Jounce Therapeutics Presents Data Highlighting Advances From Two Programs in its Immuno-Oncology Pipeline at the 2016 AACR Annual Meeting

On April 17, 2016 Jounce Therapeutics, Inc., a company focused on the discovery and development of novel cancer immunotherapies coupled to patient enrichment strategies,reported that they have presented new preclinical data from two programs in the company’s immuno-oncology pipeline at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Jounce Therapeutics, APR 17, 2016, View Source [SID:1234511009]). The data presented represent the broad applicability of Jounce’s Translational Science Platform.

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ICOS Program
Jounce’s first presentation highlighted JTX-2011, a humanized ICOS (inducible costimulator molecule) agonist antibody being developed for the treatment of solid tumors. JTX-2011 has a dual mechanism of action, stimulating T effector cells and selectively reducing intra-tumoral T regulatory cells, thereby shifting the balance of T cells in a tumor toward anti-tumor activity. JTX-2011 has demonstrated durable anti-tumor efficacy in multiple preclinical tumor models as both a single agent and in combination with anti-PD-1 therapy. Today’s presentation provides preclinical data on JTX-2011, including evaluation of JTX-2011 in non-human primates, in which the antibody was shown to be well tolerated.

Jounce plans to file an investigational new drug application for JTX-2011 in mid-2016 and commence clinical trials evaluating JTX-2011 both as a monotherapy cancer immunotherapeutic and in combination with other immunotherapies for solid tumors in the second half of 2016.

Beyond T Cell Program
Beyond the JTX-2011 lead program, Jounce has utilized its Translational Science Platform to characterize the immune cell type infiltrate in human tumors in a large scale analysis. Using an immune cell type signature approach, tumors are characterized by the prevalence of a particular immune cell type, facilitating relevant target prioritization of that cell type and coordinated biomarker identification of those tumors. Jounce is applying this strategy to multiple immune cell types, including immuno-suppressive macrophages.

Today’s presentation demonstrates that TIM-3 and LILRB2, a novel protein-to-protein binding pair on human macrophages, discovered through this platform, may provide a new therapeutic opportunity to convert immune-suppressive macrophages to immuneenhancing macrophages. Jounce researchers were able to identify a specific "myeloid functional" epitope (the defined segment of the TIM-3 protein to which the antibody binds). In in vitro assays, only the antibodies directed to this epitope converted macrophages to a more immune active, anti-tumor type. While the "myeloid functional" anti-TIM-3 antibodies did not directly affect T cells, targeting TIM-3 on myeloid cells in this manner did have a secondary, stimulatory effect on the adaptive immune system.

"Our Beyond T Cell programs are based on the importance of targeting different immune cells types, outside of the T cell," said Deborah Law, D. Phil., chief scientific officer, Jounce. "It is our belief that this approach will allow us to pursue tumor types not currently served by therapies that target adaptive immune cells by potentially converting the tumor microenvironment from an immune-suppressive state to an immune activating, anti-tumor state. We are tremendously excited to present the first data from this program today as we work to develop myeloid-functional TIM-3 antibodies to expand the potential immunotherapeutic approaches beyond T cells. We think this approach has the potential to bring the benefits of immunotherapy to patients that are not responsive to current immunotherapies."
About the Jounce Translational Science Platform Jounce is working to develop therapies that enable the immune system to attack tumors, thereby bringing long-lasting benefits to patients. Jounce has developed its Translational Science Platform to use an unbiased bioinformatics-based approach to interrogate particular cell types within the human tumor microenvironment (the cellular environment that makes up a tumor). This platform is designed to prioritize targets and identify related biomarkers to match the right therapy to the right patients.

Upregulation of RNA Processing Factors in Poorly Differentiated Lung Cancer Cells.

