Circulating Tumor DNA Helps Identify Targets for Personalized Immunotherapy

Personalized cancer immunotherapies depend on identifying neoantigens that can make tumors recognizable to the immune system. This process often requires tumor tissue obtained through biopsy or surgery, which may not be feasible for patients with inaccessible tumors or those unable to undergo invasive procedures. Blood-based analysis could offer a less invasive route to detect tumor-specific immune targets. 

Researchers at the Vall d’Hebron Institute of Oncology (Barcelona, Spain) evaluated a blood-based approach that uses circulating tumor DNA (ctDNA) and immune cells to support neoantigen discovery. The method analyzes DNA shed by cancer cells into the bloodstream, known as ctDNA, to identify mutations that may generate neoantigens. Researchers also examined immune cells in blood samples to determine whether T cells recognized and reacted to neoantigens identified through ctDNA, tumor tissue, or both.

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The study included patients with metastatic melanoma, breast cancer, head and neck cancer, or colorectal cancer. Researchers successfully isolated and sequenced ctDNA from blood samples of six patients, while it could not be isolated from two additional patients, one with breast cancer and one with head and neck cancer. The researchers noted that this was consistent with the tendency of some tumors to shed very little DNA into the bloodstream. Blood-based neoantigen findings from the six evaluable patients were then compared with results from conventional tumor tissue analysis.

Across the six patients, ctDNA analysis identified 63.25% to 97.4% of the neoantigens detected by conventional tumor tissue analysis. The blood-based approach also identified many neoantigens not found by standard tumor tissue analysis. T cells isolated from blood samples from six of eight patients recognized and reacted to neoantigens identified by ctDNA, tumor tissue, or both.

Researchers also evaluated a separate cohort of 69 patients with various metastatic solid tumors to assess broader applicability. ctDNA was detectable in 32 of 69 patients, or 46.4%, across solid tumor types. Among 17 patients with colorectal cancer, ctDNA was detectable in 14 patients, or 82.4%, including patients with mismatch repair-deficient tumors. 

The study was published in Cancer Discovery under the title “Peripheral Blood as the Sole Source for Cancer Neoantigen and reactive T cell discovery.” The researchers noted limitations including the small patient population and low prevalence of certain cancer types, and stated that larger cohorts are needed before broad clinical use.

“Our study suggests that blood-based neoantigen identification has the potential to replace or complement the traditional tissue-based approach in many patients and cancer types. Because blood is easier and faster to collect than tumor tissue, this approach could reach patients who have inaccessible tumors or are unable to undergo a biopsy. It could also allow patients to begin treatment sooner because they wouldn't have to wait for a biopsy,” added Alena Gros, Ph.D., senior author of the study and group leader of the Tumor Immunology and Immunotherapy Group at the Vall d'Hebron Institute of Oncology.

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Vall d’Hebron Institute of Oncology