On June 22, 2020 Tyme Technologies, Inc. (NASDAQ: TYME), an emerging biotechnology company developing cancer metabolism-based therapies (CMBTs), reported new preclinical findings that describe the unique mechanism of action of its lead cancer metabolism-based candidate, SM-88 (racemetyrosine), that are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Meeting from June 22 to June 24, 2020 (Press release, TYME, JUN 22, 2020, View Source [SID1234561337]).

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TYME’s CMBTs are proprietary investigational compounds that leverage cancer’s altered metabolism and associated vulnerabilities to specifically disrupt fundamental cellular processes. This can include altering protein synthesis, increasing oxidative stress, decreasing pH levels, and compromising protein or lipid barriers. In addition, CMBTs may target select survival mechanisms including autophagy, as well as alter the tumor microenvironment to improve immune recognition of the cancer cell.

"These preclinical results advance our understanding of the effect of SM-88 as a standalone oral therapy and begin to describe the mechanisms which underlie the clinical responses observed across multiple tumor types, both solid and liquid," said Jonathan Eckard, Ph.D., Chief Business Officer at TYME. "Key findings suggest that single agent SM-88 increases levels of oxidative stress in cancer cells; interferes with the multifaceted survival mechanism of autophagy; and modulates tumor immunity. These findings begin to highlight the unique profile of SM-88, and the ongoing work will aid in future clinical development of SM-88, both as monotherapy and in combination approaches with existing therapies."

TYME has initiated comprehensive in vitro and in vivo experimental studies that are designed to elucidate the mechanism of action and further characterize the anti-cancer effects of SM-88 as a standalone investigational compound. In a human colon cancer animal model study (HCT-116), the results showed that mice treated with the highest dose of oral SM-88 alone achieved a statistically significant (p < 0.05) reduction in tumor size compared to control-treated mice (n=11 per group). To further validate the anti-cancer effects of SM-88, a second in vivo study was conducted using a pancreatic cancer animal model (PAN02). The data from this study demonstrated that mice treated with intraperitoneally administered with the highest dose of SM-88 alone had a statistically significant tumor reduction compared to those treated with control alone (n=10 per group).

Increasing Reactive Oxygen Species (ROS):

Oxidative stress is the result of elevated levels of reactive oxygen species in cancer cells. Cancer cells are recognized to have elevated ROS levels and attempt to carefully balance these levels to prevent self-destruction. If oxidative stress is too high or prolonged it can lead to death of the cancer cell.

The effects of SM-88 on ROS levels was assessed in four cell lines: two pancreatic cancer cell lines (Pan02 and PANC1) and two breast cancer cell lines (4T1 and MCF-7). In this study, following 24 hours of exposure SM-88 achieved dose dependent increases in ROS production across three of the four cell lines (Pan02, 4T1 and MCF-7) and an overall increase in the fourth (PANC1).1

Modifying Autophagy:

Autophagy is cellular catabolic degradation that often occurs in response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolism. This process is utilized by cancer cells as a survival mechanism in periods when nutritional sources are low. However, cancer cells also leverage autophagy to reduce the expression of proteins that allow the body’s immune system to recognize them, such as the major histocompatibility complex 1- MHC1 in pancreatic cancer. This observation is supported by preclinical research at NYU Langone’s international center of excellence in translational and clinical research for gastrointestinal cancers as well as Yamamoto, Keisuke et al1. Therefore, disruptions of autophagy could have an impact on both viability and immune recognition of cancer cells.

In the present study, SM-88 altered autophagy in two pancreatic cancer cell lines (Pan02 and PANC1) and one ovarian cancer cell line (HeLa). SM-88 induced disruptions in autophagy were marked by elevations in LC3B and p62. Additional studies are ongoing to explore these effects and other important catabolic processes, such as mitophagy, a selective degradation of the mitochondria by autophagy.

In addition, in the PAN02 animal model, exposure to SM-88 appeared to impact tumor associated macrophages (TAMs), reducing the population of immunosuppressive M2 macrophages while preserving the more cancer directed M1 population. In addition, SM-88 treatment exhibited a dose dependent reduction in regulatory T lymphocytes, another cell type reported to create an immunosuppressive tumor environment.

Overall, these initial data suggest that SM-88 has direct effects on killing cancer cells by increasing oxidative stress and altering important processes like autophagy. In addition, SM-88 appears to cause immune modulation, creating a more toxic environment and inducing cancer cell death.

