On June 22, 2020 Alkermes plc (Nasdaq: ALKS) and Clovis Oncology, Inc. (Nasdaq: CLVS) reported positive preclinical data from a study designed to evaluate the combination potential of ALKS 4230, Alkermes’ investigational engineered interleukin-2 (IL-2) variant immunotherapy, with lucitanib, Clovis’ investigational angiogenesis inhibitor (Press release, Clovis Oncology, JUN 22, 2020, View Source [SID1234561298]). The data will be presented during a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020.

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The study evaluated the antitumor efficacy and mechanism of action of mALKS 4230, a mouse ortholog of ALKS 4230, and lucitanib as monotherapies and in combination in a preclinical syngeneic mouse model of colon cancer. The combination of mALKS 4230 with lucitanib resulted in dose-dependent, durable complete responses (absence of any detectable tumor) and enhanced survival compared with monotherapy treatment with mALKS 4230 and lucitanib.

"Combining treatments with complementary mechanisms may offer synergistic clinical benefit and expand treatment options for a broader set of patient populations," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "These compelling preclinical data provide a foundational rationale to further explore novel combination options, such as an angiogenesis inhibitor, for ALKS 4230, with the goal of bringing improved therapeutic outcomes to patients across multiple tumor types."

Key findings presented in the poster include the following:

In the group that received the higher dose of mALKS 4230 (out of two doses tested) combined with lucitanib, 100 percent of the treated mice exhibited complete tumor regression and protection from new tumor growth upon re-challenge, an indication of the development of immunological memory.
The combination of mALKS 4230 with lucitanib resulted in an increase in intratumoral immune cells, including CD8+ T cells and dendritic cells, compared to monotherapy treatment, changes that are associated with anti-tumor immune responses.
The combination of mALKS 4230 with lucitanib elicited a distinct gene expression profile associated with anti-tumor activity, including increased immune cytolytic gene expression with decreased expression of genes with pro-angiogenic functions.
A virtual poster titled, "The Combination of a Mouse Ortholog of ALKS 4230, a Selective Agonist of the Intermediate-Affinity IL-2 Receptor, and the Angiogenesis Inhibitor Lucitanib Enhances Antitumor Activity," along with a pre-recorded audio presentation by Dr. Jared Lopes, Principal Scientist, Alkermes will be available on the AACR (Free AACR Whitepaper) website at View Source

About ALKS 4230

ALKS 4230 is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex. The selectivity of ALKS 4230 is designed to leverage the proven anti-tumor effects of existing IL-2 therapy while mitigating certain limitations.

About Lucitanib

Lucitanib is an oral, potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3), platelet-derived growth factor receptors alpha and beta (PDFGRα/β) and fibroblast growth factor receptors 1 through 3 (FGFR1-3). Emerging clinical data support the combination of angiogenesis inhibitors and immunotherapy to increase effectiveness in multiple cancer indications. Angiogenic factors, such as vascular endothelial growth factor (VEGF), are frequently up-regulated in tumors and create an immunosuppressive tumor microenvironment. Use of antiangiogenic drugs reverses this immunosuppression and can augment response to immunotherapy.

Lucitanib is an unlicensed medical product.

On June 22, 2020 Ribon Therapeutics, a clinical stage oncology company developing first-in-class therapeutics targeting stress response pathways, reported new data to be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II, taking place from June 22-24, 2020 (Press release, Ribon Therapeutics, JUN 22, 2020, View Source [SID1234561315]).

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"PARP7 is a fundamental regulator of intrinsic stress support pathways and represents a novel cancer cell vulnerability," said Heike Keilhack, Ph.D., Senior Vice President of Biological Sciences, Ribon Therapeutics. "RBN-2397 is the first potent and selective inhibitor of PARP7 and exhibits potent anti-tumor activity as a monotherapy, as well as in combination with other therapies, including immune checkpoint inhibitors."

"The posters presented at AACR (Free AACR Whitepaper) provide a glimpse into Ribon’s unique ability to interrogate the complex biology of stress support pathways to identify novel therapeutic targets," said Kevin Kuntz, Ph.D., Senior Vice President of Molecular Discovery, Ribon Therapeutics. "The multi-dimensional, in silico mining tools and bespoke screening assays Ribon has developed were instrumental in the identification of PARP7 and RBN-2397 and are critical components of the platform, which we have assembled to validate new monoPARP and NADase targets and develop novel therapeutics."

