Photo: MD Anderson researchers advancing brachyury-targeted immunotherapy
Brachyury (also called TBXT) is a hallmark and major driver of chordoma. It’s present in virtually all chordoma tumors and critical for their growth, but barely found in normal tissue — making it an especially promising target for therapies that attack tumor cells while sparing healthy ones. Figuring out how to exploit this vulnerability is among our top research priorities.
Immunotherapy, an approach that leverages the immune system to attack cancer cells, offers one promising path to targeting brachyury. But we first need to overcome a key obstacle: brachyury operates inside tumor cells, where it’s hidden away from the immune system.
Fortunately, our cells provide the immune system with a report on what’s happening inside by displaying tiny fragments (peptides) of their internal proteins on the cell surface via a structure called the major histocompatibility complex (MHC). Detecting abnormal peptides presented on MHC molecules is a key way immune cells can recognize, and then destroy, diseased cells. In recent years, researchers have found brachyury peptides presented on MHC molecules in chordoma and several other cancers in which brachyury is present, and have proposed various ways to target them.
Initially, research focused on developing vaccines that aimed to stimulate the immune system to mount an attack on cells displaying brachyury peptides. These were tested in a series of clinical trials for multiple cancers, including trials for chordoma which the Chordoma Foundation helped facilitate. Encouragingly, they succeeded in generating some degree of immune response against brachyury and several patients had their tumors shrink or stabilize. However, the vaccines failed to provide significant benefit to most patients, possibly because they couldn’t trigger a strong enough immune response or overcome the tumors’ defenses.
So we’re excited that, with support from the Chordoma Foundation and the Cancer Research Institute (CRI), a team of researchers at MD Anderson Cancer Center led by Cassian Yee, MD have made an important discovery: they identified new, more abundant brachyury-MHC peptides than the ones targeted by the vaccines, and they were able to generate T cells against these peptides that are able to effectively kill chordoma cells in the lab. This finding opens the door to applying multiple, more powerful immunotherapy approaches to brachyury-expressing tumors.
Building on this exciting progress resulting from our prior funding, Dr. Yee and a team of MD Anderson investigators have received a multi-million-dollar NIH grant to test a brachyury-targeted cell therapy in the first clinical trial of its kind. The trial, to be led by Anthony Conley, MD will open next year, evaluating whether this approach can safely and effectively treat chordoma patients.
In parallel with this trial, ongoing research at MD Anderson aims to develop and test next-generation immunotherapies targeting brachyury. To make that work possible, we and CRI recently awarded a new $300,000 grant for a two-year project led by Ke Pan, PhD in Dr. Yee’s group. With this grant, Dr. Pan and Dr. Christopher Alvarez-Breckenridge (also at MD Anderson) aim to engineer T cells that can better zero in on chordoma tumors and break through their defenses, testing this strategy in cell and animal models. Additional research is also planned to leverage other emerging immunotherapy technologies to target brachyury, and to extend these approaches to other brachyury-expressing tumors, potentially creating an incentive for even greater investment in this area.
Taken together, these milestones at MD Anderson mark real momentum in our quest to bring about effective brachyury-targeting immunotherapies: extending lab breakthroughs into preclinical development, and soon into the clinic. These immunotherapy approaches also complement our ongoing efforts to develop drugs that block brachyury’s function inside tumor cells — a potential one-two punch that could overcome possible mechanisms of resistance.
We’re grateful to the entire MD Anderson team for their dedication to this important research, and to CRI and our donors whose generosity has helped make it possible.
To stay up to date on more new developments in chordoma research and care, sign up for our newsletter.