Stratégies vaccinales contre le mélanome

Le mélanome est une pathologie de plus en plus fréquente, sévère, pour laquelle les traitements antitumoraux standards sont peu efficaces. Étant donné la chimiorésistance et la radiorésistance intrinsèque de cette tumeur, d’une part, et d’autre part l’existence d’un rejet spontané, certes rare, de certains mélanomes, de grands espoirs se portent sur les techniques d’immunothérapie. Le développement récent de techniques de surveillance immunologique, l’« immunomonitorage », la caractérisation de nombreux antigènes tumoraux et la découverte de cytokines nécessaires à la culture ex vivo de cellules dendritiques ont ouvert de nouvelles voies thérapeutiques. Cet article fait le point sur les différentes stratégies de vaccination contre le mélanome.Melanoma incidence increases and conventional antitumor therapies are often ineffective, encouraging the design of novel therapies. Several lines of evidence support the notion of an immunological control of melanoma growth. Based on this information, active immunotherapy (vaccination) and adoptive immunotherapy trials (T cell therapy) were conducted in metastatic melanoma patients. The proof of principle of effective immunotherapy was brought up by pionnering trials using tumor infiltrated lymphocytes in lymphodepleted recipients or anti-CTLA4 Ab leading to tumor eradication but also autoimmune diseases. With the identification and characterization of tumor antigens recognized by cytotoxic T lymphocytes, the utilization of tumor rejection antigens along with adjuvants become available as tumor vaccines. The last five years have witnessed the emergence of dendritic cell based-vaccines that were efficient in priming and/or boosting T cell responses in normal volunteers and patients. This review highlights preclinical bases of cancer vaccines, their clinical development and discusses their limits. Correlations between immunomonitoring and tumor regressions await larger trials

Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers

The tumor microenvironment is highly heterogeneous. It is composed of a diverse array of immune cells that are recruited continuously into lesions. They are guided into the tumor through interactions between chemokines and their receptors. A variety of chemokine receptors are expressed on the surface of both tumor and immune cells rendering them sensitive to multiple stimuli that can subsequently influence their migration and function. These features significantly impact tumor fate and are critical in melanoma control and progression. Indeed, particular chemokine receptors expressed on tumor and immune cells are strongly associated with patient prognosis. Thus, potential targeting of chemokine receptors is highly attractive as a means to quench or eliminate unconstrained tumor cell growth

