A novel immuno-oncology approach to treating a rare childhood brain cancer

A rare type of childhood brain tumor called diffuse intrinsic pontine glioma (DIPG) has a distinct characteristic that may prove to be its undoing—a misshapen protein displayed prominently on the surfaces of its cells. Scientists at the University of California at San Francisco have developed a therapeutic vaccine that can recognize the protein and prompt the immune system to launch an attack against the tumor.

The UCSF scientists have started a phase 1 trial in children with DIPG and related gliomas, according to a press release from the university. They also believe their preclinical discoveries should support the development of a new approach to fighting the disease, which would involve removing immune cells from patients and engineering them to recognize the errant protein.

Many cancers possess such misshapen proteins, which are dubbed “neoantigens,” and several ideas for basing cancer therapies on them are being studied around the world. Problem is, neoantigens can be difficult to target because they often resemble normal proteins in the body, making it unlikely the immune system would recognize them as a threat that needs to be eradicated.

The protein in DIPG, called histone 3 variant 3, doesn’t present that challenge—it is found only on the tumor cells. Furthermore, a similarly mutated form of the protein is present in 70% of DIPG cases, and when it’s there, it’s on nearly all of the tumor cells, according to UCSF.

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In laboratory studies, the researchers paired a protein fragment containing histone 3 variant 3 with another protein called HLA A, which is present in about 40% of DIPG patients. The combo was designed to train the immune system to recognize and attack DIPG tumors.

They then took T cells from DIPG patients with HLA A and used them to identify the T cell receptor proteins that would be best equipped to respond to the protein combination in the vaccine. Once they found the best receptor, they cloned it, infused it into other T cells, and grew those cells in the lab. They found that the lab-made cells could effectively shrink glioma tumors that had been grown in mice, they reported in the Journal of Experimental Medicine.

DIPG affects about 300 patients per year in the United States but is almost always fatal within a year of diagnosis. The UCSF researchers believe the distinctive nature of the DIPG neoantigen they’re focusing on could provide hope for these young patients.

"Most neoantigens in cancer are unique to individual patients, but this is one of very, very few examples of a shared, common neoantigen that may have the potential to be used in many patients," said senior author Hideho Okada, M.D., Ph.D., professor of neurological surgery and director of the Brain Tumor Immunotherapy Center at UCSF, in the release.

Neoantigen-targeting vaccines that are made to target individual patients’ specific mutations are starting to show some promise—particularly when they’re paired with drugs that inhibit immune checkpoints. Fierce 15 company Neon Therapeutics, for example, turned out promising results over the summer from a phase 1 trial of its personalized neoantigen vaccine in melanoma, which included evidence that the vaccine used along with drugs that inhibit the checkpoint PD-1 might help eliminate tumors that have recurred.

More recently, startup NousCom pulled in €42 million ($49 million) in funding to develop its portfolio of neoantigen vaccines. The company’s goal is to identify neoantigens that are common among patients with specific types of cancers so it can develop vaccines that can be mass produced and used off the shelf for all patients.

The tumor that the UCSF scientists are targeting, DIPG, is particularly challenging because it grows in an area of the brain stem that controls vital functions such as heart rate and breathing, making it difficult to remove surgically. The clinical trial of their neoantigen vaccine is being funded by several organizations, including the Parker Institute for Cancer Immunotherapy, formed last year by Silicon Valley billionaire Sean Parker.