In the summer of 2015, Jennifer McNeer, MD, MS, joined a task force on the acute lymphoblastic leukemia (ALL) committee within the Children’s Oncology Group (COG), a National Cancer Institute supported clinical trials group. This task force began developing the next generation of studies for pediatric patients with B-cell lymphoblastic leukemia/lymphoma (B-ALL). Now, McNeer is gearing up for the launch of a study born from that task force. In 2019, pediatric, adolescent and young adult patients with high-risk B-ALL will be randomized to receive either the current gold standard of treatment or that treatment along with the drug inotuzumab (Besponsa®). This trial will also include patients with mixed phenotype acute leukemia and disseminated B-lymphoblastic lymphoma, two diseases for which there have not previously been dedicated clinical trials. This trial will be open across North America, as well as COG sites in Europe and Australia. It follows the publication of a study in the journal Leukemia, co-authored by McNeer, showing the efficacy of inotuzumab in children with relapsed or refractory B-ALL.
The nine-person team from the McNerney Lab is addressing the big question of how to improve outcomes for patients with high-risk blood cancers — especially in patients who don’t respond to current treatments. To do this, researchers have been hard at work identifying genomic abnormalities and vulnerabilities of current leukemia therapies. One of the five projects being executed by researchers involves modeling therapy-related myeloid malignancies (secondary cancers caused by chemotherapy and radiation). Through years of research, Megan McNerney, MD, PhD, and her team discovered that CUX1 and RAS genes play a role in triggering high-risk childhood myeloid malignancies. In 2019, McNerney will test existing drugs in mice to see if and how these two genes converge on a signaling pathway that causes cancer. She anticipates this will lead to new ways of using existing drugs to prevent disease before it starts. The lab’s research was published this year in the journal Blood showing that the reduction of the CUX1 gene in mice led to myelodysplastic syndrome (MDS).
In addition to funding from the National Institutes of Health, James LaBelle, MD, PhD, received $300,000 from Hyundai’s Hope on Wheels program for research on peptide-based therapeutics.
For five years, the team at the LaBelle Lab has been researching how to more precisely deliver targeted therapies directly into diseased cells. While new cancer-fighting therapeutics are more effective than ever, they still aren’t focused enough to completely and specifically target problem cells. This is one of the reasons that cancers become resistant to treatment. To overcome this therapeutic hurdle, LaBelle’s group has been working with Matthew Tirrell, PhD, founding director of the University of Chicago’s Institute for Molecular Engineering. Using nanotechnology and advances in molecular engineering, Dr. LaBelle expects to simultaneously target multiple specific protein-to-protein interactions inside cells that lead to disease.
The University of Chicago Medicine Comer Children’s Hospital is a leader in the development of new neuroblastoma therapies that have dramatically altered the lives of children with high-risk disease. Neuroblastoma is the most common cancer in infants and the most common extracranial solid tumor in children. Approximately 45 percent of children with neuroblastoma have clinically aggressive high-risk disease. In the 1980s, only 20 percent of children with high-risk neuroblastoma survived their cancer. Today, over half will survive. This substantial improvement in outcomes is due to a series of successive institutional and cooperative-group randomized clinical trials, which have led to identification of more effective treatment strategies and refined risk classification. In concert with these clinical trials, genomic interrogation analysis of large numbers of clinically annotated tumor and germline samples has contributed to significant advances in our understanding of neuroblastoma epidemiology and biology.
Susan Cohn, MD, section chief of Hematology, Oncology and Stem Cell Transplantation in the Department of Pediatrics, and her colleagues at Comer Children’s and in the Children’s Oncology Group (COG) have conducted the seminal studies that have led to tailored treatment approaches for children with neuroblastoma based on a combination of prognostic markers. Other critical COG clinical trials conducted at Comer Children’s have demonstrated the efficacy of tandem stem-cell transplants and post-consolidation immunotherapy with dinutuximab in newly diagnosed high-risk patients. In addition, treatments, including radiolabeled meta-iodobenzylguanidine (MIBG) or the combination of dinutuximab plus chemotherapy, have been shown to be effective in the setting of relapsed or refractory neuroblastoma. Based on these promising results, ongoing COG clinical trials will test these strategies in newly diagnosed patients.
