Learning from results of three recent brachyury vaccine trials

Take-home message for patients

Some results have been released from recent clinical trials. The trials tested vaccines aimed at harnessing the immune system to destroy cells that express brachyury. While the researchers saw some hints that the vaccines might be helpful to certain patients, further studies will be needed to understand how to best leverage the immune system against chordoma. A trial to test the next-generation brachyury vaccine is already underway, and brachyury remains a strong target for other types of therapies. Read on to learn more.

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We know that chordoma is a tricky adversary. So when a recent clinical trial testing a therapeutic vaccine came back with unsatisfactory results, we were disappointed, but wholly undeterred. After all, scientific progress is almost never linear — and perseverance is the name of the game in this community.

The vaccine, GI-6301, aimed to stimulate patients’ immune systems to seek out and destroy cells that express brachyury, which is present in chordoma but not in most normal cells. Unlike “prophylactic” vaccines designed to prevent disease (e.g., the flu vaccine), therapeutic vaccines like GI-6301 aim to help the immune system fight disease more effectively. A team led by Dr. James Gulley of the National Cancer Institute evaluated whether GI-6301 given in combination with radiation would be more effective than radiation alone in shrinking chordoma tumors or preventing tumor growth. Despite promising results in a Phase 1 trial, the vaccine’s Phase 2 trial didn’t demonstrate a sufficiently beneficial effect, and the study ended early. The findings are published in the May 2021 issue of The Oncologist.

Chordoma researchers gleaned critical insights from this work, however. For example, it was the first time that RECIST responses — the standard, if imperfect, measure of a cancer therapy’s effectiveness based on whether the widest part of a tumor shrinks significantly — were evaluated prospectively in chordoma patients treated with radiation. These data can serve as a baseline for the effects of radiation alone, which will be useful in designing and evaluating future clinical trials involving radiation. The trial also highlighted that a deeper understanding of how to disrupt chordoma’s ability to evade immune attack will be needed in order to effectively target chordoma with immunotherapy approaches. And it represents a major milestone: the first-ever randomized control trial for chordoma, and the first we supported through our Clinical Trials Program.

Importantly, a negative result from this trial doesn’t diminish the significant potential in targeting brachyury using other therapeutic vaccines. In fact, on the heels of the GI-6301 results came preliminary results from another Phase 2 trial testing a different brachyury vaccine called BN-Brachyury, made by the company Bavarian Nordic. Like the GI-6301 vaccine, BN-Brachyury showed promising initial results but did not meet its primary endpoint: RECIST responses in four out of 29 participants. However, two patients did achieve a partial response and 19 participants had stable disease according to RECIST criteria. Of those, several also experienced a reduction in the volume of their tumors, even if not sufficient to be counted as a RECIST response.

These hints of clinical activity prompted Bavarian Nordic to continue efforts to develop immunotherapeutic approaches to targeting brachyury for chordoma patients. Their next attempt was a Phase 1 trial that administered the vaccine intravenously in order to stimulate more than one aspect of the immune response. Unlike the previous Phase 2 brachyury vaccine trials, this one tested the vaccine alone — not in combination with radiation. Efficacy results from this study, though preliminary, are more exciting, showing a RECIST response in one patient and stable disease in several others. Additionally, two patients with stable disease reported significantly reduced pain symptoms. The work will be presented in a poster at this year’s ASCO Annual Meeting, taking place June 4-8, 2021.

Currently, a new trial is underway for chordoma and other cancer patients testing IV administration of Bavarian Nordic’s newest generation brachyury vaccine, called TAEK-VAC-HerBy, which builds upon the learnings from their earlier vaccine trials. Not only does it leverage intravenous administration, it’s designed to stimulate a more robust and intricate immune response.

Looking ahead

Taken as a whole, results from these trials signal, even if modestly, that immunological targeting of brachyury may provide clinical benefit to some chordoma patients. But they also suggest that additional strategies will be necessary to augment the immune response and/or to overcome chordoma’s resistance to immune attack. Further research is needed to understand how chordoma interacts with the immune system and what accounts for variability in response to therapeutic vaccines, which will help determine the full complement of support that the immune system might need to mount an effective response against chordoma.

These trials also reinforce previous clinical observations that have suggested that RECIST may underestimate treatment response for chordoma tumors. In addition, because immunotherapy takes time to work, longer study durations may be needed to observe a RECIST response. Thus, future chordoma trials may benefit from the development and validation of endpoints other than RECIST, such as reduction in tumor volume and/or symptomatic improvement.

Importantly, brachyury also remains a highly promising target for therapies not reliant on an immune response, with numerous promising drug discovery projects in the pipeline. So with great momentum, we’re redoubling our efforts to attack brachyury from multiple angles, accelerate basic immunology research, and make sure promising new clinical trials include chordoma patients.