LCP2

Inflammation is the sign that our body is defending itself against an aggression. But when this response escalates, for example in the brain, it can lead to serious neurological or psychiatric diseases. A team investigated a marker protein targeted by medical imaging to visualize cerebral inflammation, but whose interpretation was still uncertain. The team reveals that a large quantity of this protein goes hand in hand with a large quantity of inflammatory cells, but its presence is not a sign of their overactivation. These results pave the way for optimal observation of neuroinflammatory processes and a re-reading of previous studies on the subject. Inflammation is the sign that our body is defending itself against an aggression. But when this response escalates, for example in the brain, it can lead to serious neurological or psychiatric diseases. A team from the University of Geneva (UNIGE), the University Hospitals of Geneva (HUG), Imperial College London and Amsterdam UMC, investigated a marker protein targeted by medical imaging to visualise cerebral inflammation, but whose interpretation was still uncertain. The team reveals that a large quantity of this protein goes hand in hand with a large quantity of inflammatory cells, but its presence is not a sign of their overactivation. These results, published in Nature Communications, pave the way for optimal observation of neuroinflammatory processes and a re-reading of previous studies on the subject. Inflammation is a natural defensive reaction initiated by the immune system. It enables our cells to fight off aggression, such as injury or infection. But this response can also get out of control and lead to the onset of serious pathologies. When it occurs in the brain -- in which case it is known as neuroinflammation -- this overactivation can play a part in the mechanisms of neurodegenerative diseases (Alzheimer's, amyotrophic lateral sclerosis, multiple sclerosis) and psychiatric diseases (schizophrenia, bipolar disorder, depression). In the brain, microglial cells play an important role in inflammation and its potential overactivation. They can be ''activated'' when dysfunction occurs, phagocytize pathological cells or proteins and even produce protective substances. Currently, in medical imaging, only one marker can be used to locate and measure microglia non-invasively and in vivo: the TSPO protein, which is present in these cells. This protein can be observed by Positron Emission Tomography (PET), a common imaging technique. What does TSPO protein reveal? ''Hundreds of studies have used PET scans of this protein to explore and quantify microglia. However, no study has succeeded in precisely interpreting the significance of its quantity in the context of an inflammatory reaction,'' explains Stergios Tsartsalis, senior clinical associate in the Department of Psychiatry at the UNIGE Faculty of Medicine. Does a large quantity of TSPO correspond to a large quantity of inflammatory cells? Is it a sign of their overactivation? Together with researchers from Imperial College London (Dr David Owen) and Amsterdam UMC (Prof Sandra Amor), Stergios Tsartsalis and members of Prof Philippe Millet's team from the HUG's Laboratory of translational imaging in psychiatric neuroscience and the UNIGE's Group of molecular neuroimaging in psychiatry set out to find out. The international research team worked on the brains of mouse models of Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis, and on post-mortem brain samples from patients affected by the same diseases. ''We discovered that a high density of TSPO protein is indeed an indicator of a high density of microglia. On the other hand, the observation of TSPO does not allow us to say whether or not the inflammatory cells are overactivated,'' explains the UNIGE researcher, co-first author of the study. Re-reading the past, optimising the future This discovery highlights the value of medical imaging of TSPO: it makes it possible to identify cases where the neuroinflammatory disease is linked to a deregulation in the number of glial cells. In addition, the scientists have identified two markers of the state of microglia activation in humans -- the LCP2 and TFEC proteins -- which pave the way for new medical imaging approaches. ''These results represent a further step towards understanding the role of microglia in neuroinflammation. They will help to optimise the focus of future studies and also to review the conclusions of previous research,'' enthuses Stergios Tsartsalis. Combined with the significant development of molecular imaging at the UNIGE and the HUG, this study, supported by the Swiss National Science Foundation and the Prof Dr Max Cloëtta Foundation, set the scene for effective observation of the immune mechanisms of neurological and psychiatric diseases, within the two Geneva institutions and beyond.

