Creating the opportunity for every child with cancer to enjoy a healthy life beyond their cancer experience is the dream for pediatric oncology researchers. New grants awarded by the National Cancer Institute Moonshot Initiative through a multi-institutional, collaborative group — the Pediatric Immunotherapy Discovery and Development Network (PI-DDN) — aim to bring this dream closer to reality by fundamentally changing our understanding of how to harness the power of the immune system to treat childhood cancers.
In the PI-DDN’s first round of funding, John M. Maris, MD, pediatric oncologist and Giulio D’Angio Chair in Neuroblastoma Research at Children’s Hospital of Philadelphia, and his research team received funding to lead a pediatric immuno-oncology Center for Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers. The Center includes three highly integrated multicomponent projects that will occur in parallel and inform each other. Additionally, two CHOP investigators, Andrei Thomas-Tikhonenko, PhD, chief of the Division of Cancer Pathobiology and professor in the Department of Pathology and Laboratory Medicine, and Sarah Tasian, MD, attending physician in Division of Oncology, received funding for PI-DDN projects.
In project one by the Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers team, the researchers aim to discover lineage-specific cell surface molecules that have project-defined optimal attributes for synthetic immunotherapeutic-based targeting. They will use their findings to create and credential new therapeutics based upon preclinical efficacy in high-risk childhood cancer models.
The second project will focus on major mechanisms of immunotherapy resistance by developing approaches to circumvent the fundamental issues of intra- and inter-tumoral heterogeneity and T cell dysfunction due to both intrinsic and extrinsic factors.
Project three will probe the major difference between pediatric and many adult malignancies: Pediatric cancers typically elicit little adaptive immunity. Scientists’ goal will be to develop approaches to enhance adaptive immune responses against pediatric cancer-specific antigenic targets.
Beyond the stated goals of the grant, researchers are working to identify opportunities for collaboration. “The idea is for this to be greater than individual projects, that there will be a network of expertise with the mark of the Moonshot behind it along with some significant resources to help us with our research goals,” Dr. Maris said.
Those resources include prioritized access to the specialized technology at the Frederick National Cancer Research Laboratory, such as the National Cryo-Electron Microscopy Facility, Nanotechnology Characterization Laboratory, Molecular Characterization Laboratory, and high-performance biomedical computing. Local resources include one of the largest neuroblastoma tumor banks, maintained at CHOP by Dr. Maris, and the career-long connections of all involved researchers to access tumor samples from collaborating institutions.
With the underpinnings of state-of-the-art technology and interdisciplinary teamwork, the Center is poised to extend the early accomplishments of CD19-directed immunotherapies in a limited number of highly refractory cases of pediatric leukemia and neuroblastoma. They will use these insights to improve scientists’ understanding of the fundamental mechanisms in other high-risk or difficult-to-treat childhood cancer phenotypes, including how these malignancies evolve to evade the immune system and resist modern therapies.
Dr. Maris and his team’s exploration of the concept that childhood cancers harbor lineage-specific mechanisms of oncogenesis and immune invasion that can be precisely targeted by rationally designed immunotherapeutic regimens aligns with the PI-DDN’s goal to overcome barriers to the development of effective immunotherapies for children, such as lower expression of proteins recognizable by immune cells and the immunosuppressive environments of tumors in some pediatric cancers.
“Cancer is sinister and, generally, when you think you have a leg up on cancer, it figures out a way to outsmart you,” Dr. Maris said. “We are trying to develop breakthrough therapies to fundamentally change the paradigm of how we treat childhood cancers.”
A key part of this success, he said, will be to discover immunotherapeutic strategies for childhood cancer that not only improve cure rates, but also are less toxic than current therapies.
“Too many children with cancer still die from their disease, indicating our therapies are ineffective,” Dr. Maris said, “but even the survivors often have very significant lifelong side effects from the horrific chemotherapy and radiation therapy we use.”
The PI-DDN was created in response to 10 transformative research recommendations by the Cancer Moonshot Blue Ribbon Panel, assembled by the NCI in 2016. The Blue Ribbon Panel established seven working groups focused on major topic areas; Dr. Maris participated as part of the pediatric working group. Another member of the CHOP research community, Peter Adamson, MD, chair of the Children’s Oncology Group, was among the members of the panel with oversight of the working groups. Among the panel’s recommendations were the need to advance immunotherapy research for children and adolescents with cancer through a translational science network, overcoming drug resistance, and improving understanding of fusion oncoproteins in order to develop inhibitors to target these drivers of pediatric cancer.