On November 9, 2021 Dragonfly Therapeutics, Inc., a clinical stage biotechnology company developing novel immunotherapies, reported that its wholly-owned HER2-targeted NK cell engager therapy, DF1001, has been granted Orphan Drug Designation (ODD) in the US for treatment of esophageal cancer (Press release, Dragonfly Therapeutics, NOV 9, 2021, View Source [SID1234594929]).

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An estimated 19,260 new cases of esophageal cancer will be diagnosed this year and the disease could lead to more than 15,500 deaths in the US in 2021.1 The Food and Drug Administration (FDA) grants ODD to medicines intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US. HER2 is expressed in a large subset of esophageal cancers, even in patients without amplification of erbb2.

An ongoing Phase 1/2 clinical trial for the DF1001 TriNKET is a first-in-human study exploring the safety, tolerability and preliminary biological and clinical activity of DF1001. Dragonfly has treated 40 patients with DF1001, with no DLTs to date. Clinical trial sites are open in the U.S., France, Belgium, Denmark and The Netherlands. Additional information about the trial, including eligibility criteria, can be found at: View Source (ClinicalTrials.gov Identifier: NCT04143711).

Esophageal Cancer

Esophageal cancer is relatively rare and represents 1% of all new cancer cases in the U.S. Esophageal cancer is more common in men than women and is the sixth most common cause of cancer-related death worldwide3. In the U.S., esophageal adenocarcinoma is more common than squamous cell carcinoma, and its incidence has increased more quickly than any other malignancy in many western countries. Current treatment options include surgery, radiation therapy, chemotherapy, and targeted therapy (and combinations thereof), depending on stage and type of disease4. Despite multimodality treatment strategies, survival remains disappointing, with a 5-year survival rate of 47% for localized disease. When disease has spread to surrounding tissues or organs and/or lymph nodes, the 5-year survival rate is only 25%, and when spread to distant parts, prognosis is particularly poor with a survival rate of just 5%. Approximately one in five people with esophageal cancer have increased HER2 protein on the surface of their cells, so-called HER2-positive cancers.

About DF1001

DF1001 is an investigational first-in-class drug candidate that targets natural killer (NK) cells and T-cell activation signals to specific receptors on cancer cells. DF1001 is being evaluated in adult patients for the treatment of advanced solid HER2-positive tumors. DF1001 was discovered and developed using Dragonfly’s TriNKET Platform. DF1001 has the potential to stimulate effective anti-tumor immunity in patients who are not eligible for, or not adequately responding to, current therapies. DF1001 is the most advanced drug candidate in a pipeline of TriNKETs that Dragonfly is developing to address high unmet needs for patients across a broad range of disease areas.

About Dragonfly’s TriNKET Platform

Dragonfly’s TriNKET Platform is the basis for a portfolio of novel therapeutics that are designed to harness Natural Killer cells and other cells of the innate immune system which can provide direct killing of disease promoting cell types and provide a unique therapeutic window beyond current therapies for treatment of cancer and chronic inflammatory diseases.

On November 9, 2021 NeoTX Therapeutics, Ltd. (NeoTX), a clinical-stage immuno-oncology company, reported a presentation on the company’s lead program, naptumomab estafenatox (NAP), at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 36th Annual Meeting being held November 10-14, 2021 at the Walter E. Washington convention Center, Washington D.C (Press release, NeoTX, NOV 9, 2021, View Source [SID1234594928]). The poster presentation will highlight preclinical data demonstrating that NAP enhances CAR-T cells potency and can boost CAR-T efficacy against solid tumors.

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Details on the poster presentation are as follows:

Title: Tumor Targeted Superantigen (TTS), Naptumomab Estafenatox (NAP), enhances CAR-T cells potency and can boost CAR-T efficacy against solid tumors
Abstract Number: 576 (ePoster)
Lead Author: Yael Sagi, Ph.D.
Category: Combination Immunotherapies
Date & Time: The ePoster will be on display on the SITC (Free SITC Whitepaper) 2021 virtual meeting platform from 7 a.m. EST on Friday, Nov. 12, 2021 until the virtual meeting platform is closed on Jan. 9, 2022.

On November 9, 2021 HUYABIO International, the leader in accelerating global development of China’s pharmaceutical innovations, reported it had licensed exclusive worldwide ex-China rights to the Wee1 inhibitor from Shanghai Pharma, the second largest pharma group in China with annual sales of over $30 billion (Press release, HUYA Bioscience, NOV 9, 2021, View Source [SID1234594927]). This is the first program that Shanghai Pharma has outlicensed to a global partner.

