Therapeutic targeting of immune checkpoints such as programmed death-ligand 1, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with ICB has revolutionized the treatment of advanced melanoma. Several landmark randomized controlled trials have shown notable and durable survival benefits, resulting in changes to standard of care internationally. Presently, over 50% of patients treated with a combination of PD-1 and CTLA-4 blockade are alive after five years.
The discovery of a link between the gut microbiome and response to ICB in melanoma and other tumours, highlighted the gut microbiome as a potential biomarker of response as well as a therapeutic target.
The same authors have previously showed that the gut microbiome prior to therapy can predict response to ICB (Lee et al. 2022, Nature Medicine). However, little was known about how the gut microbiome changes during ICB and how these changes affect therapy response and the development of side effects. First authors Johannes Björk and Laura Bolte from the UMCG investigated how microbial species and pathways changed during 12 weeks of ICB treatment, comparing patients who achieved progression-free survival at 12 months or longer to patients with progression free survival shorter than 12 months.
Bacterial species associated with response at baseline may reflect an “immunogenic profile” that confers a treatment benefit, whereas species that increase in abundance after the initiation of treatment only in patients with progression-free survival at 12 months or longer may reflect actionable targets for intervention strategies. These new findings could inform the design and application of microbiome-targeted interventions to maximize outcomes of ICB.
Recent early phase clinical trials conducted by other groups suggested that faecal microbiota transplants from responders (Baruch et al. 2021, Science; Davar et al. 2021, Science) or healthy donors (Routy et al. 2023, Nature Medicine), when combined with ICB, can induce treatment responses in patients that are refractory to ICB treatment or treatment-naive. However, there is large interindividual variability in the engraftment of donor strains and in the induced response to ICB. At the same time, cross-sectional studies have pointed towards a role for the microbiome in predicting ICB-response at baseline, but no single microbial species has emerged as a fully consistent biomarker across the various studies (Lee et al. 2022, Nature Medicine). This new study helps to reconcile these results.
This work was conducted in multiple centres across Europe and at the UMCG within the department of Medical Oncology (Rudolf Fehrmann, Liesbeth de Vries and Geke Hospers) and the department of Gastroenterology and Hepatology (Johannes Björk, Laura Bolte and Rinse Weersma). This research was made possible by patients’ participation in the following studies: COLIPI (NCT02600143), POINTING (NCT04193956) and Oncolifes (https://www.trialregister.nl/trial/7839) and supported by the Seerave Foundation (www.seerave.org) and the Dutch Cancer Foundation (KWF; grant number 10034).
Link to paper:
Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma
