Expert Case Study: Understanding How the Microbiome Can Make Immune Checkpoint Inhibitors Work Better for Cancer

In association with Dr. Andrew Y. Koh, a physician-scientist and Director of the Cellular and ImmunoTherapeutics Program at University of Texas Southwestern Medical Center and Children’s Health in Dallas.

The Convergence of Cancer Immunology and Microbiome Research

Years of research have shown clear connections between the human immune systems and the trillions of microbes living in and on us, with major implications for diseases – including cancer, where immunotherapies have proven to be blockbuster drugs against cancer. One notable possibility is in a class of therapies known as immune checkpoint inhibitors (ICIs), which have been extremely successful across a number of cancers – but only in a minority of patients.

“There have been a number of recent high-profile papers showing that patients who receive antibiotics before they get checkpoint blockade don’t seem to respond as well,” said Dr. Andrew Y. Koh, a physician-scientist who is Director of the Cellular and ImmunoTherapeutics Program at University of Texas Southwestern Medical Center and Children’s Health in Dallas. The antibiotics connection led to additional research that showed associations between ICI responders and certain non-pathogenic bacteria found in the human gut microbiome.

Exploring the Connection Between the Microbiome and Immune Checkpoint Inhibitor Response

Dr. Koh has long been interested in how the gut microbiome influences immune function. His research has explored how microbes impact stem cell transplant patients and graft-versus-host disease, as well as the role of Candida albicans – which is both an ubiquitous member of the human gut microbiota and a sometimes-dangerous opportunistic fungal pathogen. But the intersection of disciplines in the red-hot area of cancer immunotherapy is a natural draw for him: as a physician, he specializes in pediatric oncology, and he previously completed a dual fellowship in both infectious diseases and hematology/oncology at Boston Children’s Hospital and Dana Farber Cancer Institute.

To move beyond associations and understand what’s happening in these patients – hopefully in order to exploit it – Dr. Koh spearheaded a study to profile immune changes related to the microbiome during ICI therapy. This required a toolset that could sensitively measure the cytokines and proteins produced by immune cells, down to the single-cell level – and they identified IsoPlexis as best able to deliver this.

IsoPlexis’ Functional Proteomic Product Suite for Immune Profiling

His team utilized both IsoCode for single-cell cytokine profiling and CodePlex for high-sensitivity multiplexed bulk cytokine data analysis. “We use both modalities to try to understand how specific changes that we introduce – whether adding gut microbiota-based therapy or antibiotics – change the overall immune profile of a mouse or a human. And then particularly how that seems to correlate or provide insight into how it changes your response ICIs,” said Dr. Koh.

Dr. Koh was inspired to use CodePlex after a member of his lab used the platform to find a striking cytokine signature in plasma of patients with eating disorders like anorexia and bulimia, which another multiplex tool had missed. In the more recent experiments, his team used CodePlex to confirm its hypothesis that antibiotics reduced the antitumor T helper 1 (Th1) cell response.

Harnessing Microbes for Improved Cancer Immunotherapy Outcomes

The next big step: turning microbes into a therapy that can help ICIs work for more patients. Dr. Koh’s research helped secure three NIH grants to support understanding how the microbiota modulates immune checkpoint therapy, and development of an injectable microbiota-based therapeutic. The unconventional approach has so far been effective in animal models of cancer when combined with ICIs. He has also co-founded the biotech startup Aumenta Biosciences, which is now gearing up to do its first study in non-human primates. Dr. Koh expects the IsoPlexis platform will play a key part for quality control of the products to monitor cytokine responses in human immune cell lines.

“Having a multiplex ELISA platform – for both single cell and bulk – will be really helpful as we push this into patients. Because the question will be again, and again, and again: are you sure it’s safe?” said Dr. Koh.

Next Steps

There’s a kind of synergy working with IsoPlexis, said Dr. Koh, whose lab is interested in beta-testing some of the latest technology and looking to expand its applications. “We created an additional bioinformatics analysis pipeline to go along with their prepackaged software. We’re making it a two-way street.”

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