Therapeutic modulation of the gut microbiome in oncology settings

The gut microbiome is exceedingly recognized for its role in supporting the anti-tumor functions of the immune system and response to immunotherapy with immune checkpoint inhibitors (ICIs). Recently, microbiome-modifying strategies are being explored for combination treatment with ICIs in different cancers. One strategy to modify a cancer patient’s microbiome is to use fecal microbiota transplantation (FMT) either from a treatment responder patient or a healthy donor. Both strategies have shown promising results in successfully changing melanoma patients’ gut microbiome and potentially conferring treatment response to ICIs.

We have shown that combining FMT from healthy donors to anti-programmed cell death-1 (PD-1) immunotherapy is safe in the first-line setting in advanced melanoma patients and associated with improved clinical response. In our study, patients who experienced a successful donor microbiome engraftment and retention, determined by longitudinal metagenomics shotgun sequencing and 16s rRNA gene sequencing, became responders to anti-PD-1 therapy. These patients also experienced changes in their metabolite profile measured in plasma including increase of histidine post FMT that was stable overtime. We have also observed enrichment of certain immunogenic bacteria in these patients post FMT such as Ruminococcaceae SGB15234 and SGB14909, Alistipes communis, and Blautia SGB4831. Conversely, non-responder patients had an overrepresentation of Enterocloster asparagiformis and Catabacter hongkongensis. We have also observed an increase in ICOS+ CD8+ T-cells in the peripheral blood of responders indicating of the activation of the immune system post FMT and anti-PD-1 combination therapy. Avatar mouse models colonized with patients’ stool confirmed the role of donor FMT in driving response to anti-PD-1 therapy in advanced melanoma patients.

Our results indicate that FMT from healthy donors is safe in the first-line setting in melanoma and can potentially improve clinical response. We are now testing combination of FMT with immunotherapy in lung cancer, melanoma, and renal cell carcinoma. We are also combining healthy donor FMT to chemotherapy in pancreatic cancer and to neoadjuvant chemoimmunotherapy in triple-negative breast cancer. More clinical and translational studies are required to further support the role of microbiome interventions in oncology.

Development of in vitro tools to study mature B cell malignancies using patient samples.

The landscape of the genomic, epigenomic and transcriptional features from patients with B-cell lymphomas has been described in several pivotal sequencing studies. These included chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), two lymphoid neoplasms characterized by the proliferation and accumulation of mature small CD5+ B cells. CLL is considered an indolent disease, whereas the clinical course of the majority of MCL patients is aggressive. However, the clinical evolution of both malignancies is very heterogeneous. While the prognostic significance of some of the described genomic and epigenomic alterations is known, their specific contributions to disease pathogenesis remains largely unexplored. Attempts to address this experimentally using CLL and MCL primary cells have encountered several challenges, mostly owing to the importance of the tumour microenvironment factors for the survival and proliferation of the malignant B cells. Thus, most experimental settings used include genetically modified mouse models for CLLor xenograft models for MCL, and human cell lines which have numerous discrepancies with human primary cells limiting the conclusions that can be draw from such experiments. Importantly, these model systems mostly recapitulate the more aggressive forms of both neoplasms, but they are not appropriate tools for studying the indolent subtypes of the disease. Thus, there is a need to directly apply molecular methods, such as stable gene transduction and CRISPR-Cas9 genome editing, in primary malignant B cells as they preserve the clinico-biological spectrum of CLL and MCL. To overcome these limitations, we have developed a method that permits gene transfer with high transduction efficacy and minimal toxicity, which allows the functional investigations of genes recurrently mutated in primary malignant B cells. We employed this technique to interrogate the molecular functions of NOTCH1 and NOTCH2, which are two of the most commonly mutated genes in B-cell lymphomas¹. Moreover, we have established a robust method for CRISPR-Cas9 editing of patient derived CLL and MCL cells². With it we have shown a permanent protein depletion that is maintained in any offspring cell enabling longer follow up of downstream analyses, even targeting several candidate genes simultaneously. Importantly, these methods permit to deepen into CLL and MCL biological complexity using directly primary samples, overcoming the current dependency on cell lines and murine models.

Clinicogenetic stratification to enable precision medicine in Parkinson’s disease

Neurodegenerative diseases like Parkinson’s disease (PD) represent a major burden for people worldwide and still no curative treatments are available. Trials aiming at discovering neuroprotective treatments failed, because they did not account for the clinical and pathophysiological heterogeneity of PD. Genetics of PD provided first insight into the complex mechanisms underlying this fastest growing neurodegenerative disease and enable first neuroprotective treatments. Based on genetic stratification and advanced cellular modelling using patient-based induced pluripotent stem cells (iPSC), important mechanisms of neurodegeneration were deciphered, that define first entry points to develop disease-modifying compounds for more targeted therapies. Together with novel biomarkers that for the first time allow a reliable diagnosis of PD and support a biological staging of the neurodegenerative process, novel strategies for early detection and clinical decision support. This translates into the increasing importance of high quality data related to people with PD and individuals at risk to develop neurodegeneration to define novel markers for target engagement and therapeutic outcomes. This now starts to be translated into novel strategies, not only better treatments, but – even more important – for first steps into precision prevention to decrease the impact of neurodegenerative diseases on our ageing societies.