A primary goal of these preclinical studies is to help guide the company’s future clinical development of SM-88 and other novel CMBTs. These results and future experiments may help inform patient selection and identify complementary combination strategies with existing treatment options.

Inducing Immunomodulation:

Innovative therapeutics that leverage the immune system to fight cancer have demonstrated to be effective. Immuno-oncology continues to play a key role in the future treatment of cancer. Small molecule therapies that can either reduce immune suppression in the tumor microenvironment or enhance activation of cytotoxic lymphocyte responses to the tumor are actively being pursued. Unique treatment strategies with oral small molecules might be used as monotherapies or combined with other cancer therapies to increase and broaden their efficacy.

In this preclinical program, the potential effects of SM-88, as an oral small molecule, on the tumor microenvironment were evaluated. Flow cytometry was used to characterize the immune populations present in five randomly selected pancreatic cancer tumors (Pan02) collected from each group at the end of the study. Exposure to SM-88 appears to decrease intra-tumoral CD4+ T-cell populations, while preserving CD8+ populations, leading to a statistically significant (p= 0.015) decrease in the CD4+/CD8+ ratio in mice treated with the highest dose of SM-88 alone versus control. Based on these outcomes, exposure to SM-88 may decrease intra-tumoral regulatory T-cells (Tregs), a unique subset of helper T-cells, which play a critical role in reducing immunosuppressive signaling within the cancer cell. Small increases in intracellular B cell populations were also observed following treatment with oral SM-88.

Details of this preclinical study were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting from June 22 to June 24, 2020. The poster is available on our website (www.tymeinc.com/data-publications).

Details for the SM-88 poster presentation are as follows:

Title: In Vitro and In Vivo Anticancer effects of D/L-alpha-metyrosine (SM-88), a Novel Metabolism-Based Therapy

Authors: Alexander G. Vandell1, Jonathan Eckard1, Steve Hoffman1, Giuseppe Del Priore1, Martin Fernandez-Zapico2

Institutions: (1) Tyme Inc., New York, NY, (2) Mayo Clinic, Rochester, MN.

Virtual Session Date: June 22-24, 2020
Virtual Session Location: AACR (Free AACR Whitepaper) e-poster website
Abstract Number: 20-A-7314

About SM-88

SM-88 is an oral investigational modified proprietary tyrosine derivative that is believed to interrupt the metabolic processes of cancer cells by breaking down the cells’ key defenses and leading to cell death through oxidative stress and exposure to the body’s natural immune system. Clinical trial data have shown that SM-88 has demonstrated encouraging tumor responses across 15 different cancers, including pancreatic, lung, breast, prostate and sarcoma cancers with minimal serious grade 3 or higher adverse events. SM-88 is an investigational therapy that is not approved for any indication in any disease.

About TYME-88-Panc Pivotal Trial

The TYME-88-Panc pivotal trial applies the latest advances in the field of cancer metabolism by evaluating the efficacy and safety of an oral investigational compound that targets the metabolic mechanisms of the disease at its source. A prospective, open label pivotal trial in metastatic pancreatic cancer for patients who have failed two lines of any prior systemic therapy. The trial is designed to evaluate the safety and efficacy of SM-88 used with MPS (methoxsalen, phenytoin and sirolimus) in advanced pancreatic cancer and will measure multiple endpoints, including overall survival, progression free survival, relevant biomarkers, quality of life, safety, and overall response rate. Learn More.

On June 22, 2020 Exicure, Inc. (NASDAQ: XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA) constructs, reported that updated pharmacodynamic and safety data at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, occurring June 22 – 24, 2020 (Press release, Exicure, JUN 22, 2020, View Source [SID1234561336]).

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The AACR (Free AACR Whitepaper) poster, titled "Phase 1b/2 Study of an Intratumoral TLR9 Agonist Spherical Nucleic Acid (AST-008) and Pembrolizumab: Evidence of Immune Activation," is presenting new preliminary pharmacodynamic and safety data of cavrotolimod (AST-008), alone and in combination with pembrolizumab, from Exicure’s ongoing Phase 1b/2 clinical trial (ClinicalTrials.gov identifier: NCT03684785). Cavrotolimod (AST-008) is a novel SNA configuration of a toll-like receptor 9 (TLR9) agonist oligonucleotide, designed to trigger anti-tumor immune responses.

Gene expression analysis data from patient tumor biopsies demonstrated increases in leukocytes in injected tumors after intratumoral (IT) cavrotolimod (AST-008) alone and in combination with pembrolizumab versus baseline. Uninjected tumors also showed increased immune cell levels after patients received cavrotolimod (AST-008) and pembrolizumab, suggesting immune cell trafficking.