New research at Comer Children’s also has the potential to shape the standards of care in children with neuroblastoma. Ami Desai, MD, and Mark Applebaum, MD, are conducting research that will provide new tools for accurate risk-based treatment stratification with the hope of improving response to treatment and increasing survival in children with neuroblastoma. Tara Henderson, MD, MPH, is evaluating the long-term effects of the current intensive multimodality approach to treating high-risk patients to find ways to reduce the toxicity of treatment and to create new early screening standards to mitigate future adverse health effects.
A blood biomarker could make all the difference for children with high-risk neuroblastoma. With funding from the National Institutes of Health, Mark Applebaum, MD, is using technology developed at UChicago Medicine to understand the epigenetic modifications to DNA that turn genes on or off. Using the tools of bioinformatics, he aims to find an epigenetic biomarker that will rapidly identify aggressive tumors so that the intensity of therapy can be individualized to each child with neuroblastoma.
Applebaum is currently looking at blood samples from children with neuroblastoma at multiple points during and after treatment, searching for different epigenetic patterns that track with their outcomes. “If we can predict which patients will relapse, perhaps we can intervene early with alternative therapies,” says Applebaum. “Robust blood biomarkers will provide a minimally invasive, simple way to monitor response to treatment and prognosis.” If Applebaum’s initial analysis shows that neuroblastoma patients can be risk-stratified via a blood biomarker, a prospective clinical trial will follow.
If we can predict which patients will relapse, perhaps we can intervene early with alternative therapies.
Mark Applebaum, MD
Applebaum has also zeroed in on hypoxia, as an indicator of an aggressive tumor phenotype. “Hypoxia is a common characteristic of many pediatric solid tumors, which often grow faster than their blood supply,” says Applebaum. “The tumor cells that adapt to hypoxia become hardier. They revert to more primitive tumor cells, which have mechanisms to kick out chemotherapy from the cells or increase their DNA repair abilities — resulting in resistance to treatment.” Hypoxia increases levels of TET1, an enzyme that modifies DNA structure, leading to gene activation. Applebaum is doing genome-wide epigenetic profiling of more than 100 different neuroblastoma tumors and comparing them to hypoxic cell lines to create an algorithm that identifies which tumors have the hypoxia-induced TET1 activation and increased DNA modifications that drive aggressive neuroblastoma.
A final goal of Applebaum’s research is to determine the specific function of these DNA modifications in neuroblastoma cell lines to identify novel therapeutic targets. “The beauty of the epigenetic mark we are studying in neuroblastoma is that it is one of the few DNA modifications that act as an on switch. By understanding which genes the tumor turns on, we can see certain cellular functions that are overactive and may be potential targets for drugs that can shut down the cancer,” says Applebaum.
The role of gut bacteria in the development of certain adult cancers and its ability to modify the immune system has generated considerable excitement in the treatment of adults with cancer who receive immunotherapy with checkpoint inhibitors. Now Ami Desai, MD, is translating pioneering research on the adult microbiome and cancer conducted by Thomas Gajewski, MD, PhD, who leads the Immunology and Cancer Program at UChicago Medicine, to pediatrics. In a first-of-its-kind study, Desai is evaluating whether the microbiome in children with high-risk neuroblastoma will similarly influence the immune system, impact tumor biology, and modify response to immunotherapy.
“There is compelling evidence that the intestinal microbiota plays a critical role in systemic immunity through immune cell priming,” says Desai. “Immunotherapy has revolutionized treatment of high-risk neuroblastoma, but more than 40 percent of patients will relapse after receiving immunotherapy, and we don’t currently know which patients will benefit and which won’t respond.” Desai is looking for intestinal microbiota patterns that can become biomarkers of response or resistance to immunotherapy to guide treatment decisions. The research may also lead to treatment approaches that involve modifying the intestinal microbiota with probiotics or other strategies to improve response to immunotherapy and survival in children with neuroblastoma.
