The tiny alteration - sometimes only a single protein building block has been changed - gives the protein on the tumor cell surface novel immunological characteristics that can be recognized as "foreign" by the immune system's T cells. Therapeutic vaccines using a short protein fragment, or peptide, specifically containing the mutated site can then direct immune cells specifically to the tumor. A vaccine peptide must exactly match specific presentation molecules, called MHC molecules, on the surface of the tumor cells. This will only be possible if the cell has the appropriate molecular make-up. Immune cells will only respond if the antigen is displayed on the matching MHC molecules. If this is not the case, the body will fail to mount an immune response.
Even if cancer-specific neoantigens are present in tumor cells, this does not necessarily mean that they can be presented by the MHC molecules. Professor Michael Platten, of the German Cancer Research Center, Deutsches Krebsforschungszentrum, DKFZ, is working on a tumor vaccine and has been searching for a method to test, in tumor biopsies, whether or not MHC molecules display the neoantigen on the tumor cell surface.
Platten and colleagues have now described a solution to this problem: The PLA test - Proximity Ligation Assay - is based on the use of two antibodies, one that recognizes the neoantigen, and another that recognizes the MHC molecule. Only if the target structures of both antibodies are located in immediate proximity to each other will specific molecular-biological reactions produce a light signal.
The investigators demonstrated the effectiveness of the new test by using a tumor neoantigen found in brain cancer as an example. More than 70 percent of the time, specific brain tumors known as low-grade gliomas exhibit an identical "typo" in their DNA As a result, a single, specific protein building block in an enzyme called isocitrate dehydrogenase 1 (IDH-1) is exchanged at the 132nd position in the protein's sequence.
The researchers used their PLA test in tissue samples from glioma cells and were able to show that the IDH-1-mutated peptide is actually found on the surface of the cancer cells together with MHC molecules. The test worked equally well for another tumor antigen called NY-ESO-1. This antigen is not a mutation-induced neoantigen, but rather a protein in the body that normally only plays a role in certain developmental steps. In many types of cancer, however, it is produced "out of line" by cancer cells. The PLA test enabled the researchers to detect NY-ESO-1 in conjunction with MHC molecules in melanoma cells.
Numerous clinical trials are currently being conducted across the globe with the goal of testing promising vaccines and targeted immunotherapies, e.g. to treat malignant melanoma, renal cell cancer and lung cancer. "Our test could help identify those patients beforehand who might actually benefit from such a vaccination," says Lukas Bunse, one of the first authors of the study. He adds: "However, the prerequisite is that a specific antibody against the tumor antigen be available."
They would like to launch a clinical Phase I trial with the goal of evaluating the safety of the peptide vaccine against IDH-1-mutated glioma.
Citation: Lukas Bunse, Theresa Schumacher, Felix Sahm, Stefan Pusch, Iris Oezen, Katharina Rauschenbach, Marina Gonzalez, Gergely Solecki, Matthias Osswald, David Capper, Benedikt Wiestler, Frank Winkler, Christel Herold-Mende, Andreas von Deimling, Wolfgang Wick and Michael Platten: Proximity ligation assay evaluates IDH1R132H presentation in gliomas. The Journal of Clinical Investigation 2015,DOI: 10.1172/JCI77780
- New Test To Predict The Effectiveness Of Cancer Vaccines
- Novel Antigen-cloning Technique May Boost Efforts To Develop A Melanoma Vaccine
- Genomic Analysis Leads To More Accurate Classification Of Brain Tumors
- Genome Misfolding Unearthed As New Path To Cancer
- How A Master Regulator In Ovarian Cancer Can Go From Helpful To Harmful