Caractérisation de la mort cellulaire induite par un anticorps trifonctionnel

Le développement d un cancer chez un individu immunocompétent témoigne, en partie, d un échappement tumoral au système d immunosurveillance. Par conséquent, la restauration ou l induction de ces mécanismes de défense anti-tumorale est une des stratégies thérapeutiques actuelles. Un des principes de l immunothérapie est basé sur l injection d anticorps ayant pour cible la cellule tumorale ou les cellules effectrices de l immunité. L efficacité anti-tumorale de ces anticorps a été considérablement améliorée par une meilleure compréhension des modes d action et des effets modulateurs de ces anticorps. Ainsi, afin d optimiser l action des effecteurs immunitaires sur les cellules tumorales, un anticorps bispécifique, trifonctionnel, le catumaxomab, capable de se lier à la molécule d'adhérence des cellules épithéliales (EpCAM) exprimée par les cellules tumorales et à l'antigène CD3 des lymphocytes T, a été développé, essentiellement en traitement intra-péritonéal des ascites néoplasiques réfractaires.L objectif de cette étude était de déterminer les effets immunomodulateurs du catumaxomab sur des cellules néoplasiques exprimant EpCAM, à partir de deux modèles expérimentaux (allogénique et autologue), de rechercher une cytotoxicité induite par la catumaxomab, et de la caractériser, notamment en analysant la présence ou non de signaux de stress inducteurs d une mort immunogène tels que l exposition membranaire de la calréticuline par les cellules tumorales pré-apoptotiques, la libération d HMGB1 et d adénosine triphosphate (ATP) dans le milieu extra-cellulaire, responsables d une activation des lymphocytes T.En présence de cellules EpCAM+, le catumaxomab entrainait une activation majeure des lymphocytes T (expression de CD69, CD107a, HLA-DR et PD1), stimulait une réponse inflammatoire de type Thelper 1(Th1), et provoquait la synthèse d interféron-gamma par les lymphocytes T CD8. Le catumaxomab engageait le CD16 (FcR) des cellules monocytaires et NK. De plus, sur des modèles allogéniques, le catumaxomab, provoquait une mort cellulaire associée à la libération d ATP et induisait une mort immunogène après pré-incubation dans de l oxaliplatine.Par conséquent, le catumaxomab permet de moduler l environnement immunitaire dans les ascites néoplasiques, et de convertir une inflammation chronique et immunosuppressive (Th2) en une inflammation aigüe et immunogène (Th1). En revanche, dans ces conditions, l administration seule de catumaxomab ne semble pas déclencher de mort immunogène.Différents moyens pourraient permettre d améliorer la cytotoxicité de cet anticorps bispécifique : (1) le combiner avec un agent anti-néoplasique tel que l oxaliplatine afin de promouvoir une mort immunogène, (2) affiner son action sur le CD3 des lymphocytes en modifiant sa configuration spatiale (anticorps BiTE), (3) amplifier son affinité pour le récepteur Fc des cellules accessoires (Fc défucosylé), (4) augmenter sa cytotoxicité en modifiant la cible dirigée contre la molécule du système immunitaire (anti-PD-1 ). Enfin, l utilisation clinique pourrait être facilitée en humanisant cet anticorps chimérique murin afin d éviter la formation d anticorps anti-murins, dirigés contre le catumaxomab.Un essai thérapeutique de phase II dont le but est d évaluer l efficacité du catumaxomab intrapéritonéal après chirurgie de cytoréduction complète d une carcinose gastrique, chez des patients ayant reçu en préopératoire une chimiothérapie systémique à base d oxaliplatine vient de débuter. Au cours de cette étude, nous allons valider la capacité du catumaxomab 1) à induire un stress cellulaire immunogène et la mort des cellules cancéreuses, 2) à modifier la polarisation des cellules effectrices vers une maladie inflammatoire Th1, 3) à promouvoir l'expression des molécules de costimulation et TRAIL sur les cellules NK et monocytes, et corréler ces biomarqueurs immunitaires à l efficacité du traitement.The development of cancer in an immunocompetent individual reflects, in part, a tumor escape from the immunosurveillance. The tumor escape is a complex, multifactorial, in which tumor cells will evade the defense mechanisms of the host by changing their microenvironment. Therefore, restoration or induction of these defense mechanisms is one of the therapeutic strategies against cancer. One of the principles of immunotherapy is based on the injection of antibodies that target tumor cells or effector cells of immunity. The anti-tumor efficacy of these antibodies has been greatly improved by a better understanding of modes of action and modulatory effects of these antibodies.Thus, to optimize the action of immune effectors to tumor cells, a bispecific antibody, trifunctional: catumaxomab, capable of binding to the adhesion molecule of the epithelial cells (EpCAM), expressed by tumor cells and the CD3 antigen of T cells, has been developed mainly in intraperitoneal treatment of refractory malignant ascites.The objective of this study was to determine the immunomodulatory effects of catumaxomab on tumoral cells expressing EpCAM, from two experimental models (allogeneic and autologous), evaluate and characterize cytotoxicity induced by catumaxomab, and analyze the presence of stress signals inducing immunogenic cell death such as membrane exposure of calreticulin by pre-apoptotic tumor cells, release of HMGB1 and of adenosine triphosphate (ATP) in the extracellular medium, inducing a T cell activation.In the presence of EpCAM + cells, catumaxomab induced a major the activation of T cells (expression of CD69, CD107a, HLA-DR and PD1), stimulated an inflammatory response Thelper type 1 (Th1) and the synthesis of interferon-gamma by CD8 T cells. Catumaxomab committed CD16 NK cells and monocytes. More, in models allogeneic catumaxomab, caused cell death associated with ATP release and induced an immunogenic cell death after pre-incubation of oxaliplatin.Therefore, catumaxomab modulates the immune environment in malignant ascites, and convert chronic and immunosuppressive inflammation (Th2) in acute and immunogenic inflammation (Th1). However, in these conditions, catumaxomab alone does not seem to trigger immunogenic cell death.the cytotoxicity of this bispecific antibody could be enhance by different techniques: (1) combining with chemotherapy such as oxaliplatin to promote immunogenic cell death, (2) refining its action on CD3 lymphocytes by changing its spatial configuration (BiTE antibody), (3) increasing its affinity for the Fc R of accessory cells (Fc aglycosylated), (4) increasing its cytotoxicity by changing the target directed against the immune molecule (anti-PD-1 ...). Finally, the clinical use could be facilitated by this humanizing murine chimeric antibody to prevent the formation of anti-murine antibodies directed against catumaxomab.A phase II clinical trial aimed to evaluate the efficacy of intraperitoneal catumaxomab after complete cytoreductive surgery of gastric carcinomatosis in patients who received preoperative systemic chemotherapy with oxaliplatin have just started. In this study, we will validate the ability of catumaxomab 1) to induce immunogenic cell stress and death of cancer cells, 2) to change the polarization of effector cells to Th1 inflammatory disease, 3) to promote the expression of costimulatory molecules and TRAIL on NK cells and monocytes, and we will correlate these immune biomarkers to treatment efficacy.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Microbiome and Cancer Immunotherapies