Desai will sequence stool samples from patients with low-, intermediate- and high-risk neuroblastoma at diagnosis and during therapy to determine whether specific microbial species are associated with the clinical aggressiveness of the tumor. The study will also examine how the intestinal microbiota influences response to immunotherapy regimens, including post-consolidation dinutuximab plus cytokines for newly diagnosed patients, or dinutuximab plus chemotherapy for patients with refractory or relapsed disease. “We will be looking at how the microbiome affects survival in the upfront setting and in patients who relapse,” says Desai. “If our pilot study is successful, we will confirm the results in a larger multi-institutional study.”
Since little is known about the microbiota in children with neuroblastoma, Desai’s research may provide insight for novel treatment strategies. The principles of the study may also apply to other types of immunotherapy drugs. “We’re starting with neuroblastoma, but we plan to expand this research to pediatric patients who are being treated with immunotherapy for other types of cancer,” says Desai.
"The therapies that have dramatically improved survival in children with high-risk neuroblastoma are also among the most intensive and toxic a child with cancer will face," says Tara Henderson, MD, MPH, director of the Childhood, Adolescent and Young Adult Cancer Survivors Center at UChicago Medicine.
“More than 70 percent of childhood cancer survivors who received standard chemotherapy and radiation in the 1970s and 1980s developed at least one chronic health condition as they aged, and a third of those were severe or life-threatening,” says Henderson, citing the landmark Childhood Cancer Survivor Study. High-risk neuroblastoma survivors appear to have treatment-related health problems that exceed those of other cancer survivors, with published case series describing significant second cancers, hearing loss, delayed growth, and learning disabilities, among other chronic problems. Forty-five percent of all neuroblastoma patients have high-risk cancer.
We will be looking at everything: cardiac, pulmonary, endocrine and auditory function; growth and bone age; dental development; fertility; and neurocognitive and behavioral function in survivors of neuroblastoma.
Tara Henderson, MD, MPH
To better understand the long-term effects associated with high-risk neuroblastoma therapy and find ways to potentially mitigate the adverse impact of treatment on children, Henderson and Lisa Diller, MD, at Dana-Farber Cancer Institute in Boston, are leading a first-of-its-kind study of patients who have survived five or more years with the cancer. With a goal of enrolling 360 patients, the Late Effects After High-Risk Neuroblastoma (LEAHRN) study, sponsored by the Children’s Oncology Group, aims to precisely characterize late effects of treatment. “We will be looking at everything: cardiac, pulmonary, endocrine and auditory function; growth and bone age; dental development; fertility; and neurocognitive and behavioral function,” says Henderson. In addition to gathering data on phenotype, the study will also collect biologic specimens to help researchers understand why some children develop late effects of treatment while others don’t.
Henderson believes the results of the study will lead to new screening recommendations to identify adverse effects early, such as secondary cancers, and to develop interventions or treatments to minimize them. Ultimately, our goal is to tailor therapy at diagnosis such that patients continue to be cured while avoiding these late effects. She points to leukemia as the success story neuroblastoma will follow. “As the cure rate of leukemia rose, we realized that the significant radiation these children were receiving to their brains was causing secondary cancers, cognition deficits, and metabolic syndrome,” says Henderson. “Now children with leukemia get chemotherapy intrathecally, and the later impact of treatment is greatly minimized. We hope to do the same for children with high-risk neuroblastoma.”
CANCERS WE TREAT
BLOOD DISEASES WE TREAT
Jorge Andrade, PhD
Riyue Bao, PhD
Viviana Berthoud-Barrandeguy, PhD
Alexandre Chlenski, PhD
Joanna Gemel, PhD
Kyle M. Hernandez, PhD
Oscar Jara Leiva, PhD
Anoop Mayampurath, PhD
Elizabeth Sokol, MD
Xinan (Holly) Yang, PhD