A newly developed method that combines sequencing with bioinformatics can help monitor the effectiveness of immunotherapy in patients being treated for cancer, according to Johns Hopkins researchers.
Their study, “The Mutation-Associated Neoantigen Functional Expansion of Specific T Cells (MANAFEST) Assay: A Sensitive Platform for Monitoring Antitumor Immunity,” was published in the journal Cancer Immunology Research.
One of the key roles of T-cells, a type of immune cell, is helping to fight cancer. Patients with cancer can develop T-cells that are specifically targeted toward mutation-associated neoantigens (MANA).
MANA are antigens (a protein molecule capable of inducing an immune response) encoded by mutated genes in tumor cells. They are produced by the tumor and then displayed on the surface of tumor cells. This puts MANA in a prime position for T-cells to recognize them and attack.
But these MANA-specific T-cell responses are opposed by immunosuppressive signals that are naturally present in our body, known as checkpoints.
Therefore, treatments that overcome these checkpoints — a term called checkpoint blockade — cause the body to develop high levels of MANA-specific T-cells.
High levels of MANA-specific T-cells have been associated with tumor regression in patients who achieve clinical responses. So monitoring the population of these MANA-specific T-cells can help assess response to treatment.
Unfortunately, there is a lack of sensitive and specific T-cell tests, or assays, that can help physicians and researchers determine the repertoire of MANA-specific T-cells present in patients.
Current approaches to determine T-cell anti-tumor activity involve looking at levels of cytokines, which are secreted by T-cells. These are not useful in identifying individual subtypes of T-cells.
In this study, researchers developed the FEST (functional expansion of specific T-cells) assay, which combines sequencing of the T-cell receptors — which identify and bind the antigens — with a bioinformatics platform that can help identify the antigen with the T-cells that are targeted.
This FEST assay can be used to identify tumor-associated antigens (TAAFEST), viral antigens (ViraFEST), and MANAs (MANAFEST).
Researchers show that the MANAFEST assay, which is supported using a web-based analytic platform, is able to appropriately identify the MANA-specific T-cell subpopulations.
These subpopulations can also be matched to the subpopulations detected in tumor tissues and in the blood of cancer patients treated with checkpoint blockades.
“MANAFEST can therefore validate the tumor specificity of [MANA-specific T-cell subpopulations], interrogate the dynamics of the antigen-specific T-cell response over time, and monitor the efficacy of checkpoint blockade using liquid biopsies obtained before or after treatment,” the investigators wrote.
Researchers hope that this bioinformatics platform, which can be conducted using blood, tumor, and normal tissue, may allow physicians to monitor the effectiveness of checkpoint blockade treatment.
“Once people are diagnosed with cancer, we hope to use this procedure to develop the best treatment options for them,” senior author Kellie Smith, PhD, of the Johns Hopkins Kimmel Cancer Center, said in a press release.
“Previously, the technology [for MANAFEST] wasn’t there. In the last few years, the technology has evolved to enable us to come up with the way to analyze the data to help patients,” Smith said.
