Q&A: Dr. Miguel Zugman, 2025 KCA Grant Winner
Dr. Miguel Zugman received a 2025 KCA Trailblazer Award in partnership with Kure It Cancer Research for research on “Stool microbiome assessment in a randomized phase I trial of nivolumab and ipilimumab with or without EXL01 in the first-line treatment of metastatic renal cell carcinoma (mRCC)”. Dr. Zugman is a postdoctoral research fellow at City of Hope Comprehensive Cancer Center in Duarte, California. We spoke with him about his work and the impact it could have on people with kidney cancer.
Briefly describe your project.
Our project investigates microbiome-linked biomarkers present in stool specimens to predict response to immunotherapy in kidney cancer. The gut microbiome — the community of bacteria and other microorganisms that live in our digestive system — has been linked to immune function and can influence mechanisms of response or resistance to immunotherapy drugs, such as checkpoint inhibitors.
We will collect stool specimens from patients receiving first-line immunotherapy for clear cell renal cell carcinoma, at baseline and again after 12 weeks of therapy. These samples will be analyzed using metagenomic sequencing and computational profiling to characterize bacterial composition, diversity, and specific immune-related microbial signatures such as the TOPOSCORE, a composite biomarker reflecting microbiome health.
In addition, patients will receive, in a randomized 2:1 fashion, a novel live biotherapeutic product (LBP) called EXL01, composed of a single strain of Faecalibacterium prausnitzii, a bacterium shown to modulate the immune system through T-cell–mediated pathways. This will allow us to test whether microbiome modulation can enhance immunotherapy effectiveness in kidney cancer.
How difficult is it to determine the impact of a single gut bacteria type on treatment efficacy when our bodies are a complex biological system, there may be other medications involved, and lifestyle plays a role?
That is certainly one of the key challenges of testing microbiome-modulating interventions, since many factors — including diet, geographic region, age, and medications — affect a person’s microbiome composition.
Nevertheless, studies have consistently shown that specific bacterial strains can correlate with either response or resistance to therapy, and that dysbiosis (an unhealthy microbial imbalance) is associated with multiple disease states. Our best current definition of dysbiosis in the context of cancer immunotherapy is the TOPOSCORE.
By measuring individual TOPOSCOREs at baseline and after 12 weeks of therapy, we will correlate our findings with clinical outcomes and test both the biomarker’s ability to predict response and its intermediary effect in patients whose dysbiosis improves during treatment.
We hope to establish proof of concept — that improving one’s TOPOSCORE with a microbiome-modulating compound can increase the likelihood of responding to immunotherapy, regardless of baseline characteristics.
Do patients have access to any supplements or treatments at this moment that can influence how effective their treatment is? How soon might a product like the compound you’re working on be available?
That’s an excellent and very common question in clinic. Our research touches on an area that patients are eager to explore.
However, while many studies suggest promising effects of microbiome-modulating products, there was also a Science paper showing that patients who took over-the-counter probiotics actually had worse outcomes. So, despite growing interest, there are still many gaps in our knowledge. For now, we prefer to use these interventions within clinical trials, where they can be safely tested and carefully monitored.
On the other hand, the same Science study showed that high dietary fiber intake is associated with potentially better outcomes to immunotherapy. Therefore, we can confidently recommend increasing the intake of fruits and vegetables, the main natural sources of dietary fiber.
Regarding EXL01, the FDA has created a designated regulatory pathway for LBPs, which maintains the same safety standards as any drug while supporting their commercial development. Since EXL01 involves both a highly selected bacterial strain and a specific delivery system, full availability will require FDA approval for each intended clinical use.
Our trial will be the first to bring EXL01 to the United States. Four additional trials are currently ongoing in Europe — in liver, gastric, lung cancers, and inflammatory bowel disease — all showing encouraging and reassuring safety data so far.
What would you say to patients eagerly awaiting such a product?
As frustrating as it may sound, I would tell them to trust the scientific and regulatory process — its main purpose is to keep patients safe. The burden of proof is still on us as researchers. The best way to help is by supporting more studies, promoting clinical trial participation, and backing organizations like the Kidney Cancer Association that make this research possible.
What are the immediate treatment implications of your research?
If the TOPOSCORE or other microbial features in stool can reliably identify who will respond to immunotherapy, it would strengthen their use in clinical practice for decision-making. Developing a practical workflow for stool collection, processing, and rapid readout — one that integrates smoothly into routine oncology care — could be the next frontier.
What kind of next step or follow-on research questions do you think might come from your eventual findings?
Our next steps will focus on understanding how shifts in the microbiome, and specifically the reversal of dysbiosis, may influence treatment outcomes. We aim to validate and further develop the TOPOSCORE as a biomarker to guide microbiome-targeted strategies in immuno-oncology and to identify opportunities to personalize these interventions across different cancer types.
What about your research could be most exciting for patients and families?
One concern with microbiome research and lifestyle-based findings is that they can sometimes be misinterpreted in a way that creates guilt — for example, “If only I had eaten more fiber” or “If only I hadn’t taken antibiotics.” I worry about patients blaming themselves for factors outside their control.
That’s why I find the investigation of live biotherapeutics so exciting: it offers a way to modulate the microbiome safely and effectively, without placing that burden on patients. Not that healthy habits aren’t important, but the goal is to develop interventions that can benefit everyone — not just the exceptionally motivated few. That sense of broad accessibility is what excites me the most.
What motivates you?
Patients and their families are at the center of everything we do. I feel deeply grateful to care for people when they are at their most vulnerable — every patient is a world of their own. As a medical oncologist, I learned early on that the journey matters, and I feel privileged to be part of it.
Research, on the other hand, fuels my curiosity. It allows me to transform questions that arise in the clinic into discoveries that may one day come full circle to benefit patients. It’s also profoundly collaborative — bringing together basic and translational scientists, research nurses, and many other dedicated professionals. That close teamwork reminds me how interconnected our efforts are, and how progress in science often depends on collective, incremental steps. It challenges you to develop new skills, think differently, and grow — and that process is deeply rewarding in itself.
I must acknowledge that an opportunity like this would never have been possible if not for my mentor, Dr. Sumanta Pal. His outstanding example, constant support, and trust have been central to my growth as both a clinician and researcher.
What else do you want others to know about your research?
Our goal is to bridge science and patient care. By integrating microbiome research into oncology, we hope to better understand why treatments work for some patients and not for others. Incorporating microbiome biomarkers and microbiome-modulating interventions into clinical trials may help move us toward a future in which treatment decisions are guided not only by tumor genetics but also by each patient’s microbial and immune profile — and where that understanding can ultimately make immunotherapy more effective and safer.