Only 10 percent of colorectal cancer (CRC) patients, those with microsatellite-high unstable tumors, respond to immune checkpoint inhibitors.
Robert Coffey, M.D., Ingram Professor of Cancer Research, and Ken S. Lau, Ph.D., director of the Center for Computational Systems Biology at Vanderbilt, are focused on testing antibodies that inhibit tumor growth in the other 90 percent.
Coffey is co-director of the Epithelial Biology Center and the principal investigator of the Vanderbilt-Ingram Cancer Center Gastrointestinal Specialized Programs of Research Excellence (SPORE) which focuses on colorectal cancers. He sat down with Discoveries in Medicine to discuss the state of the research.
Discoveries in Medicine: Where did this work on immunotherapy-resistant tumors start?
Coffey: Until recently, there were no immunotherapies for any colorectal tumors.
Several years ago, I organized an American Association of Cancer Research CRC national meeting where a prominent physician-scientist named Luis Diaz Jr., M.D., introduced his findings that microsatellite unstable, locally advanced rectal cancers respond dramatically to immunotherapy. I can remember, at that meeting, people were just so excited about this practice-changing advance, knowing that those of us who have worked in the field for 25 to 30 years now finally had something that was really impacting tumors.
However, these microsatellite unstable CRCs make up only about 10 percent of colorectal cancers, so it really inspired Ken Lau and myself to look more carefully at genes that might be preferentially upregulated in the microsatellite stable CRC – genes that correlate with the absence of tumor-fighting CD8+ T cells.
Discoveries: What did you learn about how these microsatellite stable tumors thrive?
Coffey: Thanks to the Human Tumor Atlas Network and our SPORE studies, we have learned a lot about both types of tumors and their precursors in the colon.
In both cancers, CD8+ T cells are capable of destroying tumor cells. But the tumors, which are very clever, set up ways to block the tumor-killing properties of these T cells. In microsatellite unstable tumors, immunotherapy is effective because CD8+ T cells populate the tumor environment.
To put it simply, our overarching goal is to find a way to transform an “immune cold” tumor into one that is “immune hot,” so that immunotherapy can unleash the CD8+ T cells to kill cancer cells.
In microsatellite stable CRC, however, we find a paucity of these CD8+ T cells in and around the tumors. Until now, we had not found a proven means of inhibiting this ‘mmune exclusion’ mechanism and recruiting and activating the CD8+ T cells to kill the tumor cells. That interested Ken Lau and me and led to our discovery of three genes in microsatellite stable colorectal cancer that might thwart the CD8+ T cells from getting to the tumor in the first place.
To put it simply, our overarching goal is to find a way to transform an “immune cold” tumor into one that is “immune hot,” so that immunotherapy can unleash the CD8+ T cells to kill cancer cells.
Discoveries: What are the genes you discovered?
Coffey: We have found that DDR1, TGFBi and DPEP1 are preferentially upregulated in microsatellite stable but not in unstable tumors. They are critical to the tumor cell subterfuge.
The gene products are packaged as proteins into nanoparticles and small extracellular vesicles released from cancer cells, which function in transporting these tumor-promoting proteins into the tumor microenvironment and beyond.
These nanoparticles include supermeres, which we discovered in 2021. Supermeres secrete DDR1 and TGFBi into the extracellular microenvironment and are culprits in drug resistance. We believe they can either cause a physical barrier to be erected or facilitate signaling to macrophages to keep CD8+ T cells from approaching the tumor. DPEP1 recruits and binds neutrophils that are able to exclude CD8+ T cells from the tumor proper.
Discoveries: What are the interventions that might shut these genes down?
Coffey: Our current trial will test an antibody (peptide) PRTH-101, which binds to and blocks the DDR1 gene product from promoting immune exclusion. We also have plans to target DPEP1 with FDA-approved inhibitors to disable DPEP1’s enzymatic activity and a second agent to block neutrophils from getting to the tumor. We are also working with a colleague to deploy a TGFBi-neutralizing antibody to disrupt its immune-excluding properties.
Discoveries: What is the status of enrollment for the PRTH-101 antibody trial?
Coffey: Vanderbilt is now recruiting for a Phase 1 and Phase 1b clinical trial sponsored by Incendia Therapeutics. The 1b component is there so that if we are seeing success in the original study cohort, we can bring in microsatellite CRC patients and put them on an optimized dose of the antibody plus an immune checkpoint inhibitor.
Discoveries: What epidemiological trends are you seeing in CRC, and do these amplify the importance of this work?
Coffey: We’re seeing a rise in colorectal cancer among younger people.
There is a lot of interest in what is contributing to the increase in early onset CRC. But at this point, microbiome studies have not identified any specific cause linked to an increased development of early-onset CRC. As far as we know, we’re seeing basically the same kind of risk factors – diet, heredity, sedentary lifestyle – for both kinds of CRC. We are conducting projects to identify any specific factors that might elevate risk of onset.
Portions of this story were first reported in a VUMC News article by Tom Wilemon.