SOUTH SAN FRANCISCO, Calif., March 10, 2021 (GLOBE NEWSWIRE) -- RAPT Therapeutics, Inc. (Nasdaq: RAPT), a clinical-stage, immunology-based biopharmaceutical company focused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in oncology and inflammatory diseases, today announced several upcoming preclinical poster presentations at the American Association for Cancer Research annual meeting demonstrating promise and potential of its pipeline of anti-cancer agents. “Our posters at AACR reflect our continued exploration into the role of the immune system in cancer and the potential of immunology-based therapies to address certain challenges in oncology,” said Dirk Brockstedt, Ph.D., Chief Scientific Officer of RAPT. “Specifically, the role and importance of CCR4 inhibition will be highlighted and continue to support the early clinical data we have observed with FLX475, our CCR4 inhibitor being evaluated in a Phase 1/2 trial in multiple tumors. In addition, we will also present preclinical data on two exciting next-generation immune-oncology targets, HPK1 and GCN2, which show that orally available inhibitors elicit potent antitumor immune responses in a variety of cancer models.” Summaries of the studies to be presented: Poster: 1585Title: T-regulatory cells impair CAR T-cell-mediated antitumor activity in a murine solid tumor model Session Title: Combination Immunotherapies Chimeric antigen receptor (CAR) T cell immunotherapy has had only modest success in solid malignancies due in part to tumor antigen heterogeneity and the immunosuppressive tumor microenvironment, which is believed to be at least in part due to immunosuppressive regulatory T cells (Treg). Treg express CCR4 and migrate toward CCL17 and CCL22 which are frequently upregulated in a subset of tumors or increased following immunotherapy. In a murine mesothelioma model, a combination of CAR- T-cells plus CCR4 antagonist significantly slowed tumor growth and significantly improved survival compared to untreated control. Furthermore, enhanced antitumor activity was observed with the combination of CAR T cells and CCR4 antagonist compared to either monotherapy, with 4/9 mice treated with the combination becoming tumor free and experienced significantly increased survival. Poster: 1646Title: Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responsesSession Title: Immune Checkpoints Hematopoietic progenitor kinase 1 (HPK1) is an intracellular protein kinase that is associated with inhibition of critical immune T cell signaling and proliferation important for mounting an effective immune response against tumor cells.  RAPT’s small-molecule compounds demonstrated potent inhibition of HPK1 in biochemical assays, reduction of levels of phosphorylated SLP76 and concomitant increase in IL-2 production.  In addition, the Company’s HPK1 inhibitors enhanced cytokine production of human and mouse primary T cells above that observed with T-cell receptor activation alone. Notably, treatment of mice with an orally available HPK1 inhibitor resulted in increased activation of antigen-specific CD8 T-cells and decreased tumor growth as monotherapies and in combination with clinically relevant checkpoint inhibitor antibodies. Poster: 3153Title: Targeting the stress response kinase GCN2 to restore immunity in the tumor microenvironment Session Title: Tumor Microenvironment Recent advances in cancer metabolism suggest that targeting amino acid metabolism represents a promising strategy for the development of novel therapeutic agents. Tumor, stromal and myeloid-derived suppressor cells (MDSC) within the tumor microenvironment (TME) create a nutrient-poor environment that inhibits immune function and support tumor growth. GCN2 (general control nonderepressible 2), a stress response kinase, plays a key role in maintaining cellular homeostasis under a wide range of stressors, leading to T cell anergy, apoptosis, enhanced MDSC-dependent immune suppression and tumor cell survival. The treatment of nutrient-deprived T cells in vitro with a GCN2 inhibitor enhanced CD4 and CD8 T-cell proliferation and effector functions. The GCN2 inhibitor also reversed T cell suppression mediated by MDSCs derived from healthy donors or cancer patients. In syngeneic mouse tumor models, oral administration of a GCN2 inhibitor showed impressive drug-target engagement and potently inhibited GCN2 kinase in the tumor microenvironment. Furthermore, the GCN2 inhibitor as a single agent and in combination with checkpoint inhibitors and angiogenesis inhibitor (anti-VEGFR) delayed tumor growth in renal cell carcinoma and lung cancer syngeneic tumor models. About RAPT Therapeutics, Inc.RAPT Therapeutics is a clinical stage immunology-based biopharmaceutical company focused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in oncology and inflammatory diseases. Utilizing its proprietary discovery and development engine, the Company is developing highly selective small molecules designed to modulate the critical immune drivers underlying these diseases. RAPT has discovered and advanced two unique drug candidates, FLX475 and RPT193, each targeting C-C motif chemokine receptor 4 (CCR4), for the treatment of cancer and inflammation, respectively. The Company is also pursuing a range of targets that are in the discovery stage of development. Forward-Looking StatementsThis press release contains forward-looking statements. These statements relate to future events and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future performances or achievements expressed or implied by the forward-looking statements. Each of these statements is based only on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties. Forward-looking statements include, but are not limited to, statements about the significance of early results from the Phase 1/2 clinical trials of FLX475 and preclinical studies of HPK1 and GCN2, and statements about the potential of CCR4, HPK1 and GCN2 to enhance antitumor activity. Detailed information regarding risk factors that may cause actual results to differ materially from the results expressed or implied by statements in this press release may be found in RAPT’s most recent Form 10-Q filed with the Securities and Exchange Commission and subsequent filings made by RAPT with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof. RAPT disclaims any obligation to update these forward-looking statements. Investor Contact:Sylvia Wheelerswheeler@wheelhouselsa.com Media Contact:Aljanae Reynoldsareynolds@wheelhouselsa.com