Intratumoral heterogeneity in non-small cell lung cancer (NSCLC) has been appreciated at the histological and cellular levels, but the association of less differentiated pathology with poor clinical outcome is not understood at the molecular level. Gene expression profiling of intact human tumors fails to reveal the molecular nature of functionally distinct epithelial cell subpopulations, in particular the tumor cells that fuel tumor growth, metastasis, and disease relapse. We generated primary serum-free cultures of NSCLC and then exposed them to conditions known to promote differentiation: the air-liquid interface (ALI) and serum. The transcriptional network of the primary cultures was associated with stem cells, indicating a poorly differentiated state, and worse overall survival of NSCLC patients. Strikingly, the overexpression of RNA splicing and processing factors was a prominent feature of the poorly differentiated cells and was also observed in clinical datasets. A genome-wide analysis of splice isoform expression revealed many alternative splicing events that were specific to the differentiation state of the cells, including an unexpectedly high frequency of events on chromosome 19. The poorly differentiated cells exhibited alternative splicing in many genes associated with tumor progression, as exemplified by the preferential expression of the short isoform of telomeric repeat-binding factor 1 (TERF1), also known as Pin2. Our findings demonstrate the utility of the ALI method for probing the molecular mechanisms that underlie NSCLC pathogenesis and provide novel insight into posttranscriptional mechanisms in poorly differentiated lung cancer cells.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

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Redx Pharma to present at the Annual Meeting of the American Association for Cancer Research (AACR) in New Orleans on 20 April

On April 16, 2016 Redx Pharma’s cancer subsidiary, Redx Oncology, reported that it has developed novel, differentiated, reversible small molecule inhibitors of Bruton’s tyrosine kinase (BTK) and will be presenting its poster to the scientific community next week at the AACR (Free AACR Whitepaper)’s 2016 annual gathering (Press release, Redx Pharma, APR 16, 2016, View Source [SID1234524743]). Redx’s lead compound has a favorable in vitro safety profile and drug-like properties, displaying an improved CYP profile to competitor compounds. In vivo PK demonstrated good oral bioavailability.

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This breakthrough is part of Redx’s work to develop best-in-class treatments for leukaemia, other blood cancers, and autoimmune diseases such as rheumatoid arthritis, lupus, and Sjögren’s Syndrome.

Dr Nicolas Guisot will be presenting the program on Wednesday 20 April between 7:30 and 11:00am in Section 19, Poster Board Number 20. If you would like to meet with our scientists or business development team please contact Dr Matilda Bingham, Executive Director of Redx Oncology.

The presentation abstract and author information is available here:
View Source

Bioorthogonal Turn-On Probe Based on Aggregation-Induced Emission Characteristics for Cancer Cell Imaging and Ablation.

Bioorthogonal turn-on probes have been widely utilized in visualizing various biological processes. Most of the currently available bioorthogonal turn-on probes are blue or green emissive fluorophores with azide or tetrazine as functional groups. Herein, we present an alternative strategy of designing bioorthogonal turn-on probes based on red-emissive fluorogens with aggregation-induced emission characteristics (AIEgens). The probe is water soluble and non-fluorescent due to the dissipation of energy through free molecular motion of the AIEgen, but the fluorescence is immediately turned on upon click reaction with azide-functionalized glycans on cancer cell surface. The fluorescence turn-on is ascribed to the restriction of molecular motion of AIEgen, which populates the radiative decay channel. Moreover, the AIEgen can generate reactive oxygen species (ROS) upon visible light (λ=400-700 nm) irradiation, demonstrating its dual role as an imaging and phototherapeutic agent.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Functional Characterization of D9, a Novel Deazaneplanocin A (DZNep) Analog, in Targeting Acute Myeloid Leukemia (AML).

Aberrant epigenetic events contribute to tumorigenesis of all human cancers. Significant efforts are underway in developing new generation of epigenetic cancer therapeutics. Although clinical trials for agents targeting DNA hypermethylation and histone deacetylation have yielded promising results, developing agents that target histone methylation remains to be in the early stage. We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range of anticancer effects in various human cancers. Here, focusing on acute myeloid leukemia (AML) as a model, we reported a less toxic analog of DZNep, named D9, which is shown to be efficacious in AML cell lines and patient-derived samples in vitro, as well as AML tumorigenesis in vivo. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy.

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