Dynamic profiling of immune microenvironment during anti-PD-1 immunotherapy for head and neck squamous cell carcinoma: the IPRICE study.

BACKGROUND: Immune checkpoint inhibitors of programmed cell death protein 1 (PD-1) represent a significant breakthrough in treating head and neck squamous cell carcinoma (HNSCC), with long-lasting responses and prolonged survival observed in first- and second-line therapy. However, this is observed in < 20% of patients and high primary/secondary resistance may occur. The primary objective of the identification of predictive factors for the response to anti-PD-1 immunotherapy in head and neck squamous cell carcinoma (IPRICE) study is to identify predictive factors of response to anti-PD-1 immunotherapy. METHODS: The IPRICE study is a single-center, prospective, non-randomized, open-label, and interventional clinical trial. Liquid and tumor biopsies will be performed in 54 patients with recurrent/metastatic (R/M) HNSCC undergoing anti-PD-1 immunotherapy alone to compare the evolution of gene expression and immunological profile between responders and non-responders. We will use a multidisciplinary approach including spatial transcriptomics, single seq-RNA analysis, clinical data, and medical images. Genes, pathways, and transcription factors potentially involved in the immune response will also be analyzed, including genes involved in the interferon-gamma (IFN-γ) pathway, immunogenic cell death and mitophagy, hypoxia, circulating miRNA-mediated immunomodulation, cytokines, and immune repertoire within the tumor microenvironment (TME). With a follow-up period of 3-years, these data will help generate effective biomarkers to define optimal therapeutic strategy and new immunomodulatory agents based on a better understanding of primary/secondary resistance mechanisms. Tumor biopsy will be performed initially before the start of immunotherapy at the first tumor assessment and is only proposed at tumor progression. Clinical data will be collected using a dedicated Case Report Form (CRF). DISCUSSION: Identifying predictive factors of the response to anti-PD-1 immunotherapy and optimizing long-term immune response require a thorough understanding of the intrinsic and acquired resistance to immunotherapy. To achieve this, dynamic profiling of TME during anti-PD-1 immunotherapy based on analysis of tumor biopsy samples is critical. This will be accomplished through the anatomical localization of HNSCC, which will allow for the analysis of multiple biopsies during treatment and the emergence of breakthrough technologies including single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. TRIAL REGISTRATION: Clinicaltrial.gov. Registered April 14, 2022, https://www. CLINICALTRIALS: gov/study/NCT05328024 .

Selective aminopeptidase-N (CD13) inhibitors with relevance to cancer chemotherapy.

Aminopeptidase-N (APN/CD13) is highly expressed on the surface of numerous types of cancer cells and particularly on the endothelial cells of neoangiogenic vessels during tumourigenesis. This metallo-aminopeptidase has been identified as a potential target for cancer chemotherapy. In this work, we evaluated the efficacy of a novel series of benzosuberone analogues, which were previously reported to be highly potent, selective APN inhibitors with Ki values in the micromolar to sub-nanomolar range. Endothelial cell morphogenesis as well as cell motility were inhibited in vitro in a dose-dependent manner at concentrations that correlated with the potency of the compounds, thus confirming the key role of APN in these established models of angiogenesis. We report toxicity studies in mice showing that these compounds are well tolerated. We report the effects of the compounds, used alone or in combination with rapamycin, on the growth of a select panel of tumours that were subcutaneously xenografted onto Swiss nude mice. Our data indicate that the in vivo efficacy of these new APN inhibitors during the initial phase of tumour growth can be ascribed to their anti-angiogenic activities. However, we also provide evidence that these compounds are effective against established solid tumours. For colonic tumours, the anti-tumour effect depends on the level of APN expression in epithelial cells, and APN expression is associated with down-regulation of the transcription factor HIF-1α. These effects seem to be distinct from those of rapamycin. Our finding that the anti-tumour effect of the inhibitors in the colon requires APN expression strongly suggests that APN plays a crucial function in tumour cells that is distinct from its known role in neovascularisation.

Liposomal encapsulation of trans-crocetin enhances oxygenation in patients with COVID-19-related ARDS receiving mechanical ventilation.

Current therapeutic treatments improving the impaired transportation of oxygen in acute respiratory distress syndrome (ARDS) have been found to be relevant and beneficial for the therapeutic treatment of COVID-19 patients suffering from severe respiratory complications. Hence, we report the preclinical and the preliminary results of the Phase I/II clinical trial of LEAF-4L6715, a liposomal nanocarrier encapsulating the kosmotropic agent trans-crocetin (TC), which, once injected, enhance the oxygenation of vascular tissue and therefore has the potential to improve the clinical outcomes of ARDS and COVID-19 in severely impacted patients. We demonstrated that the liposomal formulation enabled to increase from 30 min to 48 h the reoxygenation properties of free TCs in vitro in endothelial cells, but also to improve the half-life of TC by 6-fold in healthy mice. Furthermore, we identified 25 mg/kg as the maximum tolerated dose in mice. This determined concentration led to the validation of the therapeutic efficacy of LEAF-4 L6715 in a sepsis mouse model. Finally, we report the preliminary outcomes of an open-label multicenter Phase I/II clinical trial (EudraCT 2020-001393-30; NCT04378920), which was aimed to define the appropriate schedule and dosage of LEAF-4L6715 and to confirm its tolerability profile and preliminary clinical activity in COVID-19 patients treated in intensive care unit.