Children’s National Hospital experts developed a new approach that discovered unique proteins in an individual tumor’s cells, which then helped scientists generate personalized T cells to target and kill tumors, according to a preclinical study (“Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors”) published in Nature Communications.
This effort is reportedly the first to create a new workflow for neoantigen identification that incorporates both genetic sequencing and protein identification to create a personalized treatment for medulloblastoma in children, a common malignant brain tumor. Given these findings, the researchers are now designing a Phase I clinical trial slated to open in 12–18 months.
“Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. Here we develop a proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy,” write the investigators.
“Our data indicate that aberrant splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies.
“These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.”
First, the researchers sequenced the DNA of small tissue samples while studying its complete set of proteins that influence cancer biology—also named a “low-input proteogenomic approach” by the authors. After analyzing the empirical data, which shies away from the commonly used predictive models, the researchers developed a T cell immunotherapy that targets the tumor’s unique proteins and allows the T cells to distinguish between healthy cells and tumor cells.
This means that Rivero-Hinojosa et al. managed to merge two research fields, proteogenomics and immunotherapy, and lay the groundwork for personalized, targeted T cell therapies to treat children with brain tumors.
“Neoantigen discovery techniques have either been dependent upon in silico prediction algorithms or have required a significant amount of tumor tissue, making them inappropriate for most brain tumors,” noted Brian Rood, MD, medical director of Neuro-oncology and the Brain Tumor Institute at Children’s National. “This neoantigen identification pipeline creates a new opportunity to expand the repertoire of T cell-based immunotherapies.”
“We developed a new filtering pipeline to remove non-annotated normal peptides. Targeting antigens that are completely specific to the tumor, and expressed nowhere else in the body, will potentially increase the strength of tumor antigen-specific T cell products while decreasing the toxicity,” added Samuel Rivero-Hinojosa, PhD, staff scientist at Children’s National and first author of the study.
Once the experts identified these unique peptides, they used them to select and expand T cells, which showed specificity for the tumor specific neoantigens and the ability to kill tumor cells. The next step is to conduct a clinical trial in which a patient’s own T cells are trained to recognize their tumor’s unique neoantigens and then reinfused back into the patient.
From an immunotherapy standpoint, tumor specificity is important because when clinicians treat patients with T cell therapies, they want to make sure that the T cells directly target and kill the tumor and will not cause devastating harm to healthy cells. This paper demonstrated that it may be possible to create a better efficacy and safety margin with this new technique.