Ribon will present the following from its development program and platform:

Abstract Title: PARP7 negatively regulates the Type I interferon response in cancer cells and its inhibition leads to tumor regression
Abstract ID: 3405
Session Type: Minisymposium (oral presentation)
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Mechanisms Enabled by Tool Molecules
Date/Time: June 23, 2020, 9:00 – 11:00 a.m. EDT
Presenter: Joseph M. Gozgit, Ph.D.
Summary:

Data demonstrate that cancer cells use PARP7 to suppress the Type I IFN response to cytosolic nucleic acids. RBN-2397, a first-in-class, potent and selective inhibitor of PARP7 is shown to restore Type I IFN signaling in the tumor and cause complete tumor regressions and adaptive immunity in murine models.
Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy being explored in oncology. PARP7 expression is increased by cellular stress and aromatic hydrocarbons, and the PARP7 gene is amplified in cancers, especially in those of the upper aerodigestive tract. PARP7 has also been reported to negatively regulate the Type I IFN response by interacting with TBK1 during viral infection. PARP7 is identified as a novel negative regulator of cytosolic nucleic acid sensing in tumor cells.
Title: A bespoke screening platform to study mono(ADP-ribosylation)
Abstract ID: 506 / 2
Session Type: Poster Session
Session Title: Screening, Lead Identification, and Optimization
Date/Time: June 22, 2020, 9:00 a.m. – 6:00 p.m. EDT
Presenter: Tim J. Wigle, Ph.D.
Summary:

Development of robust, high-throughput biochemical and cellular monoPARP assays that overcome the lack of knowledge around the substrates and construction of a family-wide screening panel. These assays have been used in high-throughput screening campaigns, as well as in the development of potent and selective inhibitors of multiple monoPARP enzymes, including cell active chemical probes for PARP3, PARP7, PARP10, PARP12, PARP14 and PARP16.
Title: A multi-omic characterization of PARP enzymes in cancer to identify novel monoPARP drug targets
Abstract ID: 4381
Session Type: Poster Session
Session Title: Knowledge, Networks, Graphs, and Models for Discovery
Date/Time: June 22, 2020, 9:00 a.m. – 6:00 p.m. EDT
Presenter: Ryan Abo, Ph.D.
Summary:

The first pan-cancer in silico characterization of the PARP family, revealing a broad molecular and potential mechanistic diversity among the PARPs across cancer. Notwithstanding the lack of traditional oncogenic features, such as mutational hotspots, in the PARPs, analyses highlight several monoPARPs with potential oncogenic roles and further support our focus of targeting these in the clinic.
AACR Virtual Meeting II the second of two virtual meetings being held by AACR (Free AACR Whitepaper); the first, AACR (Free AACR Whitepaper) Virtual Meeting I, took place April 27-28, 2020. Presentations from Virtual Meeting I can be accessed at View Source

On June 22, 2020 BioInvent International AB ("BioInvent") (OMXS: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, and Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported preclinical data demonstrating high cure rates in solid tumors of BT-001, an anti-CTLA4 antibody-encoding oncolytic virus (Press release, BioInvent, JUN 22, 2020, View Source [SID1234561331]).

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Cure rates exceeding 70% were seen in multiple mouse models, demonstrating the powerful therapeutic effect of BT-001 when used as a single agent, providing a solid basis for BT-001’s upcoming clinical development, with a phase I clinical trial expected to start before the end of 2020.

BT-001 is a next-generation oncolytic virus (OV) being co-developed by Transgene and BioInvent. It was generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR oncolytic virus, which has been engineered to encode a Treg-depleting, anti-CTLA4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, as well as the cytokine GM-CSF.

BT-001 has multiple mechanisms of action. It has been designed to combine the killing of cancer cells (oncolysis), and the production of the anti-CTLA4 antibody and GM-CSF directly in the tumor site, while also generating an immune response against tumor cells.

These data indicate that BT-001 has the potential to make a significant difference in the treatment of solid tumors and as such, underpin the effectiveness of both BioInvent’s and Transgene’s technology platforms.

Main points from the presentation included:

The anti-CTLA-4 antibody and GM-CSF accumulate in tumors with low systemic exposure. Concentrations of the anti-CTLA-4 antibody in the tumor after intratumoral injection of BT-001 is more than 10-fold higher than after intraperitoneal injection of 3 mg/kg of the recombinant antibody in a xenograft tumor model.
When new tumor cells were implanted in mice that had been cured after a first BT-001 treatment, a strong tumor-specific response and long-lasting immune memory were developed by these mice.
BT-001, even at sub-optimal dose, reinforced the therapeutic activity of an anti-PD-1 antibody – opening up potential combinations for powerful dual checkpoint blockade treatment regimens.
These promising findings are available in a poster being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, on June 22-24, 2020. It can be downloaded from the AACR (Free AACR Whitepaper) website and from both BioInvent’s and Transgene’s websites.

Title of the poster: "BT-001, an oncolytic Vaccinia virus armed with a Treg-depletion-optimized recombinant human anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment."
Authors: Jean-Baptiste Marchand, Monika Semmrich, Laetitia Fend, Matilda Rehn, Nathalie Silvestre, Ingrid Teige, Johann Foloppe, Linda Mårtensson, Eric Quéméneur, Björn Frendeus
Session Date: June 22-24, 2020
Poster Session Title: Inflammation, Immunity, and Cancer / Modifiers of the Tumor Microenvironment 2
Poster Number: 5602 // Abstract Number: 2902
About BioInvent

BioInvent International AB (OMXS: BINV) is a clinical stage company that discovers and develops novel and first-in-class immuno-modulatory antibodies for cancer therapies, with two ongoing programs in Phase l/ll clinical trials for the treatment of hematological cancer and solid tumors, respectively. Two preclinical programs in solid tumors are expected to enter clinical trials by the end of 2020. The Company’s validated, proprietary F.I.R.S.TTM technology platform simultaneously identifies both targets and the antibodies that bind to them, generating many promising new drug candidates to fuel the Company’s own clinical development pipeline or for additional licensing and partnering.

