Oncolytic virus to potentiate immune-checkpoint blockade in immunologically cold pediatric brain tumors

Email Principal Investigator
Ongoing
Specimen
Medulloblastoma
Asset 5.png
Aaron_Diaz.jpg

Aaron Diaz

UCSF Benioff Children's Hospital
San Francisco and Oakland, CA, USA

CBTN Samples Used

6

CBTN Participants

6

CBTN Samples

Backer

DoD Translational Team Science Award

About this

Project

Our proposal develops an exciting new approach known as oncolytic virus. It is a remarkable fact that some common viruses (e.g. measles, poliovirus) preferentially infect and kill tumor cells. This fact was discovered at the beginning of the 20th century. However, it was not until recently that this approach was recognized as an immunotherapy, as it has the ability to stimulate an immune response in immunologically cold solid tumors. Our proposal applies single-cell sequencing to tumor biopsies from patients in a measles-virus pediatric brain-tumor clinical trial (PNOC-005) to determine novel targets to enhance oncolytic virus and reduce immunosuppression. We also perform studies in mice that test the effect of combining oncolytic virus with checkpoint-blockade strategies.

Ask The

Scientists

Ask the scientists

What are the goals of this project?

We will perform single-cell profiling, spatial proteomics and transcriptomics assays on tumor, blood and cerebral-spinal fluid specimens from medulloblastoma patients treated with measles virus as part of NCT02962167. We will also profile analogous specimens from treatments applied to an immunocompetent mouse model of medulloblastoma.

What is the impact of this project?

his project will produce preclinical evidence for the use of oncolytic virus in combination with immune-checkpoint blockade in pediatric medulloblastoma. Moreover, we will identify biomarkers for response to oncolytic viral therapies and additional targets to enhance efficacy. This project is partially based on specimens from an ongoing clinical trial (NCT02962167) for measles virus in pediatric medulloblastoma. Our ongoing Phase I trial supports a favorable side-effect profile which makes the strategy of combination therapy very feasible. Thus, therapy combinations developed in this project will form the basis of an expansion of this trial.

Why the CBTN request is important to this project?

This project is based on tumor, blood and cerebral-spinal fluid specimens from clinical trial NCT02962167. The CBTN has carefully archived these tissues and this work is only possible as a result of those efforts.

Project

Results

In year one of the project period we have made significant advances in the acquisition of clinical specimens, the multi-omics profiling of clinical specimens, and bioinformatics analysis of the resulting data. We have completed the projected prospective collections of blood and CSF from the clinical trial NCT02962167 and met our project’s targets. All archival tumor, blood and CSF specimens from the PNOC trial have been transferred to the Diaz lab. We have made significant progress in our analysis of our archival specimens. We have subjected the frozen tumor specimens to single-nucleus RNA-sequencing (snRNA-seq) and most blood specimens to bulk RNA-seq. We have completed the bioinformatics pre-processing of the snRNA-seq/RNA-seq data. This included: quality control of sequenced reads, alignment and gene quantification, filtering of low-quality/doublet capture events, calling somatic mutations and filtering neoplastic cells based on those results, clustering, and cell-type classification for non-neoplastic cells.

Specimen Data

The Children's Brain Tumor Network contributed to this project by providing flash frozen tissue.