Here, we present 3 different perspectives on how the microbiome has impacted cancer patients, treatment, and clinical studies. We hear about the challenges of implementing microbiome analyses into the clinics, the impact these analyses might have on patients\u27 care, and treatment in the future, specifically for gastric cancer treatment. These are a few of the many voices that are highlighting the role of the microbiome in cancer development, treatment, and clinical outcomes

The European Academy of Tumor Immunology: Bridging fields, continents and generations

The European Academy of Tumor Immunology (EATI, official website: http://eati.landesbioscience.com/index.html) has been founded in 2011 with the idea of creating a novel organization that responds to the need of structuring the European research space in this expanding, clinically ever more important area of research. Rapidly, this initiative, which regroups (part of) the elite of tumor immunologists, has been joined by 110 scientists, who accepted to join EATI as founding members. Obviously, EATI will not enter in competition with existing prestigious organizations, be they supranational (such as the Cancer Research Institute, CRI; the European Society for Cancer Immunology and Immunotherapy, ESCII; and the Society for the Immunotherapy of Cancer, SITC), or national [such as the Cancer Immunology Working Group, CIMM, of the American Association for Cancer Reserch; the (German) Association for Cancer Immunotherapy, CIMT; the (US) Cancer Immunotherapy Consortium, CIC; the (US) Cancer Vaccine Consortium, CVC; and the Italian Network for Cancer Biotherapy, NIBIT]. The choice of cooperation (rather than competition) with these organizations is clearly documented by the fact that many prominent members of CIMM, CIC, CIMT, CRI, CVC, ESCII, NIBIT and SITC are also EATI Academicians

Effects of the intestinal microbiota on prostate cancer treatment by androgen deprivation therapy

Prostate cancer (PC) can be kept in check by androgen deprivation therapy (ADT, usually with the androgen synthesis inhibitor abiraterone acetate or the androgen receptor antagonist such as enzalutamide) until the tumor evolves to castration-resistant prostate cancer (CRPC). The transition of hormone-sensitive PC (HSPC) to CPRC has been explained by cancer cell-intrinsic resistance mechanisms. Recent data indicate that this transition is also marked by cancer cell-extrinsic mechanisms such as the failure of ADT-induced PC immunosurveillance, which depends on the presence of immunostimulatory bacteria in the gut. Moreover, intestinal bacteria that degrade drugs used for ADT, as well as bacteria that produce androgens, can interfere with the efficacy of ADT. Thus, specific bacteria in the gut serve as a source of testosterone, which accelerates prostate cancer progression, and men with CRPC exhibit an increased abundance of such bacteria with androgenic functions. In conclusion, the response of PC to ADT is profoundly influenced by the composition of the microbiota with its immunostimulatory, immunosuppressive and directly ADT-subversive elements

Gut OncoMicrobiome Signatures (GOMS) As Next-Generation Biomarkers for Cancer Immunotherapy

Oncogenesis is associated with intestinal dysbiosis, and stool shotgun metagenomic sequencing in individuals with this condition might constitute a non-invasive approach for the early diagnosis of several cancer types. The prognostic relevance of antibiotic intake and gut microbiota composition urged investigators to develop tools for the detection of intestinal dysbiosis to enable patient stratification and microbiota-centred clinical interventions. Moreover, since the advent of immune-checkpoint inhibitors (ICIs) in oncology, the identification of biomarkers for predicting their efficacy before starting treatment has been an unmet medical need. Many previous studies addressing this question, including a meta-analysis described herein, have led to the description of Gut OncoMicrobiome Signatures (GOMS). In this Review, we discuss how patients with cancer across various subtypes share several GOMS with individuals with seemingly unrelated chronic inflammatory disorders who, in turn, tend to have GOMS different from those of healthy individuals. We discuss findings from the aforementioned meta-analysis of GOMS patterns associated with clinical benefit from or resistance to ICIs across different cancer types (in 808 patients), with a focus on metabolic and immunological surrogate markers of intestinal dysbiosis, and propose practical guidelines to incorporate GOMS in decision-making for prospective clinical trials in immuno-oncology