The Company generates revenues from research collaborations and license agreements with multiple top-tier pharmaceutical companies, as well as from producing antibodies for third parties in the Company’s fully integrated manufacturing unit. More information is available at www.bioinvent.com.

On June 22, 2020 KIYATEC, Inc. reported that it will present data at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, June 22-24, revealing how its 3D cell culture models characterize ex vivo tumor response and immunoreactivity to immune checkpoint inhibitors (i.e. PD-1, PD-L1 inhibitors) in solid tumors (Press release, KIYATEC, JUN 22, 2020, View Source [SID1234561347]). These emerging capabilities address a significant unmet need in both preclinical drug development and clinical decision-making in oncology.

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PD-1/L1 inhibitors have experienced meteoric growth over the last decade, offering hope to hundreds of thousands of cancer patients every year in the US alone. However, typically no more than 25-30% of eligible cancer patients who receive PD-1/L1 inhibitors actually respond to them. Given that the direct costs associated with PD-1/L1 therapy can run into the hundreds of thousands of dollars per patient, KIYATEC believes that pre-treatment, patient-specific PD-1/L1 response prediction could one day offer clinicians, patients and payers a more objective basis for determining PD-1/L1 inhibitor patient eligibility vs. today’s commonly used population-based biomarkers.

Evidence presented by KIYATEC at AACR (Free AACR Whitepaper) 2020 will highlight findings of the company’s ability to detect dose-dependent response to checkpoint blockade and corresponding correlation with immune cell activation in high-throughput ex vivo 3D tumor spheroid models. KIYATEC believes these recent advances may represent key building blocks toward the eventual development and validation of clinical assays capable of accurate pre-treatment, patient-specific prediction of response to immuno-oncology drugs.

"We’re constantly innovating and expanding the capabilities of our 3D cell culture technologies to reduce the cost and risk of preclinical drug development for our immuno-oncology customers," said Matthew Gevaert, CEO of KIYATEC. "As we continue to make these advances in immuno-oncology drug response on higher-throughput platforms, we can begin to envision a time when such capability would inform clinical decision-making for cancer patients as well."

KIYATEC’s poster presentations at AACR (Free AACR Whitepaper) 2020 are as follows:

Title: Multifaceted functional assessment of checkpoint inhibitor efficacy using 3D tumor spheroids

Abstract: 7397 / Poster: 315 / Session: 3D & Tissue Recombinant Models / June 22-24
Title: PARP inhibition in combination with pembrolizumab enhances cytotoxicity in ovarian cancer patient-derived 3D spheroids

Abstract: 7132 / Poster: 2244 / Session: Immune Checkpoints 2 / June 22-24
Title: The perfused 3DKUBE rare tumor assay models in vivo drug response

Abstract: 7132 / Poster: 2244 / Session: Immune Checkpoints 2 / June 22-24

On June 22, 2020 Rakuten Medical, Inc. (Rakuten Medical) reported the results of two preclinical studies presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting II (Press release, Rakuten Medical, JUN 22, 2020, View Source [SID1234561363]). These studies further demonstrate the mechanism of action of Rakuten Medical’s Illuminox technology platform with its antibody-IRDye 700DX conjugate and how this unique technology induces tumor cells and enhances the adaptive immune response.

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"We are excited to present data on the mechanism of action of the Illuminox technology to induce rapid cell membrane disruption of cells targeted with the antibody-IRDye 700DX conjugate and the induction of cell necrosis and immunogenic cell death," said Miguel Garcia-Guzman, Ph.D., Chief Scientific Officer, Rakuten Medical. "Consistent with this mechanism of action, the study also shows that Illuminox treatments induce robust anti-cancer effects in immunocompetent animals by activating tumor specific innate and adaptive anticancer immunity with long term immune memory."

The following preclinical poster presentations were showcased during the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting II:

"Molecular mechanism of action of photoimmunotherapy with antibody-IR700 dye conjugates: Role of singlet oxygen in cell membrane disruption and necrotic cell death." (Abstract 480), presented by Roger Heim, Rakuten Medical.

This poster investigates the mechanism of action of Rakuten Medical’s proprietary Illuminox photoimmunotherapy through a series of preclinical experiments. These data describe the unique biophysical processes by which photoimmunotherapy with antibody-IR700 dye damages cell membranes and induces cell death.

"Anticancer activity by photoimmunotherapy is driven by adaptive immune responses and induces vaccinal effects in mice." (Abstract 949), presented by C. Daniel De Magalhaes Filho, Rakuten Medical.

This poster confirms previous data demonstrating that photoimmunotherapy induces cell death in tumor cells and ignites an immune response against the tumor [Hsu M, et al. AACR (Free AACR Whitepaper) 2019].

In this study, mice implanted with photoimmunotherapy-treated tumor cells rejected new tumor challenges, indicating that photoimmunotherapy induces immunogenic cell death and activates immune responses in the host mice protecting against future tumor challenges.