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"HUYABIO International has pioneered an innovative approach for partnering with Chinese research institutions and pharmaceutical companies. It identifies and licenses the most promising pre-clinical and clinical stage compounds in China, leverages and extends the research efforts of its Chinese partners, and provides a bridge into the international development process and global biopharma market. We are glad to collaborate with them on our SPH6162 as this collaboration is an important milestone of our global strategy due to our Licensed Molecules and Licensed Products," said Min Zuo, CEO Shanghai Pharmaceuticals.

Wee1 regulates the G2 checkpoint and stimulates entry into mitosis in response to DNA damage. It is a nuclear kinase belonging to the Ser/Thr family of protein kinases and its cell size by inhibiting Cdk1. Wee1 over-expression has been observed in solid tumors including hepatocellular carcinoma, colon cancer, glioblastoma, non-small-cell lung cancer (NSCLS), neuroblastoma, and gastric cancers.

Dr. Mireille Gillings, CEO & Executive Chair of HUYABIO, said, "We are delighted to partner with Shanghai Pharmaceuticals for a therapeutic mechanism that promises broad synergy across treatments for many tumor types. HUYABIO is the first global company with which Shanghai Pharma has signed a major outlicensing agreement and we look forward to co-development of this innovative program in China."

On November 9, 2021 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of first-in-class allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported new data validating its Smart Allostery platform in the elucidation and preclinical evaluation of a novel allosteric inhibitor of the E3 ubiquitin ligase CBL-B (Press release, HotSpot Therapeutics, NOV 9, 2021, View Source [SID1234594926]). The data will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting, which is being held from November 10-14, 2021.

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"CBL-B’s role as a master negative regulator of T cells and NK cells makes it a very attractive target for cancer immunotherapy, but it has proven difficult to inhibit with traditional small molecules," said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer at HotSpot Therapeutics. "We’re thrilled to share these new data showing that we can successfully inhibit CBL-B with a novel allosteric inhibitor identified through our Smart Allostery platform and promote T cell responses in vitro and in mice. To better treat patients, we need new mechanisms to enhance and sustain effective anti-tumor immunity and to address suboptimal responses. Our small molecule allosteric inhibitor of CBL-B may bring such benefit with the added advantage of convenient oral delivery."

CBL-B sits at a pivotal node in immune cell activation, and its inhibition holds the potential to address several key mechanisms where translational data supports a causative role in suboptimal response to current immunotherapies. Because inhibition of CBL-B lowers the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, it may bring benefit to patients with low antigen levels (e.g., low TMB), low inflammation (e.g., low PDL-1) and/or sub-par co-stimulation (e.g., low CD28).

HotSpot’s Smart Allostery approach offers a diversity of advantages in delivering highly selective and differentiated orally bioavailable medicines against proteins that are undruggable or poorly druggable targets, including CBL-B. The platform utilizes a suite of computational algorithms powered by machine learning to uncover natural hotspots that control protein function, employs an array of specialized assays to identify hotspot binders and subsequently uses chemistry to selectively drug these sites with allosteric inhibitors.

SITC Presentation Overview:

Title: Identification of A Novel Allosteric Oral CBL-B Inhibitor that Augmented T Cell Response and Enhanced NK Cell Killing in vitro and in vivo
Authors: Jun Kuai, Yingzhi Bi, Yilin Qi, Deborah G Conrady, Rajiv G Govindaraj, Graham Hone, R. Aldrin Denny, Ken Carson, Geraldine Harriman, Fang Wang
Poster Number: 864
Session: Novel Single-Agent Immunotherapies

Summary of Poster

CBL-B is activated by tyrosine kinases and undergoes a large conformational change from closed inactive form to open active form.
Through the utilization of HotSpot’s proprietary Smart Allostery platform, including its AI-powered SpotFinder technology, a druggable phosphoregulatory pocket was identified in the inactive form of CBL-B.
HotSpot identified an inhibitor that binds to a regulatory hotspot on CBL-B, locking it in its inactive form, as confirmed by co-crystal structures.
This molecule prevents CBL-B phosphorylation, inhibits E3 ligase activity, promotes cytokine release, enhances T cell proliferation, and stimulates NK cell activation/killing.
In vivo, the molecule enhances T cells responses in anti-CD3 treated mice.

