Recently published in the Journal of Experimental Medicine, a study led by Hideho Okada (University of California, CA, USA) has identified a neoantigen present in diffuse intrinsic pontine glioma (DIPG).
“It is important to develop more innovative treatment approaches for childhood brain cancers, which now are the leading cause of cancer death in children. DIPG is a very deadly type of brain cancer, and not many children survive beyond 12 months from the time of diagnosis.” Okada explained.
The novel immunotherapy targets the neoantigen histone 3 variant 3, which is a protein fragment that is genetically mutated in 70% of DIPG cases resulting in abnormal control of gene activity in tumor cells. “This may be an ideal case of a tumor neoantigen,” Okada, commented. “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.”
First, the researchers used computational techniques to predict that this specific protein fragment would bind especially strongly to HLA A. Second, laboratory experiments demonstrated a strong affinity between this tumor neoantigen and a type of HLA A found in 40% of DIPG patients.
Third, the study highlighted a potential form of treatment based on directly engineering patients’ T cells to recognize the target neoantigen. The researchers used T cells from patients with the HLA A type that binds tightly to a DIPG neoantigen to identify T-cells that can recognize this combination. The T cell receptor that was the best at recognizing this was then cloned and demonstrated in mice that they could effectively kill human glioma tumors.
“We saw a significant reduction in tumor progression compared to control groups,” commented co-lead author Zinal Chheda (University of California). “The T-cell receptor we selected for cloning has an affinity for the neoantigen that is in the range of what we see for antigens from viruses — orders of magnitude greater than what we generally see with neoantigens found on cancer cells.”
The goal of the neoantigen-containing vaccine now being tested in Okada’s clinical trial, is to train the immune system’s T cells to recognize the neoantigen in the vaccine triggering an immune response to tumor cells in the brain.