible deliverable to the clinic,” said Dr. Maris, who also serves on the foundation’s medical advisory board and gives advice on other institutions’ projects that have the highest potential to make an impact.

That is certainly the case for Dr. Maris’ research program, which is capitalizing on findings supported by a previous Cookies for Kids’ Cancer grant that helped investigators to identify a good therapeutic target called CDK6, which is a protein that is hyperactivated in certain neuroblastoma tumors. The current grant will extend this discovery.

Some cancer cells can figure out how to escape a single drug target. Lori Hart, PhD, a senior research scientist, is leading a program within Dr. Maris’ study team and focusing on a combination approach that aims to promote the killing of neuroblastoma cells with two new drugs in development. One inhibits CDK6, while the second inhibits MEK, a molecule that is part of a signaling pathway essential to regulating many cellular processes. Dr. Hart has shown therapeutic synergy when these two drugs are used together in neuroblastoma models.

“Cells that may be a little bit sensitive to one drug or a little bit sensitive to the other drug appear to be very, very sensitive to both,” Dr. Maris said. “There is exquisite cell death in our laboratory models.”

Based on these results, Dr. Maris has proposed a clinical trial to see if the novel combination therapy shows any benefit for children with neuroblastoma whose tumors have the genetic vulnerabilities that these drugs target. He expects that about 30 percent of children with relapsed neuroblastoma will fit the genetic qualifications required to enter the trial.

Chimeric Antigen Receptor Immunotherapy for Pediatric AML

The Cookies for Kids’ Cancer foundation also is supporting drug discovery research for AML, another pediatric cancer that urgently needs new drug options to prevent relapses and improve long-term cures. AML is the second most common blood cancer in children, affecting about 500 children in the U.S. each year. Despite treatment with the most intensive multi-agent chemotherapies available, approximately 30 to 40 percent of children with AML will relapse.

“We’re just so thankful for the support from Cookies for Kids’ Cancer,” said Richard Aplenc, MD, PhD, a CHOP pediatric oncologist and Hematologic Malignancies section chief. Dr. Aplenc and his co-investigator Sarah Tasian, MD, also a CHOP pediatric oncologist and physician-scientist, are leading the study that aims to increase therapeutic strategies for AML by rigorously testing new chimeric antigen receptor T cell (CART) approaches. “This funding will make a world of difference in our research.”

A team of investigators at CHOP and the University of Pennsylvania leads the CART field in pediatric leukemias and has demonstrated remarkable success using immunotherapy for acute lymphoblastic leukemia (ALL). B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous. The study team demonstrated in a groundbreaking trial that they could genetically program immune system T cells taken from patients’ own blood. The bioengineered “hunter” T cells, called CTL019, multiplied when they were returned to the patients’ bodies and eliminated the malignant B cells. One of the first pediatric patients to receive the investigational treatment — formerly known as CART19 — achieved a complete response and remains cancer-free now three years later.

Progress in using CART for AML, however, has proven to be more problematic so far. Many of the protein targets that researchers have identified on AML cells also appear at lower levels in normal cells that are critical to bone marrow formation. In previous studies, Dr. Tasian and colleagues have shown that CART cells can be successfully engineered to attack the protein CD123 on AML cells in mouse models, but this toxicity is long-lasting and has side effects on healthy bystander cells.

In the Cookies for Kids’ Cancer study, Drs. Aplenc and Tasian will investigate various “suicide switch” modifications to CART123 technologies that will allow effective eradication of AML but then turn off the CART cells to minimize collateral damage to healthy tissues.

“We’re looking at ways either to eliminate the T cells after they’ve killed the leukemia, perhaps with a treatment with an antibody, or even incorporation of a gene into the T cell itself that we can then turn off with a chemical or medication,” Dr. Tasian said.

In addition to finding an effective CART123 termination approach, the AML team is studying other proteins expressed by AML cells with the goal of identifying potential candidates for new CAR-based immunotherapies. Their ability to gain a better understanding of leukemia biology and explore more CAR strategies is crucial, as it is unlikely that a single agent will achieve a cure for the broad spectrum of children with AML.

Drs. Aplenc and Tasian, who are also associate and assistant professors of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, respectively, ultimately hope to develop a spectrum of innovative immunotherapies that will translate swiftly to the clinic. Based upon the team’s initial preclinical findings, a phase 1 trial of immunotherapy for pediatric AML is already under development in conjunction with co-investigators at the University of Pennsylvania.

“There is a very big need for new therapies in AML because there is not a pipeline of medications that are coming through and are available for children,” Dr. Aplenc said. “This grant is fantastic for us because its resources helped us to get started rapidly on an exciting new project.”

Sounds like both study teams are going to work up an appetite over the course of the two-year grants. Cookies, anyone?

For more information on Cookies for Kids Cancer, visit http://www.cookiesforkidscancer.org/.