A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

BackgroundImmune checkpoint therapies have led to significant breakthroughs in cancer patient treatment in recent years. However, their efficiency is variable, and resistance to immunotherapies is common. VISTA is an immune-suppressive checkpoint inhibitor of T cell response belonging to the B7 family and a promising novel therapeutic target. VISTA is expressed in the immuno-suppressive tumor microenvironment, primarily by myeloid lineage cells, and its genetic knockout or antibody blockade restores an efficient antitumor immune response.MethodsFully human monoclonal antibodies directed against VISTA were produced after immunizing humanized Trianni mice and sorting and sequencing natively-linked B cell scFv repertoires. Anti-VISTA antibodies were evaluated for specificity, cross-reactivity, monocyte and T cell activation, Fc-effector functions, and antitumor efficacy using in vitro and in vivo models to select the KVA12123 antibody lead candidate. The pharmacokinetics and safety profiles of KVA12123 were evaluated in cynomolgus monkeys.ResultsHere, we report the development of a clinical candidate anti-VISTA monoclonal antibody, KVA12123. KVA12123 showed high affinity binding to VISTA through a unique epitope distinct from other clinical-stage anti-VISTA monoclonal antibodies. This clinical candidate demonstrated high specificity against VISTA with no cross-reactivity detected against other members of the B7 family. KVA12123 blocked VISTA binding to its binding partners. KVA12123 induced T cell activation and demonstrated NK-mediated monocyte activation. KVA12123 treatment mediated strong single-agent antitumor activity in several syngeneic tumor models and showed enhanced efficacy in combination with anti-PD-1 treatment. This clinical candidate was engineered to improve its pharmacokinetic characteristics and reduce Fc-effector functions. It was well-tolerated in preclinical toxicology studies in cynomolgus monkeys, where hematology, clinical chemistry evaluations, and clinical observations revealed no indicators of toxicity. No cytokines associated with cytokine release syndrome were elevated.ConclusionThese results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors. This antibody is currently evaluated alone and in combination with pembrolizumab in a Phase 1/2 open-label clinical trial in patients with advanced solid tumors

Nouvelles approches thérapeutiques dans le traitement du lymphome non-hodgkinien (induction de l'apoptose par trail et influence du microenvironnnement)

Le lymphome non-hodgkinien (LNH) est représenté principalement par deux pathologies: le lymphome folliculaire (FL) et le lymphome diffus à grandes cellules B. Le traitement de ces lymphomes se fait par immunothérapie au rituximab, associée à la chimiothérapie CHOP. Néanmoins, ces pathologies restent actuellement incurables. L'émergence de nouvelles thérapies dans la lutte contre le LNH est donc nécessaire. Ces pathologies se caractérisent par un microenvironnement impliqué dans le développement tumoral. Il joue un rôle important dans la survie des cellules tumorales et la mise en place d'une réponse immunitaire anti-tumorale inefficace. Les stratégies thérapeutiques actuelles ne prennent pourtant pas en compte ce microenvironnement. Ainsi, notre étude a porté sur la mise en place de nouvelles stratégies thérapeutiques, en misant sur la mort des cellules B tumorales et en diminuant l'influence du microenvironnement stromal. Nos études ont donc porté sur la cytotoxicité induite par TRAIL sur les cellules de LNH, accentuée par l'emploi du celecoxib. Cet anti-inflammatoire anti-stéroïdien, inhibiteur de COX-2, sensibilise des cellules tumorales B à l'apoptose et empêche la synthèse de PGE2 par les cellules stromales. Ces PGE2 sont décrites comme ayant un rôle important dans la modulation du microenvironnement inflammatoire. Nous avons également étudié la mort des cellules de LNH suite au traitement avec un nouvel anticorps anti-CD20: le GA101. L'impact du stroma a également été pris en compte. Dans cette étude, nous avons donc évalué différentes molécules afin d'induire la mort des cellules tumorales et de limiter les messages de survie apportés par le microenvironnement.Non-Hodgkin lymphoma (NHL) is represented by two major pathologies: follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). They take place in the germinal center. The treatment of these lymphomas is mainly immunotherapy rituximab, combined with CHOP chemotherapy. However, these diseases are currently incurable after many relapses and resistance to treatment. The emergence of new therapies against the NHL is necessary. In addition, these diseases are characterized by a microenvironment involved in tumor development. This microenvironment has an important supportive role in tumor B cells survival and in the establishment of anti-tumor immune response ineffective. Current therapeutic strategies do not yet reflect this microenvironment. Thus, our study focused on the development of new therapeutic strategies, exhibiting the death of tumor B cells and reducing the influence of the stromal microenvironment. Our studies have therefore focused on the cytotoxicity induced by TRAIL on NHL-cells, increased by the use of celecoxib. This anti-inflammatory steroidal, COX-2 inhibitor, sensitizes tumor cells to apoptosis and B prevents the synthesis of PGE2 by stromal cells. PGE2 are described in the modulation of the inflammatory microenvironment, notably described in FL. We also studied cell death following treatment of NHL with a new anti-CD20 antibody: GA101, even in the presence of a stromal environment. In this study, we have evaluated different molecules to induce cell death in tumor B cells and to limit survival effects provided by the microenvironment.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Role of the tumor microenvironment in regulating apoptosis and cancer progression

International audienceApoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted, by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non-malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumormicroenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented

Noninvasive Urine-Based Tests to Diagnose or Detect Recurrence of Bladder Cancer

International audienceLiquid biopsies are increasingly used for the diagnosis and follow-up of cancer patients. Urine is a body fluid that can be used to detect cancers and others diseases. It is noninvasive and easy to collect. To detect Bladder Cancer (BC), cytology is the first assay used. It is an effective way to detect high grade BC but has a high rate of equivocal results, especially for low grade BC. Furthermore, cystoscopy is used to confirm cytology results and to determine cancer status. Cystoscopy is also effective but highly invasive, and not well accepted by patients, especially for BC follow-up. In this review we survey the numerous assays recently developed in order to diagnose BC at an early stage, and to facilitate the follow-up of patients. We discuss their effectiveness, ease of use, and applications. Finally, we discuss assays that, in the future, could improve the diagnosis and management of BC patients

CD40 ligand protects from TRAIL-induced apoptosis in follicular lymphomas through NF-kappaB activation and up-regulation of c-FLIP and Bcl-xL.

International audienceThe TNF family member TRAIL is emerging as a promising cytotoxic molecule for antitumor therapy. However, its mechanism of action and the possible modulation of its effect by the microenvironment in follicular lymphomas (FL) remain unknown. We show here that TRAIL is cytotoxic only against FL B cells and not against normal B cells, and that DR4 is the main receptor involved in the initiation of the apoptotic cascade. However, the engagement of CD40 by its ligand, mainly expressed on a specific germinal center CD4(+) T cell subpopulation, counteracts TRAIL-induced apoptosis in FL B cells. CD40 induces a rapid RNA and protein up-regulation of c-FLIP and Bcl-x(L). The induction of these antiapoptotic molecules as well as the inhibition of TRAIL-induced apoptosis by CD40 is partially abolished when NF-kappaB activity is inhibited by a selective inhibitor, BAY 117085. Thus, the antiapoptotic signaling of CD40, which interferes with TRAIL-induced apoptosis in FL B cells, involves NF-kappaB-mediated induction of c-FLIP and Bcl-x(L) which can respectively interfere with caspase 8 activation or mitochondrial-mediated apoptosis. These findings suggest that a cotreatment with TRAIL and an inhibitor of NF-kappaB signaling or a blocking anti-CD40 Ab could be of great interest in FL therapy