CANCER GENETICS & GENOMICS
CAR-T cell therapy: then and now Over a decade ago, scientists discovered a way to make immune cells called T cells fight cancer by altering them in the lab to more effectively find and destroy cancer cells. The T cells, called chimeric antigen-specific (CAR) T cells, are created by removing T-cells from a patient’s body and genetically engineering them to seek out a specific protein on the surface of the tumor cells. The cells are then infused back into the patient’s bloodstream. In 2022, the second-ever leukemia patient to receive CAR-T cells marked their 10th year since receiving the treatment. After ten years, the patient is leukemia-free and still has CAR-T cells circulating in their blood. Analysis of the patient’s blood shows that the CAR-T cells initially differentiated into CD8+ killer T cells, which destroy foreign cells, including cancer cells. Then the CAR-T cells became CD4+ helper T cells, which serve as a form of immune memory. CAR-T cell therapy is currently approved to treat leukemia, lymphoma, and multiple myeloma. The development of CAR-T cell-based cancer immunotherapy marked a breakthrough in liquid cancer treatment, but the approach has not yet made significant strides against solid tumors due in part to a lack of tumor-specific targets. In solid tumors, most proteins responsible for tumor growth and survival are inside the cells, not on the cell surface. CAR-T cells can only access proteins on the surface of cells. Major histocompatibility complex (MHC) molecules on the surface of cells present viral and bacterial peptides to the immune system. Tumor cells also have MHC molecules, which bring frag- ments of proteins, called peptides, from within the tumor cell and present them on the surface of the tumor cells. If the peptides contain mutations, they can be targeted by the immune system or immunotherapy. However, in pediatric cancers and many adult cancers, few targ- etable mutations exist. While studying neuroblastoma, an aggressive form of pediatric cancer, a group of researchers hypothesized that some of the peptides presented by MHC on the neuroblastoma cells come from proteins essential for tumor growth and survival. The team began studying whether the peptides could be targeted with
a new type of chimeric antigen receptor cell called a ‘peptide-centric’ chimeric antigen receptor cell (PC-CAR). First, the researchers had to determine which peptides in the neuroblastoma cell population were tumor-specific. They stripped the MHC molecules off of neuroblastoma cells and used advanced computational approaches to narrow in on the tumor-specific pep- tides. The team relied on large datasets to weed out peptides that have cross-reactivity to normal tissue. They narrowed in on one peptide derived from a gene called PHOX2B and designed a PC-CAR that would recognize it on tumor cells. In mice, the PC-CAR cells led to the complete and targeted elimination of neuroblastoma tumors. While the study only showed one type of cancer, the method could be used in any cancer, allowing for a more personalized approach to cancer treatment. n REFERENCES: Melenhorst, J.J., et al. Decade-long leukemia remissions w/ persistence of CD4+ CAR T cells. Nature (2022) 602, 503–509 DOI: 10.1038/s41586-021-04390-6 Yarmarkovich, M., et al. Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs. Nature (2021) 599, 477–484. DOI: 10.1038/s41586-021-04061-6 Once CAR-T cells are in a patient’s body, a protein on the cell identifies and binds to cancer cells. Other proteins on the CAR-T cell activate the T cell so it can recruit other immune cells to kill the cancer cell. REFERENCES: Degasperi, A., et al. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science (2022) 376:6591 DOI: 10.1126/science.abl9283 Liu R, et al. Systematic pan-cancer analysis of mutation-treatment interactions using large real-world clinicogenomics data. Nat Med (2022) 28(8):1656-1661. DOI: 10.1038/s41591-022-01873-5 existing mutational signatures and identified an additional 58. The new signatures will help improve the diagnosis and treat- ment of cancer patients. Another group of researchers found ties between tumor mutation profiles, cancer treatment, and survival rates using data from thousands of individuals. The team analyzed electronic health records and genetic tumor panels from patients with lung, breast, ovarian, pancreatic, and bladder cancer, along with renal cell carcinoma and melanoma. They found that mutations in 42 genes are related to survival outcomes in at least one of the cancer types studied. These are just two studies demonstrating the importance of high-quality, large-scale data from diverse patients for investigat- ing cancer and developing effective treatments. n
Large-scale studies to identify patterns in cancer
Cancer is a complex disease commonly caused by the accu- mulation of genetic changes that alter biological pathways controlling cell growth and survival. Over the past decade, advances in genomic technologies, tumor analysis, and drug development continue to yield insight into cancer formation, progression, and therapy. Several new genomic tumor profil- ing studies highlight the importance of large-scale analyses to identify yet unknown mutations and other genetic changes. One such study analyzed the whole genome sequences of more than 18,000 tumors collected through the UK 100,000 Genomes Project. Researchers were interested in mutational signatures, which paint a picture of the mutations in a tumor and can help pinpoint its cause. The group confirmed 51 of 70
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