Immunotherapies: a Phase II study confirms the benefit of combined FMT
A new step in the evaluation of FMT to improve response to immunotherapies: a Phase II study confirms its effectiveness, with the transplant helping eliminate bacteria linked to poor treatment response. 1
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(sidenote:
Immune checkpoint inhibitors (ICIs)
Therapies that seek to remove the mechanisms that inhibit the immune system’s response to cancer cells. Targeted checkpoints include Programmed Death-1 (PD-1), Programmed Death-Ligand 1 (PDL-1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Lifting these brakes allows the immune system to recognize and attack cancer cells.
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(ICI) have improved the prognosis of non-small cell lung cancer (NSCLC) and cutaneous melanoma, but more than half of patients remain resistant.
Fecal microbiota transplant (FMT) could help overcome resistance to (sidenote: Anti-PD-1 immunotherapy based on immune checkpoint inhibitors that target the PD-1 checkpoint, reversing the deactivation by the tumor of the recognition system associated with the PD-1 protein present on the surface of T lymphocytes. The immune system’s effectiveness against tumor cells is thus restored. ) : successful mouse trials, two Phase I clinical trials providing initial proof of concept, then the MIMIC Phase I trial demonstrating the safety of FMT from healthy donors to reduce primary resistance to anti-PD-1 treatment in patients with cutaneous melanoma.
1st Lung cancer is the leading cause of cancer cases and deaths worldwide with an estimated 2.5 million new cases and 1.8 million deaths in 2022. ²
2 The 2 main types of lung cancer are non-small cell lung cancer (NSCLC), which accounts for around 85% of cases, and small cell lung cancer (SCLC), which is less common but typically more aggressive. ²
39-45% Patients with NSCLC are treated with single-agent anti-PD-1 such as pembrolizumab, with an expected objective response rate (ORR) of 39−45%. ¹
Confirmed efficacy in Phase II
Hence the interest in the multicenter Phase II FMT-LUMINate trial, evaluating FMT from healthy donors combined with anti-PD-1 monotherapy in NSCLC (n = 20) or with dual immunotherapy (anti-PD-1 + (sidenote: Anti-CTLA-4 immune checkpoint inhibitor that targets the CTLA-4 checkpoint ) ) in cutaneous melanoma (n = 20). Eligible patients received one dose of FMT before immunotherapy. Ten healthy volunteer donors (10 in the NSCLC cohort, 6 in the melanoma cohort) provided stool samples.
The results demonstrate the clinical efficacy of FMT:
- for NSCLC, combined with anti-PD-1 therapy, the (sidenote: Objective response rate (ORR) Proportion of responding patients (who showed a complete or partial response), as opposed to patients with stable disease or disease progression. ) was 80% (16 of 20 patients), exceeding the predefined primary objective of 64%. Without FMT, ORR ranges from 39 to 45%.
- for melanoma, combined with anti-PD-1 and anti-CTLA-4, ORR was 75% (15/20) vs. 50–58% without FMT.
The disappearance of harmful bacteria
After FMT, patients’ gut microbiota was modified, without strong similarity to the donor. More importantly, the authors show that the clinical response is not related to the acquisition of new bacteria from the donor; it depends mainly on the disappearance of bacteria present in the patient before treatment, including species such as Enterocloster citroniae, E. lavalensis and Clostridium innocuum. Enterocloster and Clostridium spp. are known to be associated with poor response to immunotherapy and sometimes with unfavorable inflammatory profiles.
This loss of certain bacteria changes microbial metabolism, reducing tryptophan pathways involved in immunosuppression, and creates a more favorable immune environment with more cytotoxic T cells and fewer regulatory cells.
17th Skin melanoma is the 17th most common cancer and the 22nd leading cause of cancer death worldwide, with an estimated 332,000 new cases and 59,000 deaths in 2022. ³
50−58% In patients with melanoma, dual therapy with ipilimumab (anti-CTLA-4) in combination with nivolumab (anti-PD-1) is among the most commonly used frontline regimens, yielding an ORR of 50−58%. ¹
Safety assessment of FMT
In terms of safety, FMT was well tolerated in patients with NSCLC receiving anti-PD-1, with no adverse events of grade ≥3.
However, in the melanoma cohort receiving dual immunotherapy, adverse events were observed in 65% of patients, as well as a higher-than-expected rate of myocarditis in those who received FMT from a donor whose microbiota was enriched with Prevotella, including (sidenote: Segatella copri Segatella copri: formerly named Prevotella copri clade A., P. copri is not a single homogeneous species but a complex made up of 4 distinct genetic lineages (clades A, B, C, and D) with strong functional diversity. These lineages are often found together in non-Westernized populations (presence of all 4 clades, sometimes except D) but are much less frequent in Westernized populations (presence of A and B, A, or none). The decline of P. copri in Western-lifestyle populations may be linked to lifestyle and dietary changes associated with modernization. Source: Tett A, Huang KD, Asnicar F et al. The Prevotella copri Complex Comprises Four Distinct Clades Underrepresented in Westernized Populations. Cell Host Microbe. 2019 Nov 13;26(5):666-679.e7. ) . These adverse events were not seen in NSCLC patients treated with anti-PD-1 alone and receiving FMT from the same donor. This suggests an interaction between microbial taxa (involving Prevotella) and the type of immunotherapy (dual PD-1/CTLA-4).
Another lesson can thus be drawn from the study: selecting healthy donors is essential and remains to be defined.
