Cancer therapy has become increasingly personalized. Biomarker-driven treatment selection, targeted therapies, and immunotherapy have transformed outcomes across many tumor types and demonstrated the power of matching the right treatment to the right patient.
Yet even as precision medicine advances, a fundamental challenge remains. Many of our most successful strategies for improving outcomes rely on adding therapies, intensifying treatment or combining agents. One drug becomes two. Two drugs become three. That strategy has helped patients, but it has also increased the complexity and toxicity of cancer care.
The microbiome is intriguing because it may offer a different approach—one that improves outcomes without substantially increasing treatment burden.
Using the microbiome to influence outcomes
The relationship between the microbiome and cancer outcomes is no longer a novel concept. Decades of research in transplantation, cellular therapy and oncology have demonstrated that microbial communities influence clinical outcomes. Foundational research helped establish these relationships in transplantation, while subsequent studies expanded our understanding in cellular therapy and cancer.
Much of the work over the past decade has focused on understanding how the microbiome affects clinical outcomes. The opportunity now is to determine whether we can use the microbiome itself to influence those outcomes.
Testing the hypothesis
Our City of Hope-led research group has spent years studying CBM 588, an oral live bacterial product, in patients with advanced kidney cancer receiving immunotherapy. Two consecutive studies published in Nature Medicine evaluated immunotherapy with or without CBM 588. The studies demonstrated encouraging signals in progression-free survival, response rate and overall outcomes.
The most exciting aspect of microbiome research is not a single trial or a single therapeutic product. It is the possibility that we may improve efficacy without substantially increasing toxicity.
Encouraging signals are important, but they have to be tested in larger studies.
The launch of SWOG 2419 represents an opportunity to determine whether microbiome manipulation can meaningfully improve outcomes in a large patient population. The trial will evaluate the addition of CBM 588, now known as M003, to standard immunotherapy. It represents the first phase III evaluation of a live bacterial product in cancer therapy.
The trial is ultimately about more than a single product. It is an opportunity to determine whether the microbiome can become a therapeutic platform in oncology.
Rethinking drug development
The path from investigator-initiated research to a national phase III trial also reflects changes in how oncology research is conducted.
Historically, promising therapies advanced through a rigid sequence of clinical development. Increasingly, investigators are moving directly from strong early-phase data into definitive trials. Part of that shift reflects the need to answer important questions more quickly. The shift also reflects recognition that intermediate studies do not always provide definitive answers and can sometimes delay the evaluation of promising therapies.
At the same time, thoughtfully designed early-phase studies remain essential. Many of the design features incorporated into SWOG 2419 originated in earlier investigator-initiated studies at City of Hope, which established the scientific rationale for moving this approach into definitive testing.
Building the future through collaboration
A successful phase III study begins long before the phase III trial itself.
Progress depends on translational scientists, clinical investigators, cooperative groups and research networks working together. It also depends on mentorship. Much of the early work supporting CBM 588 was conducted by then-City of Hope postdoctoral fellows including Nazli Dizman, and Hedyeh Ibrahimi. Their contributions helped build the evidence that ultimately led to SWOG 2419.
These collaborations are essential because the questions we seek to answer are becoming increasingly complex. Success will require not only new drugs but also new ways of thinking about how we improve outcomes.
Looking ahead
The most exciting aspect of microbiome research is not a single trial or a single therapeutic product. It is the possibility that we may improve efficacy without substantially increasing toxicity. That hypothesis still requires definitive testing, but it has the potential to reshape how we think about cancer treatment development.
If successful, microbiome-based therapeutics could represent something oncology rarely experiences: a new mechanism for improving outcomes that does not depend on simply adding more treatment. Whether that promise can be realized is precisely the question SWOG 2419 is designed to answer.
City of Hope® is one of the largest and most advanced cancer research and treatment organizations in the U.S. To learn more about City of Hope, visit: www.cityofhope.org.
Discover the latest innovations in cancer research on City of Hope’s podcast, “On the Edge of Breakthrough: Voices of Cancer Research.” Available on Spotify, Apple Podcasts and at cityofhope.org/edge-of-breakthrough.
