St. Jude has discovered 156 potential targets for CAR T-cell immunotherapy, which aims to improve cancer treatment by targeting cancer cells specifically. This type of therapy involves re-engineering a patient’s immune cells to attack the cancer cells. However, finding effective targets for solid and brain cancers has been a challenge. Through thorough analysis and experimental validation in vivo, scientists at St. Jude have identified these potential targets, offering promise for improved cancer therapies.The results were released today in Nature Communications.
“We have found targets for cancer immunotherapy, which we hope can be used in the future to develop effective treatments,” said co-corresponding author Stephen Gottschalk, MD, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy chair. “We have identified a large number of potential targets for the field and have confirmed at least one, COL11A1.”
Although COL11A1 was one of the 156 targets that the researchers tested in mouse models, others showed promise in cell lines such as anti-fibronectin CAR T cells. Most of the targets have significance in cancer biology and immunology.be able to validate them in their own studies,” said Zhang. “We hope that by sharing this data resource, we can accelerate the discovery of new therapeutic targets for childhood cancers.”
The researchers plan to regularly update the database with new findings and expand the types of childhood cancer analyzed. They also encourage collaboration with other researchers to further advance the understanding of childhood cancer and develop effective treatments.”The data we found,” Gottschalk explained, “allows other scientists to determine if a specific target is present in a particular type of pediatric cancer. They can access this information in the Cloud and conduct their own analysis.” The researchers identified COL11A1 and other targets through a comprehensive analysis of gene exons. When a gene is transcribed into RNA, only the exonic regions are preserved to create a mature product, which serves as a template for protein translation. The team examined the entire transcriptome sequencing data from 1,532 pediatric tumor samples and 7,460 normal ones.The St. Jude method for identifying cancer-specific exons in tissue samples involves finding exons that are more highly selective or uniquely expressed in cancer cells compared to normal cells. These specific exons can be potential targets for CAR T cells without causing harm to healthy cells. The final list of targets also includes several targets identified in previous analyses and are currently being pursued clinically, which increases confidence in the group’s analytical approaches.
This method differs from previous CAR target searches in several ways. The sample size was much larger, and the study involved all major cancer types, leading to a larger candidate pool.The researchers expanded their search for relevant candidates for CAR T targets by focusing on proteins both inside the membrane and on the extracellular matrix, which was an unconventional approach. Normally, groups searching for new CAR targets only looked at membrane-associated proteins, but one of their targets suggested broadening their criteria to include extracellular matrix proteins. These proteins are not anchored to the cell, but they stick to the cell surface and can still be recognized by CAR.The scientists discovered that certain genes play a role in the development of cancer by producing specific proteins. They also found that these genes have various sections that produce different versions of a protein, known as an isoform. This is similar to a director’s cut of a movie, with altered scenes but still keeping the core similarities to the original. Cancer cells are inclined to create these isoforms, which was detected by the St. Jude analysis using a more reliable approach than previous methods.”We tested whether a subset or all of the exons within a gene showed differences between cancer and normal cells, allowing us to assess cancer-specificity at the isoform and gene levels.”
