Radiation Central to the Path to Cure:

With an investment of $40 million over five years, the NCI has funded five U54 grants and created the Radiation Oncology-Biology Integration Network (ROBIN). This is a collaborative interdisciplinary effort to create and apply new biological knowledge to optimize radiation therapy in combination with systemic drugs, immunotherapy and other agents. Each ROBIN center is described below and has materials and lectures regarding their respective topics, which are free to the community. ASTRO created a webpage for quick access to the various education materials: www.astro.org/professionaldevelopment.

Timothy Chan, MD, PhD

Center for Genomics of Biologics Enhanced Radiotherapy (GenRad)

Radiation therapy (RT) is now commonly used in combination with systemic therapies including biologics. The long-term goal of the GenRad Center is to understand the genomic and microenvironmental determinants, temporal dynamics and efficacy of radiation-based combination therapies. We have launched several trials to evaluate the effectiveness of combining radiation with various targeted biologics. First, we aim to understand the utility and molecular mechanisms that underlie the efficacy of combination with radiation treatment plus antibody drug conjugates (ADC). We hypothesize that specific genetic and immunologic events underlie treatment efficacy with radiation plus ADC treatment. Specifically, we are investigating the use of sacituzumab govetican + RT for bladder preservation therapy in muscle invasive bladder cancer and will determine the differential molecular effects between standard-of-care cisplatin + RT versus ADC + RT. In addition, we are identifying the differential mechanisms underlying anti-tumor activities of cisplatin + RT versus immune checkpoint blockade + RT in head and neck squamous cell carcinoma (HNSCC). We are working to uncover the unique genetic and immunologic factors that govern response to RT when combined with these two classes of agents. We will elucidate the differential molecular effects of the two approaches, characterize immune reprogramming and reveal mechanisms of acquired resistance. Finally, we are aiming to improve identification of patients who are sensitive or resistant to RT-based therapies based on new insights into transcriptional dynamics and temporal reprogramming during radiation-based therapies.

Our team is comprised of investigators from the Cleveland Clinic and Emory University. Our goal is to propel innovative radiation-based therapeutic approaches and to inform future trial design to improve patient outcomes.

Silvia Formenti, MD, FASTRO

Immune system and Radiotherapy (ImmunoRad) Center

The role of the immune system in cancer response to radiation therapy (RT) is critical, as early studies by Stone et al. demonstrated. They showed how immune mechanisms influence RT outcomes, particularly in tumor control. ImmunoRad, an international initiative, builds on these findings to investigate how RT impacts cancer outcomes through immune interactions, aiming to bridge preclinical evidence to clinical applications. A molecular characterization trial (MCT) involving 50 rectal cancer patients across the U.S. and Europe will assess RT’s influence on tumors, surrounding tissues, the immune system and microbiome. Rectal cancer, treated with short-course RT (SCRT) in a preoperative setting, provides an ideal model to examine these immune interactions. Seven academic centers are collaborating to conduct comprehensive tissue and immune profiling, employing advanced molecular analyses to explore RT’s effects on both tumor and healthy tissue, as well as on the host’s immune system and microbiome. Additionally, artificial intelligence and machine learning models will predict interactions between patient characteristics, tumor traits and RT parameters. The ImmunoRad initiative integrates with the ROBIN network, encouraging interdisciplinary collaboration among clinicians, scientists and radiation experts. It also includes a cross-training core to prepare the next generation of leaders in radiation science. Findings will be shared across ROBIN and with the wider scientific community, creating a valuable resource on RT’s biological effects.

Coordinated by the Immunity and Radiation Oncology Network (IRON), this project exemplifies global efforts to use cutting-edge technology to deepen our understanding of RT’s interaction with the immune system.

Daphne Haas-Kogan, MD, MBA, FASTRO

KIDSROBIN Center

Although many cancers respond well to radiation therapy, some respond poorly or not at all. Even within cancer subtypes that collectively respond well, the response of individual patients with the same tumor types is variable. Prognostic biomarkers and markers of early responses to new radiation/adjuvant combinations are needed. Toward these unmet needs, we apply contemporary tools of computational biology, data science and natural language processing. The clinical vehicle for our KIDSROBIN team is pediatric cancers — specifically two cancers of neuroectodermal origin (diffuse midline gliomas and aggressive neuroblastomas). Cancers of neuroectodermal origin are the number one solid tumor of children and the number one cause of cancer related death in children. Minimization of confounding passenger mutations is needed to unmask actionable biomarkers, and the mutational burden of pediatric cancers is low. Moreover, insights into pediatric cancers have proven to be generalizable to more common adult cancers. Pediatric solid tumors are less frequent than their adult counterparts. To address the challenge of low “n,” KIDSROBIN draws upon tissue available through large pediatric cancer consortia: Children’s Oncology Group and Pacific Pediatric Neuro Oncology Consortium and features a strategic alliance between the Dana-Farber/Harvard Cancer Center and the University of California, San Francisco.

Julie Schwarz, MD, PhD, FASTRO

MicroEnvironment Tumor Effects Of Radiotherapy (METEOR) Center

The balance between immune stimulatory and suppressive effects of radiation therapy (RT) predicts whether local treatment with RT generates a systemic anti-tumor immune response. We hypothesize that RT, and in particular standard of care chemoradiation (SOC CRT), can limit the development of anti-tumor immunity by increasing the number and tumor permissive phenotypes of myeloid derived cells in the tumor microenvironment (TME). The Washington University MicroEnvironment Tumor Effects Of Radiotherapy (METEOR) Center will comprehensively define the TME in patients receiving CRT for cervical and pancreatic cancer using biologic and radiologic specimens obtained before, during and after RT. We will leverage our institutional expertise in genomics, proteomics, tumor metabolism and immunology to take a “deep dive” into CRT-induced TME co-evolution using both single cell and spatially resolved approaches. Our overall vision is that immunosuppressive SOC CRT associated changes in the TME can be further targeted to improve systemic anti-tumor immune responses. Although our preliminary data implicates macrophages and dendritic cells, our research design will allow for detailed study of multiple immune and stromal cell types in the TME. Furthermore, our approach using only small biopsies will facilitate collaboration with others to determine what are the common and tumor site-specific mechanisms of CRT resistance.

Nicole Simone, MD

Oligometastasis (OligoMET) Center

Metastasis is the final common lethal pathway for most cancer patient’s demise and once cancer has metastasized, it was generally considered incurable. Through paradigm-shifting translational and clinical studies, some of which were pioneered by the U54 ROBIN Oligometastasis (ROBIN OligoMET) team, we now know the metastatic capacity of cancers behaves along a spectrum of disease that contains an oligometastatic state where metastases are limited in number and location. This concept has been transformational in the way the clinical field views metastasis; however, a greater biologic understanding is needed to improve cure rates. This OligoMET Center seeks to build from these initial findings to understand mechanistically how radiation may modulate metastatic biologic processes, specifically, unanswered questions related to radiation effects on tumor plasticity, metabolic reprogramming and the tumor immune microenvironment. This in turn will lead to the development of new approaches for using radiation therapy to combat metastases. The OligoMET Center uses oligometastatic prostate cancer as their model, but results will inform future treatment planning and trial design in other oligometastatic cancers. Overall, the ROBIN OligoMET Center was created as a platform for greater adoption of radiation oncology concepts, biomarkers and technologies in the oligometastatic space through academic and/or industrial partnerships.

Additional information regarding these grants and other grant opportunities can be found at the National Cancer Institute's website.