Bottom Line: Cancer neoantigens and neoantigen-specific T cells were identified from patient blood samples by analyzing circulating tumor DNA (ctDNA) and immune cells, respectively, and they largely matched those found through traditional tumor tissue biopsy in many patients.
Journal in Which the Study was Published: Cancer Discovery , a journal of the American Association for Cancer Research (AACR)
Authors: Alena Gros, PhD , is the senior author of the study and group leader of the Tumor Immunology and Immunotherapy Group at the Vall d'Hebron Institute of Oncology (VHIO) in Spain.
Andrea Garcia-Garijo, PhD, is a postdoctoral fellow in Gros' group and first author of the study.
Background: "Neoantigens, which are proteins produced by cancer cells, make tumors easily recognizable to the immune system, prompting it to mount an immune response against the cancer cells expressing these neoantigens," said Gros.
Because neoantigens are not found on normal cells, targeting them may be an effective and safe strategy for cancer immunotherapy, Gros explained. She noted that researchers are developing personalized immunotherapies that target neoantigens, including cancer vaccines and T cell-based therapies.
A crucial step in developing personalized immunotherapies is identifying the neoantigens and neoantigen-specific T cells that are present within each patient's tumor. Doing so can also help identify patients likely to benefit from immunotherapy, since the presence of these biomarkers indicates that a tumor may be immunogenic, she added.
"Currently, clinicians identify neoantigens and neoantigen-specific T cells by analyzing tumor tissue collected through a biopsy or other surgical procedure. However, many patients do not have easily accessible tumors or are not healthy enough to undergo an invasive biopsy or surgery," said Garcia-Garijo.
As a less invasive alternative to these procedures, Gros and colleagues examined whether they could identify neoantigens and neoantigen-specific T cells using only patient blood. They reasoned that the DNA shed by cancer cells into the bloodstream, known as ctDNA, could provide insights into the mutations present within the tumor.
How the Study was Conducted and Results: The researchers isolated and sequenced ctDNA from the blood samples of six patients with metastatic melanoma , breast cancer , head and neck cancer , or colorectal cancer . They were unable to isolate ctDNA from the blood of two additional patients, one with breast cancer and the other with head and neck cancer, which Gros explained is consistent with the fact that some tumors shed very little DNA.
Gros and colleagues analyzed the ctDNA sequences to identify neoantigens and compared the results to those obtained from conventional tumor tissue analysis from the same six patients. They found that, across all six patients, the ctDNA analysis identified 63.25% to 97.4% of the neoantigens identified by standard tumor tissue analysis.
Further, ctDNA analysis identified many neoantigens not found by standard tumor tissue analysis. The ability to detect neoantigens that could not be found in resected tumor tissue suggests that a blood-based approach may provide a more representative view of the different neoantigens found in patients with metastatic disease, Gros explained. "Patients with advanced disease have tumors in different organs, so a biopsy of one tumor may not capture the neoantigens found in other lesions," she said. "By accessing the blood, we can identify neoantigens present across different tumor lesions, as well as T cells able to recognize them. This gives us a broader picture of the cancer throughout the body and could help us develop T-cell therapies that target multiple tumor lesions, making it harder for the cancer to escape treatment."
Additionally, they found that T cells isolated from the blood samples of six out of eight patients recognized and reacted to neoantigens identified by ctDNA and/or tumor tissue.
To evaluate the applicability of ctDNA for neoantigen discovery in a broader population, Gros and colleagues expanded their analysis to a separate cohort of 69 patients with various types of metastatic solid tumors. They found that ctDNA was detectable in 32 of 69 patients (46.4%) across solid tumor types, suggesting that a blood-based approach to neoantigen discovery may be possible in roughly half of patients. Among 17 patients with colorectal cancer, ctDNA was detectable in 14 (82.4%), including in patients with mismatch repair-deficient tumors, which typically express more neoantigens and are often treated with immunotherapies which target neoantigens.
Author's Comments: "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," said Gros. "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."
Gros also pointed to the potential of using the blood-based approach to examine how neoantigens and patient immune responses change during treatment, which could help clinicians monitor treatment responses and provide insights into tumor evolution and treatment resistance.
Study Limitations: Limitations of the study include the small patient population and the low prevalence of certain cancer types within the population. Gros noted that additional validation in larger patient cohorts is needed before the approach could be widely used in the clinic.
Funding & Disclosures: The study was supported by Merck; Comprehensive Program of Cancer Immunotherapy and Immunology (II) supported by the BBVA Foundation; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; La Fundació La Marató de TV3; Ministerio de Ciencia, Innovación y Universidades; and Generalitat de Catalunya (Government of Catalonia). Gros has received personal fees from Roche and has patents for E-085-2013/0 (licensed and with royalties paid from Intima Bioscience Inc. and Geneius Biotechnology, Inc.) and E-149-2015/0 (licensed and with royalties paid from Intima Bioscience Inc., Intellia Therapeutics Inc., and Tailored Therapeutics, LLC). Garcia-Garijo reports grants from Generalitat de Catalunya (Government of Catalonia).
