A simple blood draw may one day replace the surgical biopsy as the starting point for designing personalized cancer immunotherapies, according to a new study published in Cancer Discovery, a journal of the American Association for Cancer Research. Researchers at the Vall d’Hebron Institute of Oncology (VHIO) in Spain have shown that the genetic material shed by tumors into the bloodstream, known as circulating tumor DNA or ctDNA, can be used to identify cancer-specific proteins called neoantigens, and that immune cells circulating in the same blood samples can often recognize those neoantigens. In many patients, the results obtained from blood closely matched, and in some cases exceeded, what conventional tumor tissue analysis could deliver.
Neoantigens are abnormal protein fragments produced by cancer cells as a consequence of the mutations they carry. Because these molecules do not appear on healthy cells, they are precisely the kind of molecular signatures the immune system can be trained to attack, making them attractive and comparatively safe targets for cancer vaccines and T cell-based therapies. The catch is that every patient’s tumor carries a unique set of mutations, so building a personalized immunotherapy requires first cataloguing which neoantigens are present in that individual’s cancer and finding immune cells capable of reacting to them. Until now, that cataloguing has depended almost entirely on analyzing tumor tissue obtained through biopsy or surgery.
That dependence creates a serious bottleneck in clinical practice. As Andrea Garcia-Garijo, PhD, a postdoctoral fellow and first author of the study, explained, many patients do not have easily accessible tumors, while others are simply not healthy enough to undergo an invasive procedure. A metastatic patient with lesions in the liver, lung, and bone may face repeated biopsies to capture the full diversity of their disease, and each procedure carries risk, cost, and delay. The VHIO team, led by senior author Alena Gros, PhD, group leader of the Tumor Immunology and Immunotherapy Group, reasoned that blood could solve this problem, since dying cancer cells continuously release fragments of their DNA into circulation, carrying with them a molecular record of the tumor’s mutations.
To test the concept, the researchers isolated and sequenced ctDNA from blood samples of six patients with metastatic melanoma, breast cancer, head and neck cancer, or colorectal cancer. From the sequenced mutations, they computationally predicted which would give rise to neoantigens, and then compared that list against the neoantigens identified through standard analysis of tumor tissue from the same patients. The overlap was striking: across all six patients, ctDNA analysis recovered between 63.25 percent and 97.4 percent of the neoantigens detected by conventional tissue-based methods. In other words, a tube of blood captured most of the therapeutic intelligence that a biopsy would have provided.
More remarkably, the blood-based approach also uncovered neoantigens that tissue analysis had missed entirely. This is not a technical fluke but a reflection of tumor biology. Patients with advanced disease harbor tumors in multiple organs, and each lesion can carry its own complement of mutations. A biopsy of a single lesion is therefore a sample of one outpost of a distributed enemy. Blood, by contrast, collects DNA shed from lesions throughout the body, offering a more representative census of the neoantigen landscape. Gros emphasized this point, noting that by accessing the blood, researchers can identify neoantigens present across different tumor lesions, as well as T cells able to recognize them, giving a broader picture of the cancer throughout the body and potentially enabling T-cell therapies that target multiple tumor sites at once, making it harder for the cancer to escape treatment.
The team did not stop at neoantigens. A second pillar of personalized immunotherapy is finding the patient’s own T cells that can react against those neoantigens, since these cells are the raw material for adoptive cell therapies and a key indicator of whether a tumor is immunogenic at all. When the researchers isolated T cells from the blood of the patients, they found that in six of the eight patients studied, circulating T cells recognized and reacted to neoantigens identified through ctDNA analysis, tissue analysis, or both. This demonstrated that the immune component of the personalized therapy equation, not just the tumor component, can be sourced from a peripheral blood sample.
To determine whether the approach could generalize beyond a handful of carefully selected cases, the researchers expanded their analysis to an independent cohort of 69 patients with a wide variety of metastatic solid tumors. Here the picture became more nuanced. ctDNA was detectable in 32 of the 69 patients, or 46.4 percent, suggesting that a blood-based route to neoantigen discovery may be feasible in roughly half of patients with solid tumors. Notably, among the 17 patients with colorectal cancer, ctDNA was detectable in 14, or 82.4 percent, including patients with mismatch repair-deficient tumors, a subtype that accumulates unusually high numbers of mutations, expresses more neoantigens, and is frequently treated with immunotherapies that depend on neoantigen recognition. For precisely the patients most likely to benefit from neoantigen-targeted treatment, the blood-based method appears most reliable.
The study also had its failures, and these are informative in their own right. In two of the initial eight patients, one with breast cancer and one with head and neck cancer, the researchers could not isolate ctDNA at all. Gros explained that this is consistent with the known behavior of some tumors, which shed very little DNA into the bloodstream. Tumor shedding rates vary with tumor type, stage, burden, and biology, meaning that blood-based neoantigen discovery will not be universal. For the substantial fraction of patients in whom ctDNA is detectable, however, the method could complement or even replace tissue analysis, and for patients whose tumors are inaccessible or who cannot tolerate a procedure, it may be the only viable option.
The clinical implications extend beyond the initial design of therapy. Because blood can be drawn repeatedly with minimal burden to the patient, the same approach could be used to track how the neoantigen landscape and the patient’s immune response evolve over the course of treatment. Gros pointed to this as a major opportunity: serial blood sampling could allow clinicians to monitor treatment responses in real time, watch for the emergence of resistant tumor subclones, and adjust therapy as the disease changes. In an era when immunotherapies are increasingly dynamic and combination-based, a monitoring tool that requires only a venipuncture rather than a repeat biopsy could fundamentally change how treatment decisions are made.
There are, of course, important caveats. The initial cohort was small, and certain cancer types were only thinly represented, so the reported detection rates carry wide uncertainty. Gros and her colleagues stress that validation in larger patient cohorts is needed before the approach can be adopted widely in the clinic. The computational pipeline for predicting neoantigens from DNA sequences remains imperfect, and detecting a neoantigen-encoding mutation in ctDNA does not guarantee that every tumor lesion expresses the corresponding protein. Still, the study establishes a proof of principle with a clear quantitative foundation: blood alone can recover the majority of tissue-derived neoantigens, reveal additional ones invisible to biopsy, and supply reactive T cells from the same sample. If larger studies confirm these findings, the biopsy, long the mandatory first step of precision oncology, may find itself sharing that role with something far simpler: a vial of blood.
Subject of Research: Blood-based identification of cancer neoantigens and neoantigen-specific T cells using circulating tumor DNA for personalized immunotherapy
Article Title: Blood could serve as a main source for finding cancer-specific proteins needed to develop personalized treatment
Article References: Blood could serve as a main source for finding cancer-specific proteins needed to develop personalized treatment. (n.d.). Original publication
Image Credits: AI Generated
DOI: Not provided
Keywords: ctDNA, neoantigens, liquid biopsy, personalized immunotherapy, T cells, metastatic cancer, melanoma, colorectal cancer, Cancer Discovery, tumor mutations, cancer vaccines, Vall d’Hebron Institute of Oncology
