Retinoblastoma is a rare cancer that affects children that are younger than 2-years-old. It develops in the retina and approximately 40 percent of cases are due to an inherited genetic mutation in a gene known as RB1. For most patients with an inherited form of the disease, the cancer affects both eyes.
CAR-T-cell therapy
Research is taking place to learn more about this form of cancer and to develop therapies that improve outcomes. One such therapy is a type of immunotherapy known as CAR-T-cell therapy. This experimental therapy uses engineered immune cells packaged in a biodegradable material known as hydrogel and injected into the tumor.
In experiments with mice, this treatment both destroyed advanced tumors and prevented mice from losing their vision. Most CAR-T-cell therapies are body-wide treatments, meaning that they are administered intravenously to patients. For cancers like retinoblastoma, being able to inject the engineered immune cells directly into the tumor can be a more effective way to treat the disease.
Model for Research
Before a treatment can be developed, scientists need to have models that show what happens when Treatment A comes in contact with Cell B. Researchers at St. Jude Children’s Research Hospital have created a lab model for studying retinoblastoma that is caused by the mutation in the RB1 gene. This model mimics the biology of retinoblastoma tumors and it provides a resource for both studying the disease in its early stage and as a way to screen new therapies.
What makes having a model for retinoblastoma so great is that this is the only cancer that is not diagnosed by way of taking a biopsy. The reason why a biopsy isn’t done is because the process might spread tumor cells outside of the eye. So, whatever tumor samples researchers have are from cancers that have evolved beyond its early stage, which means it progressed to the point that eye removal is necessary.
While using cell lines, genetically engineered mouse models or patient-derived xenografts (tumor tissue taken from a patient and implanted into mice for research purposes) are useful for research, they didn’t provide an accurate result when it comes to replicating the disease as it occurs in patients. In particular, knocking out the RB1 gene that leads to retinoblastoma in humans, did not result in mice developing the same abnormality.
In order to make a better model for research, scientists grew retinal organoids which are three-dimensional models created from stem cells. The cells were created from samples taken from retinoblastoma patients who had germline mutations in RB1. The cells were then injected into mice and retinoblastoma tumors formed. Researchers did an analysis of the tumors and found that they were indistinguishable from patient samples.
“The ability of the organoid models to do so is unique, because cell lines with RB1 mutations do not spontaneously develop into retinoblastoma tumors,” said first author Jackie Norrie, Ph.D., St. Jude Department of Developmental Neurobiology. “This underscores that both the RB1 mutation and the processes involved in the natural development of the retina play roles in the formation of this cancer.”
As a result of this work, researchers created a dataset of retinoblastoma single-cell analysis results. This data along with information from other researchers is available via the Childhood Solid Tumor Network (CSTN) found here: https://www.stjude.org/research/why-st-jude/data-tools/childhood-solid-tumor-network.html. This is a site that offers the world’s largest collection of scientific resources for those studying pediatric solid tumors and related tissue.