On November 9, 2021 Vigeo Therapeutics, a clinical-stage immuno-oncology company pioneering novel cancer therapies, reported new clinical data from its Phase 1/2 expansion study evaluating the single-agent activity of VT1021 in subjects with pancreatic cancer and recurrent glioblastoma (rGBM) (Press release, Vigeo Therapeutics, NOV 9, 2021, View Source [SID1234594925]). The data is being presented in the poster session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 2021 Annual Meeting, taking place from November 10-14, 2021.

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VT1021 is a first-in-class compound that induces the expression of Tsp-1 in the tumor microenvironment (TME). Tsp-1 then blocks the CD47 immune checkpoint and reprograms the CD36 receptor to induce tumor cell apoptosis, inhibit angiogenesis, and reprogram macrophages from the M2 to M1 phenotype. In the completed open-label, multicenter Phase 1/2 study (NCT03364400), the safety and preliminary anti-tumor efficacy of single-agent VT1021 was evaluated in subjects enrolled in both dose escalation and dose expansion cohorts. Results of the all-comer escalation cohort were presented at SITC (Free SITC Whitepaper) in 2020. In 2021, Vigeo is presenting the results of the expansion cohorts, which focused primarily on pancreatic cancer and rGBM, as well as other indications.

In the pancreatic cancer expansion cohort, VT1021, when administered as a single agent, was able to induce a reduction in tumor volume in 38% of subjects with measurable disease. VT1021 was able to reprogram the immune reactivity of the TME as evidenced by an increase in cytotoxic T lymphocytes (CTLs) as well as in the ratio of M1:M2 macrophages. These findings suggest that VT1021, in addition to its single agent activity, could be a potent and synergistic combination with checkpoint inhibitors.

Consistent with the reprogramming of the TME, Tsp-1 expression was significantly increased by VT1021 treatment across all tumor types. Induction of Tsp-1 protein was observed in circulating PBMCs, platelets and plasma, along with mRNA levels in PBMCs. Additionally, analysis of paired biopsy samples revealed increased Tsp-1 accumulation in MDSCs in the TME. Taken together these findings validate of the biological activity of VT021 via the induction of Tsp-1 in the TME.

"We are highly encouraged by the new data being presented at SITC (Free SITC Whitepaper), which demonstrate both a favorable safety profile for VT1021 as well as early signals of efficacy in pancreatic cancer – especially for those subjects with tumors expressing high levels of both CD47 and CD36," said CEO Jim Mahoney, "Out of 14 patients, 5 patients showed reduction in tumor burden. Based on these findings, we believe that VT1021, a dual-CD47/CD36 modulating agent, has strong potential as a treatment for pancreatic cancer patients."

Vigeo plans to initiate Phase 2/3 studies in both pancreatic cancer and rGBM during the first half of 2022. Vigeo will present additional results from the GBM expansion cohort at the Society for Neuro-Oncology (SNO) Conference in November 2021 in Boston, MA.

Details for the SITC (Free SITC Whitepaper) 2021 presentations are as follows:

Title: Clinical update of VT1021, a first-in-class CD36 and CD47 targeting immunomodulating agent, in subjects with pancreatic cancer and other solid tumors stratified by novel biomarkers
Presenter: Marsha Crochiere, PhD, Director of Translational Sciences, Vigeo Therapeutics
Session: Virtual Poster Hall
Poster #: 369
Date and time: A copy of the poster will be available on-demand starting Friday, November 12th at 7:00 AM ET

Title: Development of Thrombospondin-1 as a clinical pharmacodynamic biomarker for VT1021, a first-in-class therapeutic agent that reprograms the tumor microenvironment.
Presenter: Jian Jenny Chen, PhD, Director Scientific Research and Development, Vigeo Therapeutics
Session: Virtual Poster Hall
Poster #: 375
Date and time: A copy of the poster will be available on-demand starting Friday, November 12th at 7:00 AM ET

About VT1021
Vigeo’s lead asset, VT1021, is a first-in-class dual modulating compound that blocks the CD47 immune checkpoint and activates the apoptotic and macrophage reprogramming activity of CD36. The result of the dual modulating activity is the induction of apoptosis as well as an increase in both CTL:Treg and M1:M2 macrophage ratio. The biological/therapeutic activity of VT1021 is mediated by the stimulation of thrombospondin-1 (Tsp-1). Through these dual-modulating effects VT1021 reprograms the tumor microenvironment (TME) from one that is immune suppressive, or "cold," to immune enhanced (or sensitized), or "hot," that are more susceptible to attack from the immune system. Vigeo is developing VT1021 as a therapeutic agent across a range of cancers, with a current focus on solid tumors.