Pan-cancer study reveals new CAR T-cell therapy targets

Scientists at St. Jude Children's Research Hospital have made a significant advancement in the field of cancer therapy by identifying 156 potential targets for chimeric antigen receptor (CAR) T-cell immunotherapy. This innovative treatment involves re-engineering a patient's immune cells to specifically attack cancer cells. The study, which was published in Nature Communications, aims to address the challenge of finding effective targets in solid and brain cancers, which often lack clear markers.

Dr. Stephen Gottschalk, co-corresponding author and chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy, expressed optimism about the study's potential to revolutionize cancer treatment. "We have discovered targets for cancer immunotherapy, which hopefully can be translated into curative approaches in the future," he said. Among the 156 targets identified, COL11A1 was validated in mouse models, showing promising results. Other targets, such as anti-fibronectin CAR T cells, also demonstrated potential in cell lines.

The researchers have made the entire list of 156 targets publicly available, inviting other scientists to evaluate and pursue these targets. Dr. Jinghui Zhang, co-corresponding author and a member of the St. Jude Department of Computational Biology, emphasized the importance of this data resource. "We have built a data resource for the community," she said. The final list can be accessed through a web portal named SCE-Miner, available on the St. Jude Cloud platform. This portal allows external researchers to access the data and use internal analysis tools for their own research.

The discovery process for these targets involved a comprehensive analysis of gene subparts known as exons. When genes are transcribed to RNA, only exonic regions form the mature product used for protein translation. By analyzing whole transcriptome sequencing data from 1,532 pediatric tumor samples and 7,460 normal tissue samples, the researchers identified which exons were selectively or uniquely expressed in cancer cells. These cancer-specific exons can potentially be targeted by CAR T cells without harming healthy cells. The final target list includes several previously identified targets that are already being pursued clinically, lending credibility to the analytical methods used.

The study by St. Jude differs from previous CAR target searches in several ways. Firstly, the sample size was significantly larger, covering all major cancer types, which broadened the candidate pool. Secondly, the researchers expanded their criteria to include proteins in the extracellular matrix, not just those associated with the cell membrane. This approach uncovered targets that were previously overlooked. "Normally, groups looking for new CAR targets looked only at membrane-associated proteins," Gottschalk explained. "But one of our targets suggested that we needed to broaden our criteria to include proteins of the extracellular matrix."

Additionally, the research team discovered that some genes express different exons, leading to variations of proteins known as isoforms. These isoforms could be compared to a "director's cut" of a movie, where different scenes are altered while maintaining the core storyline. Cancer cells often exhibit alternative splicing of exons, resulting in isoforms, which the St. Jude analysis detected more effectively than earlier approaches.

Dr. Zhang highlighted the robustness of their analysis. "We used a more straightforward and robust analysis than prior approaches," she noted. This method allowed the team to evaluate cancer-specificity at the isoform versus gene level, providing a more nuanced understanding of the differences between cancer and normal cells.

In summary, the identification of 156 potential targets for CAR T-cell immunotherapy by St. Jude Children's Research Hospital marks a significant step forward in cancer treatment. The availability of this data to the broader scientific community holds promise for accelerating the development of new and more effective cancer therapies.