In previous The Currently Incurable Scientist columns I have focused on one arm of the immune system: the adaptive immune system. Immune system activating therapeutic vaccines and drugs such as PD-(L)1 inhibitors which remove immunosuppression interact with the adaptive immune system. But there is also a more ancient and very powerful arm of the immune system called the innate immune system. Unlike the specificity seen with the components of the adaptive immune system, immune cells within the innate immune system, albeit very powerful, exert their actions in a more non-specific way. An example of this is inflammation which although non-specific, can activate the immune system in productive and potentially anti-tumor ways. One type of cell in the innate immune system connected to inflammation is the macrophage. Macrophages can either be pro-inflammation tumor fighting (“M1-subtype”) or anti-inflammation tumor helping (“M2-subtype”). Discovering ways to control macrophages and switch which sub-type they are is an intense area of current research. In colorectal cancer (CRC), macrophages within the tumor (“tumor-associated macrophages (TAMs)”) are often of the “tumor promoting” M2-subtype. An area of active research has been to switch (or as scientists say, “repolarize”) these macrophages into M1-subtype tumor fighters. As M1-subtype tumor fighters, macrophages can either attack cancer cells directly or serve as intermediaries to facilitate attack by the adaptive immune system.

CCR5 Antagonists and Macrophage Repolarization

Scientists have discovered that one of the master switches for determining whether a macrophage is tumor promoting (M2-subtype) vs. tumor fighting (M1-subtype) is the “CCR5 receptor.” This research has been recently published in the journal Cancer Cell. Luckily, drugs targeting the CCR5 receptor have been studied for years for other uses, e.g. for their anti-HIV properties. An “antagonist” of a receptor (e.g. CCR5) is a drug which turns that receptor off. In a small exploratory clinical trial (NCT01736813, 14 patients), patients received 300 mg twice daily the FDA-approved (for HIV treatment) commercially available drug Maraviroc (Selzentry™ or Celsentri™ outside the U.S.). Maraviroc is a CCR5 antagonist (meaning it turns off the receptor). The anti-CRC effects they saw in this small, preliminary patient population were encouraging:

• Extensive tumor necrosis without harm to adjacent healthy tissue
• Partial regression of lung metastases
• Reductions in pro-tumor growth & chemo resistance signals within the tumors, as macrophages were switched to a tumor-fighting M1-subtype
• Resensitization to various, previously failed standard of care chemotherapies used for CRC producing tumor regressions
• A well tolerated side effect profile with the most common side effect being elevation of liver enzymes

A follow-up larger confirmatory Phase 2 trial, including study arms combining Maraviroc with either immunotherapy or chemotherapy drugs, is slated to begin in Germany before the end of 2016. Since a number of CCR5 antagonists have been discovered over the years by various companies, it is likely that U.S.-based trials will be started as well, in order to attempt to confirm the preliminary Phase 1 results. Overall, the preliminary data is both intriguing and promising. Since CCR5 antagonists are well known, hopefully if positive effects in CRC patients are confirmed in larger clinical trials, this will facilitate a faster than average clinical development path. This is definitely a class of drugs to keep an eye on as new clinical data are generated! Sign up for the Fight CRC newsletter to get the latest research news.

ABOUT DR. TOM MARSILJE

Dr. Tom Marsilje is a >20-year oncology research scientist with “currently incurable” stage IV non-MSI colon cancer and is a Colon Club 2016 Colondar 2.0 model. He also writes a personal blog on life at the intersection of being both a cancer patient and researcher “Adventures in Living Terminally Optimistic” and posts updates to Twitter @CurrentIncurSci. As mentioned in his introductory post to this monthly column, he is a Ph.D. scientist and not a M.D. He exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice.

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