Evidence mounts for connection between gut microbiome and immune checkpoint inhibitors

There is growing evidence of the relationship between gut microbiota and the response of immune checkpoint inhibitors (ICI). This connection was discussed in detail during Monday, April 12, Forum Microbiome Pandemonium: Checkpoints and the Microbiome.

Laurence Zitvogel, MD, PhD

Laurence Zitvogel, MD, PhD, Institute Gustave Roussy, discussed the validation of the predictive role of Akkermansia muciniphila (A. muciniphila) for response and resistance to PD-1 blockade in non-small cell lung cancers (NSCLC).

Zitvogel said that about two years ago it was first reported in a mixed population of patients with advanced renal and lung cancers that A. muciniphila was the main bacteria associated with best response and progression-free survival at three months during PD-1 blockade.

This finding was then prospectively validated in a study of 311 patients with NSCLC; of these about 50 percent were A. muciniphila positive. The study showed that objective responders harbored A. muciniphila in about 65 percent of cases. For those with stable and progressive disease, 48 percent were A. muciniphila positive. Patients that harbored A. muciniphila had a median overall survival of 19 months, compared with 11.4 months in A. muciniphila-negative patients.

Zitvogel said that harboring A. muciniphila in the gut was associated with increased richness of the microbiome as measured by Shannon diversity. Within the population of positive patients there were two groups with different taxonomic composition; one was associated with prolonged overall survival, and the other with shorter overall survival.

The researchers segregated patients according to the 25th to 75th percentile for relative abundance of A. muciniphila and found that normal relative abundance of A. muciniphila predicted sensitivity to therapy and high relative abundance of A. muciniphila predicted resistance to therapy. The three groups, A. muciniphila low, A. muciniphila high, and A. muciniphila negative, differed in their taxonomic composition of the gut microbiome and also differed in composition of tumor microenvironment.

According to Zitvogel, a multivariate Cox logistic regression analysis showed A. muciniphila overruled PD-L1 and antibiotics to predict clinical benefit to PD-1 blockade. These findings were later validated in tumor-bearing mice, she said.

Fecal microbiota transplant

Gal Markel, MD, PhD, MBA
Gal Markel, MD, PhD, MBA

Gal Markel, MD, PhD, MBA, Davidoff Center, Rabin Medical Center, explained fecal microbiota transplantation to overcome resistance to anti-PD-1 therapy in metastatic melanoma patients.

The microbiota and immune system have a strong relationship and interplay, Markel said. Several publications have demonstrated strong correlations between the composition of the microbiome and response to anti-PD-1 therapy. Markel and colleagues conducted a study to ask if alteration of the microbiome would lead to an altered immune response and, ultimately, a clinical response.

They used donors with metastatic melanoma and durable ongoing complete response to anti-PD-1 and conducted fecal microbiota transplant to recipients with metastatic melanoma with progressive disease on at least one line of anti-PD-1 therapy or BRAFV600 mutant disease that progressed on targeted therapy. After fecal microbiota transplant, anti-PD-1 was reintroduced.

Two donors with very different microbiota composition were used, and 10 patients received treatment and reintroduction of anti-PD-1 therapy. Three patients achieved meaningful response; there were two partial responses and one complete response. All responders received transplant originating from Donor 1.

The protocol was safe with no observed grade 2 or higher fecal microbiota transplant- or immune-related adverse events, Markel said. The researchers also looked at microbiome alteration after two months into the protocol and found that recipient microbiomes became similar to their donors.

However, taxonomic analysis between Donor 1 and 2 and could draw no meaningful conclusions.

The trial will continue in an additional 41 patients using five new donors and will expand beyond metastatic melanoma to also include NSCLC.

Fecal bacteriome and response

Christian Jobin, PhD
Christian Jobin, PhD

Christian Jobin, PhD, University of Florida, discussed whether there is any consensus on whether fecal bacteriome signature is associated with immune checkpoint blockade efficacy.

Jobin and colleagues built on three existing studies of the gut microbiome’s relationship to immune checkpoint inhibition response to see if they could identify a signature that could predict responsiveness. They assembled data for microbial species from the three studies. When they looked at three different machine-learning examples to see if responsiveness could be predicted, none of the signals qualified. When the same data set were assembled for microbial functional pathways, machine learning could build a predictive curve.

“This made us think that functional convergence of microbial activities rather than specific species may associate with responsiveness,” Jobin said. “It is OK to have different bugs. They may have similar activities.”

In more recent years, more publications have looked at different cancer types for microbiome association with immune checkpoint inhibitors. One study performed whole genome metagenome and metatranscriptome on the intestinal biome of patients with melanoma treated with immune checkpoint inhibitors and found certain microbial pathways were associated with poor progression-free survival and certain others were associated with longer progression-free survival. However, similar pathways, either in negative or positive association, were found. Jobin noted that this finding does not bring enough clarity to draw a better understanding of how the microbes interact with the immune system.

This study did not look at biosynthetic gene clusters, so Jobin and colleague looked at published data and compared biosynthetic gene clusters between patients with short and long progression-free survival. Their results indicated that mining biosynthetic gene clusters could open new research avenues.

For now, Jobin said, there is still a lack of clarity about the function of microbes and the presence of microbes necessary for responsiveness.

Registrants can watch a replay of this forum through June 21, 2021.