Changing the microbiome can improve responses to immunotherapy in humans.
Faecal transplants may help patients with advanced melanoma overcome resistance to immunotherapy, according to a small study published in Science in February.
Around 40% of patients with advance melanoma respond favourably to immunotherapy.
There’s a theory that has been gaining some traction lately that changing the microbiota of the other 60% of patients with advanced melanoma might help improve their response to immunotherapy – but this theory has mostly been tested in mice to date.
In one of the first trials in humans, researchers at the University of Pittsburgh in the US took faecal matter from melanoma patients who responded well to immunotherapy and delivered it via colonoscopy to patients with advanced melanoma who had shown immunotherapy resistance or no response at all.
A combination of faecal microbiota transplants and the anti-programmed cell death protein (PD-1) drug pembrolizumab saw six out of 15 patients experience a reduction in tumours or disease stabilisation for longer than a year.
Samples from these patients showed an increase in abundance of the types of bacteria that were previously shown to be associated with response to anti–PD-1.
These samples also showed immune cell activation (CD8+ T) and less immunosuppression activity (interleukin-8-expressing myeloid cells), both resulting in a better PD-1 response.
The results are among the first to show that changing the microbiome can improve responses to immunotherapy in humans.
“Our findings show that a single faecal microbiota transplants administered colonoscopically … reprogrammed the tumour microenvironment to overcome primary resistance to anti–PD-1 in a subset of patients with advanced melanoma,” the researchers said.
There were plenty of reasons the faecal transplants and immunotherapy would fail in a subset of patients with advance melanoma, such as a weak immune system, the absence of the specific bacteria needed to make the transplant effective or a failure of the transplant to successfully implant into the recipient, the researchers said.
“Our findings warrant further investigation in larger clinical trials to better identify microbial, circulating, and intra-tumoral biomarkers to select patients most likely to benefit from microbiome-based therapy of melanoma,” they said.
“We expect that such studies will lead to the identification of a bacterial consortium capable of converting a subset of melanoma patients primary refractory to anti–PD-1 therapy into responder patients.”
The researchers described faecal microbiota transplants as a means to an end, where the end was a probiotic or pill that contained the beneficial bacteria required for boosting a patient’s immunotherapy response. “Faecal microbiota transplants are difficult to implement in practice,” said Professor Maija Kohonen-Corish, the head of the Lung Cancer Centre at Woolcock Institute in Sydney.
“Transplants come from healthy donors, but how do you find these patients? If we knew which microbial strains work best with immunotherapy, it would be possible to manufacture these priobiotics for cancer patients.”
The hunt is on to identify which bacteria are the most helpful at promoting a favourable response to immunotherapy in cancer patients.
In 2018, mice with melanoma had their PD-1 responses enhanced when researchers boosted Bifidobacterium, one of the naturally dominant bacteria in the gut.
Professor Kohonen-Corish has proposed a genomics study, which is yet to be funded, to examine the intestines of patients receiving immunotherapy to identify which bacteria are most helpful.
An oncology trial in the US is rolling the dice with an undisclosed live strain of bacterium taken in pill form to see if it can reduce solid tumour sizes in patients with various kinds of cancer.
What goes into such a pill appears to be, at this stage, calculated guesswork.
The longer-term goal was to move beyond a pill containing rationally selected species, said microbiome expert Associate Professor Nadeem Kaakoush from UNSW.
“One of the complexities is that strains of the same bacterial species can behave differently, not only in how they engraft in the host but also how they influence the host’s immune response,” he said.
“The ideal scenario is that our understanding of the human gut microbiome develops to a point that we can profile a patient’s microbiome, use some form of AI to predict which microbial strains will engraft within their gut and bring about homeostasis, then provide that group of species to the patient in pill form,” he said.
