(see Cancer in 2023, p. 12). However, treatment options for certain types of cancer, such as cancers of pancreas, and those that originate in the nervous system, remain limited. Thanks to rapid advances in our understanding of how cancer develops (see Understanding the Path to Cancer Development, p. 24), researchers are taking innovative approaches to tackling difficultto-treat cancers. Here we present an overview of some of the most promising breakthroughs in treating two types of cancer— glioblastoma and pancreatic cancer—as examples of progress against currently intractable cancers. Glioblastoma Glioblastoma—the most common and deadly type of brain cancer—is highly resistant to chemotherapy, and surgery and/or radiotherapy are ineffective. No new drugs have been approved for glioblastoma over the past decade, and only 6.9 percent of patients survive five years after being diagnosed with glioblastoma (29), underscoring an urgent need to find better treatments for the disease. An active area of scientific discovery is understanding the relationship between resistance to treatment and how the tumor utilizes nutrients. Two recent studies found that certain types of gliomas, a larger category of cancers of the nervous system that includes glioblastoma, produce large quantities of chemicals, called pyrimidine nucleotides, which are the building blocks of DNA. Findings of the studies show that gliomas become dependent on these chemicals for survival, and when the production of pyrimidine nucleotides is blocked with a drug, tumors shrink in animal models of glioma (709,710). Researchers are now planning clinical trials to test the drug in people with gliomas. One of the challenges in effectively treating glioblastoma (and other cancers that originate in the brain) is delivering drugs to the brain, which is naturally protected from pathogens and other toxins by a thin layer of tissue and blood vessels, called the blood–brain barrier. Even the most potent chemotherapy drugs cannot cross this barrier. Researchers are testing novel approaches to increase the concentration of drugs in the brains of patients with glioblastoma. In a phase I clinical trial, an ultrasound device was implanted in the brains of 17 patients who had recurrent glioblastoma (711). When activated, the device repeatedly, but temporarily, opened the blood–brain barrier, increasing the concentration of a chemotherapy drug by sixfold in patients’ brains without causing any serious side effects (711). The study is now in phase II of clinical development. Clinical advances and breakthroughs in immunotherapy for other tumors (see Immunotherapy: Pushing the Frontier of Cancer Medicine, p. 99) have inspired treatment of glioblastoma with immunotherapeutics. Different classes of immunotherapeutics are at various stages of clinical development to treat glioblastoma (713). There are several ongoing CAR T-cell candidates for glioblastoma treatment, including CARs directed against proteins, such as EGFRvIII, IL13Rα2, and B7-H3, that are abundantly present on the surface of glioblastoma cells (714). In addition, CAR-NK cells are being evaluated in clinical studies of glioblastoma against different targets, such as HER2 (715). Therapeutic vaccines have also shown promise in the treatment of glioblastoma. In a phase III clinical trial, researchers added a vaccine based on dendritic cells (see Sidebar 38, p. 100) to the standard of care treatment (716). Addition of vaccine more than doubled the overall survival in patients who were newly diagnosed with glioblastoma or who had recurrence of the disease at 60 and 30 months, respectively (716). These results demonstrate a remarkable In a recent study, researchers found that lowering temperature around the tumor to 20˚C to 25˚C using an implantable device doubled the median survival in two preclinical animal models of glioblastoma (712). -20 -10 10 20 30 0 40 C SELECTED IMMUNOTHERAPEUTICS CURRENTLY IN CLINICAL DEVELOPMENT TO TREAT GLIOBLASTOMA Type of Immunotherapeutic Target Clinical Trial Phase CAR-T cells IL13 receptor I EGFRvIII I/II B7-H3 I/II CAR-NK cells HER2 I Immune checkpoint inhibitors (ICIs) PD-1/PD-L1 III PD-1/PD-L1 & CTLA-4 II PD-1/PD-L1 & LAG-3 I Oncolytic viruses – I/II Vaccines EGFRvIII II/III IDH1 I DCVax-L III Developed from (713). AACR Cancer Progress Report 2023 Envisioning the Future of Cancer Science and Medicine 148
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