ID #638 Registry study of children and adult patients with relapsed, refractory, or progressive sonic hedgehog medulloblastoma
Mohammad H Abu-Arja, Nazanin Majd, Austin Stuckert, Rahawa T Ghebrelul, Gregory K Friedman, Nabil Ahmed, Michael D Taylor, Murali ChintagumpalaAbstract
Background
Fifty percent of SHH-medulloblastoma harbor identical somatic point mutations in a non-coding small nuclear RNA called U1 (r.3A>G). This point mutation is found in the majority of SHH-α tumors (in children and toddlers) with TP53 mutations and in over 95% of SHH-α tumors (in adults). The U1 mutation results in the spliceosome failing to anneal to the proper intron-exon boundaries and instead recognizing false splice junctions inside introns. These aberrantly spliced RNA species include the 5’ end of introns, meaning that portions of the intron are translated into protein until the ribosome encounters a stop codon. This means that the tumors exhibit a unique form of post-transcriptional hypermutation. Therefore, novel epitopes may be identified in these tumors. Hypermutant tumors are responsive to immune checkpoint inhibitors (ICI). However, data for patients with relapsed medulloblastoma treated with ICI are scarce.
Methods
We established a registry study (NCT07242963) to enroll patients with relapsed SHH-medulloblastoma to assess the incidence of the U1 mutation and compare outcomes of patients with relapsed SHH-medulloblastoma harboring the U1 mutation who receive different therapies, including ICI.
Results
We activated the registry study (NCT07242963) at Texas Children’s Hospital. The study is actively enrolling patients. The registry’s primary aim is to report on the incidence of U1 mutation in patients with relapsed/refractory SHH-medulloblastoma, and their response to ICI. Our secondary aims include identifying cryptic, novel tumor antigenic epitopes by developing a first long-read sequencing and surfaceome dataset for SHH-medulloblastoma, and developing cellular and immunotherapies targeting the U1-mutation-driven tumor antigenic epitopes.
Conclusions
A subset of SHH-medulloblastomas may exhibit post-transcriptional hypermutation secondary to aberrant splicing caused by the U1 (r.3A>G) mutation. Given the small number of these patients, our registry study enables multicenter and multinational collaboration to test the effectiveness of ICI in them.