Dose-dependent activation of key immune cells, including cytotoxic T cells and natural killer cells, as well as increases in cytokine/chemokine levels were observed in patient blood after IT cavrotolimod (AST-008) treatment alone, and cavrotolimod (AST-008) plus pembrolizumab treatment. We expect that activation of these cell types and expression of immune system signaling proteins may help produce anti-tumor effects.

Cavrotolimod (AST-008) was well-tolerated, with a safety profile consisting primarily of injection site reactions and flu-like symptoms, which is believed to reflect local and systemic immune activation. No cavrotolimod (AST-008)-related serious adverse events or dose limiting toxicity have been reported.

Using these data, a recommended Phase 2 dose of 32 mg cavrotolimod (AST-008) has been identified for the Phase 2 portion of the clinical trial now underway, where cavrotolimod (AST-008) will be given in combination with pembrolizumab or cemiplimab for the treatment of locally advanced or metastatic Merkel cell carcinoma or cutaneous squamous cell carcinoma, respectively, in patients with progression despite approved anti-PD-(L)1 therapy.

This poster is being presented during the AACR (Free AACR Whitepaper) Virtual Meeting II in the session Late-Breaking Research: Clinical Research 1 / Endocrinology under abstract number LB-140. The poster will be available for viewing from June 22 – 24.

On June 22, 2020 Lantheus Holdings, Inc. (the "Company") (NASDAQ: LNTH), the parent company of Lantheus Medical Imaging, Inc. ("LMI"), a global leader in the development, manufacture and commercialization of innovative diagnostic imaging agents and products, reported that it has completed its previously announced merger with Progenics Pharmaceuticals, Inc. ("Progenics") (Nasdaq: PGNX), an oncology company developing innovative medicines and artificial intelligence to find, fight and follow cancer (Press release, Lantheus Medical Imaging, JUN 22, 2020, View Source [SID1234561335]). The merger agreement was first announced on October 2, 2019.

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"Today marks an important day for Lantheus and Progenics. This combination forms an innovative company with a diversified diagnostics and therapeutics portfolio," said Mary Anne Heino, Lantheus President and Chief Executive Officer. "The transaction leverages Lantheus’ long-standing expertise in complex manufacturing, supply chain and commercial excellence, with Progenics’ three leading FDA approved products, clinical pipeline and development capabilities. We’re excited to welcome the talented Progenics employees to the Lantheus organization to help build upon our solid foundation."

Upon completion of the merger, Progenics stockholders received, for each share of Progenics common stock, 0.31 of a share of Lantheus common stock and one non-tradeable contingent value right, which is payable in two contingent payments, subject to a cap, upon the achievement of certain milestones related to the financial performance of PyLTM (18F-DCFPyL), Progenics’ prostate-specific membrane antigen targeted imaging agent designed to visualize prostate cancer.

The Company will continue to trade on Nasdaq under the ticker symbol LNTH. Progenics is being delisted.

On June 22, 2020 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, reported its broad viral vector expertise and their potential to transform the fight against cancer at the AACR (Free AACR Whitepaper) 2020 Virtual Annual Meeting II (Press release, Transgene, JUN 22, 2020, View Source [SID1234561334]).

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myvac
Transgene presents data demonstrating that the prediction algorithm used to customize TG4050 for each patient is accurate at identifying immunogenic cancer mutations even among a large set of candidate tumor mutations.
The poster is entitled:
"Performance of neoantigen prediction for the design of TG4050, a patient specific neoantigen cancer vaccine" (#4566)

Because only 1 to 5% of tumor mutations are immunogenic, they can be particularly difficult to identify. To demonstrate the accuracy of the prediction algorithm, Transgene and NEC analyzed 6 tumor samples from patients with non-small cell lung cancer eligible for tumor resection. NSCLC are highly mutated tumors that thus generated a massive amount of data that proved compatible with the machine learning approach.
More than 86% of top ranked peptides identified were immunogenic. The NEC/Transgene prediction system was also able to identify immunogenic peptides that were missed by netMHCpan 4.0, the industry standard predictor.
These results demonstrate that the specificity of our approach outperforms the industry standard and are expected to translate in enhanced activity in patients.
Two PoC Phase 1 clinical trials evaluating TG4050, the first therapeutic vaccine leveraging this algorithm, are ongoing in the USA and in Europe.
The poster can be downloaded on the AACR (Free AACR Whitepaper) website and here.

