Colorectal Cancer
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More people could benefit from personalized cancer immunotherapy using a newly developed discovery platform that can identify novel biomarkers and targets for treatment.

The “identify-prioritize-validate” (IPV) pipeline offers a more accessible and reliable way to identify neoantigen proteins that are produced by genetic mutations in a tumor and the immune system can respond to.

The functional neoantigen discovery platform was able to identify dozens of immunogenic mutations in single blood samples. This proved true for cancers with low mutational burdens that might not be detectable using existing methods.

The novel tumor-interrogating approach could lead to ways of increasing T cells in the immune system that target the tumors and the development of new cancer vaccines.

It may expand the identification of neoantigens to different cancer types and new groups of patients, widening the use of personalized immunotherapies.

“In virtually every patient we’ve looked at, with every kind of cancer we’ve analyzed, we can detect pre-existing natural immunity against their tumor’s immunogenic subset of mutations known as neoantigens,” explained Stephen Schoenberger, PhD, who runs a lab at La Jolla Institute for Immunology.

“Therefore, we think these patients may actually benefit from empowering this response through personalized immunotherapy.”

The findings are reported in Science Translational Medicine.

Identifying and validating neoantigens in clinical samples is currently time consuming, requiring rare and specialist reagents and limited by existing algorithms.

To find a better system, Miller and colleagues developed the discovery and validation IPV platform that required minimal tumor tissue and blood specimens from patients.

The system involves sequencing and transcriptional studies of tumor cells to identify potential neoantigens. Patient-derived blood cells are then stimulated with candidate neoantigens, to determine which elicit T-cell responses.

The team used genetic sequencing to identify mutations in 13 patients with eight different types of advanced solid tumors, which generally do not respond to treatment with immune checkpoint inhibitor cancer therapies.

These included microsatellite stable colorectal, pancreatic neuroendocrine, bile duct, ovarian, pancreatic ductal adenocarcinoma, appendiceal, head and neck squamous cell carcinoma, and renal cell cancer.

Subsequently, the team discovered all patients produced T-cells that recognized neoantigens relating to their cancers.

The system was able to interrogate up to 75 mutations in a blood sample and identify mutations missed using traditional algorithms.

“The rapid and efficient identification of a patient’s tumor-specific neoantigens is crucial to the development of personalized immunotherapies, including neoantigen-specific cancer vaccinations,” said researcher Aaron Miller, an associate professor of medicine at UC San Diego School of Medicine.

“The potential for a ‘cure from within’ is in every cancer patient we’ve looked at,” Schoenberger added.

The researchers have gone on to detect T cells in more than 130 patients with 25 different types of cancer using their IPV platform.

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