Advancements in immunotherapy have proven instrumental in reshaping the face of cancer research in recent years. While these therapies can send patients with advanced cancers, who recently had no therapeutic options into remission, many patients remain unresponsive. To increase the number of patients who receive life-saving benefits of immunotherapy, a major focus of immuno-oncology research focuses on developing combination therapies involving immune-related modalities. The research community actively researches the efficacy of combining immunotherapy with radiation, chemotherapy, targeted therapies, and even other immunotherapies. Other research groups explore immunotherapeutic approaches in combination with novel interventions like beta-blockers, exercise, and diet.
It might appear that just about anything is worth testing in combination with immunotherapy! Enter another tactic- fecal transplants. (Yes, that is exactly what it sounds like!) Fecal transplantation (also referred to as fecal microbiota translation, intestinal microbiota transplant, stool transplant, and bacteriotherapy) involves inserting healthy bacteria from a donor's fecal matter into the recipient's colon. Doctors can perform fecal transplants by colonoscopy in which a long, flexible tube is inserted into the colon, releasing the donor feces. Alternatively, the donor feces can be freeze-dried and inserted into capsules for the recipient to swallow.
Patients with severe Clostridium difficile (C. diff) infections, which occur when antibiotics deplete helpful (“good”) bacteria from the colon, allowing “bad” bacteria to take over, receive fecal transplants. If successful, fecal transplants restore the recipient's bacterial landscape, also known as the microbiome.
Is it possible that fecal transplant could help patients respond more favorably to immunotherapy? Many experts believe the answer is yes! Two seminal reports, both published in Science, paved the way for this intriguing possibility. Last week a Feature in Nature explored this concept in depth.
The first study, published in December 2020, conducted a phase 1 clinical trial testing fecal transplantation in combination with αPD-1, an immune checkpoint inhibitor, for patients with metastatic melanoma who have not responded to αPD-1 alone. The trial enrolled ten patients, with three demonstrating clinical responses to the combined fecal transplant and immunotherapy. The researchers examined the participants' gut and tumors and observed that responding patients exhibited favorable immune cell and gene expression profiles. These findings indicate that the fecal transplant aided in driving anti-tumor immunity on both a cellular and genetic level.
The second study, published in February 2021, also explored the combination of αPD-1 and fecal transplant in non-responsive melanoma patients. This trial enrolled 15 participants, and six experienced clinical benefits. The responders in this study also demonstrated characteristics associated with immunotherapy benefits. For example, responding patients had more active CD8+ T cells, the immune cells responsible for killing cancer cells. The gut microbiota in patients who responded to αPD-1 plus fecal transplant also displayed distinct genetic signatures from the non-responders. This study concluded that the unique combination therapy favorably altered the microbiome and the tumor microenvironment.
While using fecal transplants to boost immunotherapy remains an exciting possibility, scientists still have much to learn before fully understanding how these treatments interact. Large-scale clinical trials could uncover what microbes help boost immunotherapy. Additional studies may also help identify the patients most likely to benefit from a re-vamped microbiota!