NEW YORK – With $7.9 million in National Institutes of Health funding, researchers at the Cleveland Clinic are gearing up to bring precision to radiation oncology.
Radiation is a mainstay of cancer treatment and more than half of all cancer patients receive it. By identifying biomarkers of response and resistance and using these biomarkers to guide radiation treatment decisions, the researchers hope more cancer patients will benefit from precision medicine, which to date has largely been confined to targeted drugs and immunotherapies.
The Cleveland Clinic is one of an inaugural three centers participating in the Radiation Oncology-Biology Integration Network, or ROBIN, which recently received research grants from the National Institutes of Health to advance this exact goal. Weill Cornell Medical College of Cornell University and the University of Maryland Baltimore are the other centers in the network.
According to Michael Graham Espey, chief of the National Cancer Institute's Radiotherapy Development Branch, the NIH has already begun soliciting applications for another two ROBIN centers. Part of the idea behind funding this research in a network structure is to encourage data sharing and collaboration across multiple institutions, and to build up a workforce in radiation precision oncology where interest has historically been lacking, according to Timothy Chan, the chair of the Cleveland Clinic's center for immunotherapy and precision immuno-oncology and the primary investigator for the new NIH-funded research.
"It's amazing that almost 50 to 60 percent of cancer patients will get radiation in some form or fashion throughout the course of their treatment," Chan said. "It's been like that for over 100 years, but there's not been that much [molecular] information regarding radiation alone, let alone radiation in combination with other therapies."
Indeed, researchers, drugmakers, and commercial labs have poured enormous resources into identifying biomarker signatures, algorithms, and scores to determine which patients are likely to benefit most from drugs like small molecules, antibody-based therapeutics, and even cytotoxic chemotherapies. Meanwhile, in the world of radiation, research into who benefits most and why using biomarkers has been relatively stagnant even as the technology used to deliver radiation — cell-killing rays, particles, and radionuclides — has improved dramatically.
With ROBIN, the NIH stated in a funding announcement last month, the overarching goal is to "move towards a new era of personalized radiation oncology," through research into patients' unique biological signatures for guiding treatment planning, predicting response and resistance, and minimizing toxicities.
Through the ROBIN network, the goal is to support the use of molecular tools and omics data in radiation oncology studies. For example, grantees could test hypotheses on radiation's effect and responses; longitudinally collect patient samples before, during, and after radiation therapy; and conduct both preclinical and translational studies that inform clinical trials of individualized or improved radiation treatment approaches. The NIH is encouraging researchers to use data science and informatics, and investigate radiation-based combination approaches.
"Because radiation oncology research is of less interest to the pharmaceutical industry, combination therapy using radiation has not been studied to the same degree as combinations of pharmaceutical agents," the NIH said in its funding announcement. "Thus, radiation oncology represents a dichotomy where the technical precision of radiation delivery to tumors continues to improve, but the biological determinants of how tumors and normal tissues respond and adapt to radiation therapy over time is far less understood, especially in humans, relative to other forms of cancer therapy."
Research components
Each ROBIN center needs to conduct a molecular characterization study of biospecimens taken during radiation and at least two research projects that "mesh within the scope and design of the molecular characterization trial," according to the NIH.
For the Cleveland Clinic, Chan explained how these molecular characterization and clinical studies focus on two groups: patients with bladder cancer receiving radiation combined with Gilead Sciences' antibody-drug conjugate Trodelvy (sacituzumab govitecan) and patients with recurrent or second primary head and neck cancer on radiation plus Bristol Myers Squibb's immune checkpoint inhibitor Opdivo (nivolumab). Both studies involve a form of external beam radiation called IMRT, or intensity modulated radiation therapy.
"The field has moved almost everything into combination therapy now," Chan said. "But very little is known about what is driving resistance and sensitivity to these combinations [with radiation] … this is actually special because there's been very little effort in this type of deep data generation during radiation-based combination therapy."
According to Chan, the hypothesis behind these studies is that specific genetic and immunologic mechanisms are driving patients' sensitivity and resistance to these radiation-based combination therapies.
The head and neck cancer trial was already underway before the NIH grant, and Chan expects the bladder cancer study will launch in the next handful of months. Both studies have funding from pharmaceutical sponsors — BMS is contributing to the head and neck trial and Gilead and Varian Medical Systems are sponsoring the bladder cancer trial.
The drugmakers, according to Chan, are generally interested in the activity of the radiation combination therapies. And in the radiation-Opdivo trial, Chan said, the primary aim of the study is to evaluate patients' one-year progression-free survival rate on the combination.
The new NIH funding comes into play in the next step — the molecular characterization portion — although Chan's group can delve into a lot more.
"We're looking at circulating tumor DNA, T cells, gene expression, and mutation analysis … and also looking deeply into how the immune system changes as a result of both the radiation and the immunotherapies," he said, adding that the NIH funding will also allow his team to collect samples from patients who just got radiation, so their biomarker profile and associated outcomes can be compared to those receiving the combination.
According to Chan, the researchers will continue to prospectively collect and analyze these samples throughout the next five years.
The forthcoming bladder cancer study, according to Chan, is especially unique. "There's never been a study done with an antibody-drug conjugate and radiation before," he said, explaining that by combining the two researchers hope to treat patients' cancers and conserve their bladder function. That trial is expected to enroll roughly 40 patients, for which the researchers will analyze samples before, during, and after treatment.
"We're going to … look at the behavior of the immune cells, the T-cell receptor repertoire and how that changes, how active the immune cells are in recognizing the tumor cells, and … how resistance can develop," he explained. Already, researchers in Chan's lab have been looking into how chemotherapies and immunotherapies change the clonal structure of cancer tumors, and this new study allows those efforts to spill over into radiation, too.
"Treatment is a selection. … You kill certain cells, but then other cells perhaps don’t have certain markers like neoantigens, and they are able to escape the immune system," he said. "We want to work out why that is and what those escape mechanisms are."
'It's time to do a lot more molecular work'
Chan hopes that he and his team will be able to publish findings throughout the coming years as they generate findings from the molecular analyses. Already, as part of the NIH funding requirements, grantees have to submit annual reports on their research progress to the NIH, and it is the responsibility of the principal investigator — Chan, in the Cleveland Clinic's case — to make sure that the results of the project are published in a timely manner.
Beyond the trials that fall under the funding for ROBIN, there are funds designated for cross-center workshops and working groups. "The NIH decided that it's time to actually do a lot more molecular work in therapies that have radiation as part of them, because we don't know anything about what goes on molecularly,'" Chan said. "This was a nice way to unite a lot of the different types of [work] going on already and allow us to work with our colleagues in different centers. … It builds a network to really support this type of work."
The research is not specific to tumor type, either. Researchers at Cornell, for instance, are molecularly characterizing irradiated rectal cancers with their ROBIN grant, and the University of Maryland researchers are molecularly characterizing radiation-treated oligometastatic prostate cancers. Researchers from Emory University, University of Chicago, and Thomas Jefferson University are collaborating with the grant recipient centers on the research, too.
The NIH certainly has high hopes for the ROBIN Network. In a description, the NIH said the network "is intended to have a national impact and provide leadership for the cancer research community," and hopes that the findings that emerge serve as a "nucleation point" for future clinical trials into radiation and radiation-combination cancer treatments.