Université de Paris

The invention relates to a method for treating cancers. Many cancers harbour sternness signature to de-differentiate into immature progenitors confer to tumor clones the re-expression of genes from fetal development. Inventors have obtained mice per group which received two boosts of vaccine 7 and 14 days with 2×106 irradiated hESCs cells that were mixed with 3 different adjuvants: 500 μg of TLR3, 50 μg of TLR9 agonist or 50 μg/ml of Quil A® Saponin vaccine adjuvant. After 14 days 5×104 4T1 cells were injected into the mammary fat pad of the mice and Valproic acid added in the drinking water at the dose of 4 mg/ml. They have shown that in contrast to the non-vaccinated mice, the mice vaccinated with hESC combined with a TLR3 agonist have generated the highest reduction of breast tumor volume (p<0.001) compared to the use of a TLR9 agonist or to Quil-A® Saponin vaccine adjuvant. Accordingly, the invention relates to a method for treating a subject suffering from a cancer with i) an agent that induces MHC-I presentation of antigens, ii) a vaccine composition containing an immunogenic element and iii) an adjuvant.

The present invention provides novel compounds of formula (I) and pharmaceutical compositions containing these compounds. The compounds of formula (I) can act as CXCR4 modulators that specifically target the CXCR4 minor pocket, and they have further been found to inhibit the production of inflammatory cytokines in immune cells, which renders these compounds highly advantageous for use in therapy, particularly in the treatment or prevention of an inflammatory disorder, an autoimmune disorder, an autoinflammatory disorder, or an interferonopathy, such as, e.g., systemic lupus erythematosus, dermatomyositis or rheumatoid arthritis.

The present invention concerns a thermosensitive polymeric hydrogel comprising at least one thermosensitive copolymer, one aqueous solution, and a mucoadhesive excipient, wherein said thermosensitive polymeric hydrogel further comprises at least one immunostimulatory adjuvant and/or at least one cytokine and/or at least one chemokine and/or atleast one heat shockprotein. Another object of the invention is a thermosensitive polymeric hydrogel according to the invention for use in the treatment of tumors or metastasis in a subject having a cancer, preferably a metastatic cancer.

The inventors assessed in locally advanced rectal cancer whether a diagnostic biopsy-adapted Immunoscore (ISg) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy (“Watch-and-Wait”). The inventors showed that IS B was an independent parameter, more informative than pre- (P<0.001) and post-nT (P<0.05) imaging to predict disease-free survival. IS B combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. Accordingly, the present invention relates to methods for predicting the recurrence and/or death of patients suffering from a solid cancer after preoperative adjuvant therapies.

Obesity is associated with low-grade inflammation in adipose tissue (AT) and dysfunctional adipocytes producing inflammatory molecules. A recent study reveals profound MAIT cell abnormalities inpatients harboring metabolic disorders, suggesting their potential role in these pathologies. Now the inventors show that MAIT cells induce adipose tissue and ileum dysfunction and inflammation in obese mice. Moreover, the inventors show that a treatment with an agent capable of inhibiting the activation of MAIT cells (i.e. Ac-6-FP) during high fat diet (HFD) improved metabolic parameters and in particular insulin sensitivity. Thus the present invention relates to the use of an agent capable of inhibiting the activation of MAIT cells for the treatment of obesity and obesity-related disorders.

As advanced cancer has poor prognosis, its detection and treatment at the earliest stages is critical to increase cancer survival rate. Therefore, elucidating the determinants of the intra-lesion immune reaction during cancer's developments is critical for moving into precision medicine and immunotherapy-based cancer prevention. Adaptive immune response within tumors was shown to be the strongest at the earliest stage of carcinoma. Thus, the inventors hypothesized that the immune microenvironment and adaptive immunity were first established at early stage of lung carcinogenesis. Here they identified changes in the tumor molecular profile and its microenvironment during the successive steps of lung squamous carcinogenesis, using gene expression profiling and multispectral imaging. A unique and invaluable dataset of (9) morphological stages of development was analyzed, including (122) well-annotated biopsies from (77) patients. In particular, the inventors show that immune activation and immune escape occur before tumor invasion, and that immunosuppressive cytokines and checkpoint receptors immune escape mechanisms are concomitant with anti-tumor immunity in high-grade dysplasia. Thus, the present invention relates to methods of predicting and preventing cancer in subjects having premalignant lesions.

Some rare and very severe autoimmune conditions are of hereditary origin such as APECED and IPEX syndrome due to altered negative selection of autoreactive T cells in the thymus or absence of regulatory T cells (Treg). Innovative strategies based on the use of regulatory T cells have been developed. The inventors have now compared 7 different experimental protocols to identify the one allowing to get the most efficacy of Treg to treat Scurfy autoimmune syndrome, a severe autoimmune model mimicking IPEX syndrome. The optimized protocol comprised a preconditioning step using cyclophosphamide and a post-conditioning step using IL-2. Thus, to present invention relates to a method for the treatment of autoimmunity in patient in need thereof comprising the steps of i) administering the patient with an amount of cyclophosphamide, ii) then engrafting the patient with an amount of the population of Treg cells, and iii) finally administering the patient with an amount of IL-2.

The present invention relates to use of soluble CD27 as a biomarker to predict the response to an immune checkpoint inhibitor treatment. Inventors have worked with two cohorts of patients and have identified a soluble marker, CD27, present in the plasma of patients with renal cell cancer whose pre-treatment concentrations predict the response to anti-PD-1/PD-L1. This marker appears more as a predictive marker of response to anti-PD1/PD-L1 treatment, than as a prognostic marker. Indeed, it is not associated with better survival in patients with metastatic renal cell cancer treated with an antiangiogenic agent. This marker is not correlated with conventional clinical markers of severity that classify patients with metastatic renal cancer.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by unleashing exhausted CD8+ T-cell thereby restoring anti-tumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Here, the inventors show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T-cells, interacts and enhances PD-1 activity. In mice, CD8+ T-cell specific deletion of Nrp1 improves spontaneous and anti PD1 antibody anti-tumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T-cells QI predicts poor outcome of patients treated with anti-PD1 (e.g. pembrolizumab). Finally, the combination of anti-NRP1 and anti-PD1 antibodies is synergistic in human, specifically in CD8+ T-cells anti-tumor response. Thus the therapeutic inhibition of NRP1 alone or combined with an immune checkpoint inhibitor (e.g. anti-PD1 antibody) could efficiently repress tumor growth in human cancer. The present invention also relates to multispecific antibodies comprising at least one binding site that specifically binds to an immune checkpoint molecule (e.g. PD-1), and at least one binding site that specifically binds to NRP-1. The present invention also relates to a population of cells engineered to express a chimeric antigen receptor (CAR) and wherein the expression of NRP-1 in said cells is repressed.

The present invention relates to nanoparticles, kits, methods and compositions which are suitable for increasing the number of B regulatory (B reg ) cells in a population of B cells; for producing Interleukin-10 (IL-10) or TGF-β. The inventors have shown that biocompatible nanoparticles comprising an antigen may be used for inducing B regulatory (B reg ) cells. This production, either ex vivo, or in vivo, or in vitro, was associated to temporary or lasting remission of disease in spontaneously diabetic NOD mice.