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Invir.IOTM

Transgene is presenting preclinical data on two oncolytic viruses derived from the Invir.IO platform, the clinical-stage BT-001 and the new candidate TG6010.

BT-001
Transgene and BioInvent are presenting a poster that supports the clinical development of BT-001, an anti-CTLA4 antibody-encoding oncolytic virus, against solid tumors:
"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." (#5602)

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 1 clinical trial expected to start before the end of 2020.
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 tumor cells were re-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 anti-PD-1 treatment – opening up potential combinations for powerful dual checkpoint blockade treatment regimens
The poster can be downloaded on the AACR (Free AACR Whitepaper) website and here.

More details are available in the press release distributed simultaneously and available on www.transgene.fr.

TG6010
Transgene is also presenting preclinical data obtained with TG6010, an Invir.IO based oncolytic virus encoding human cytidine deaminase (hCD) in a poster entitled:
"Oncolytic Vaccinia Virus expressing Cytidine Deaminase induces DNA damage and shows potent anti-tumor effects" (#4576)

In addition to the intrinsic properties of the Invir.IO viral vector (superior oncolysis, immunogenic cell death, stimulation of innate and adaptive immune responses), TG6010 directly expresses hCD in the tumor micro-environment.
hCD is an enzyme that converts cytidine into uridine. Cytidine being one of the 4 nucleotides that compose DNA, it is absolutely necessary to enable cell replication and tumor progression.
By expressing hCD in the tumor, TG6010 will indirectly deprive cancer cells from the material they need to replicate, leading to DNA instability and ultimately cell death (apoptosis).
The preclinical data presented at AACR (Free AACR Whitepaper) also show that the activity of TG6010 is associated with a significant decrease of available cytidine in the plasma, which resulted in a distant antitumor effect.
Additional experiments are being conducted to further assess the potential of TG6010 as a single agent and in combination with other treatments that target tumor cells DNA, and DNA repair mechanisms.

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, reported new proof-of-concept data for two different types of monoclonal antibodies targeting tumor necrosis factor receptor 2 (TNFR2) (Press release, BioInvent, JUN 22, 2020, View Source [SID1234561333]).

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TNFR2 is particularly upregulated on tumor-associated regulatory T cells (Tregs) and has been shown to be important for their expansion and survival. As a part of its Treg program, BioInvent identified and characterized a wide panel of TNFR2-specific antibodies, generated from its proprietary n-CoDeR library and unique F.I.R.S.TTM discovery tool, of which BI-1808 and BI-1910 are the lead development candidates.

In vivo studies show that both ligand-blocking and agonistic antibodies regress large established tumors and synergize with anti-PD-1 therapy. Further mode-of-action dissection demonstrate that while the ligand-blocking antibody depleted intratumoral Tregs, the agonist increased intratumoral CD8+ T effector cells. Both antibodies expanded tumor-specific CD8+ T cells and induced long-lasting T cell memory.

Main points from the presentation included:

The two different types of TNFR2 targeting antibodies are being developed by BioInvent – BI-1808 (a ligand blocker), and BI-1910 (an agonist).
BI-1808 and BI-1910 act through differential targeting of intratumoral Tregs and CD8+ T cells to regress large inflamed tumors and sensitize the host to anti-PD-1 therapy.
Treatment with both antibodies result in an increase in numbers and activation of tumor specific T cells at the tumor site.
Martin Welschof, CEO of BioInvent, says: "The proof-of-concept data presented in this poster show very exciting potential for these two TNFR2 antibodies in improving treatment for solid cancers, and are further reinforcement of the productivity of BioInvent’s technology platform. This provides a foundation for further development and we look forward to investigating these antibodies in clinical trials, with BI-1808 expected to start a Phase l study in 2020."

These promising findings are available in a poster, which can be downloaded from the BioInvent website.

Title of the poster: "Targeting TNFR2 for Cancer Immunotherapy – Ligand blocking depletors versus receptor agonists"
Authors: Linda Mårtensson, Kirstie Cleary, Monika Semmrich, Mathilda Kovacek, Petra Holmkvist, Carolin Svensson, Mimoza Demiri, Therese Blidberg, Ulla-Carin Thornberg, Vincentiu Pitic, Osman Dadas, Sean H Lim, Stephen A Beers, Mark S Cragg, Björn Frendéus, Ingrid Teige
Session Date: June 22-24, 2020
Poster Session Title: Immune Checkpoints 1
Poster Number: 936 // Abstract Number: 5892