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 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer and autoimmune diseases, reported the presentation of new preclinical data from three XmAb 2+1 bispecific antibody programs and its IL-12-Fc cytokine program during the second session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Xencor, JUN 22, 2020, View Source [SID1234561353]). Poster presentations and audio descriptions are available to registrants of the AACR (Free AACR Whitepaper) Virtual Annual Meeting.

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"Compared to many therapeutic targets for blood cancers like CD19 or CD20, which are generally restricted to specific cell populations, solid tumor targets often are expressed on a range of normal tissues, including critical organs, which can limit the therapeutic index for drug candidates," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "The XmAb 2+1 bispecific antibody format has two domains that bind the tumor target, and this bivalent binding can preferentially bind tumor cells with high target expression, potentially sparing low-expression normal tissues. This selectivity and potency tuning of T-cell activation may provide for higher efficacy and tolerability compared to other bispecific antibody formats.

"We have also presented data from our IL-12-Fc cytokine program, which builds off of our prior work with IL-15 and IL-2. IL-12 is a potent immune signaling protein that can have a dramatic effect on shrinking tumors; however, prior clinical studies have demonstrated IL-12 to have a narrow therapeutic window, limiting potential response rates. We created an IL-12 Fc-fusion with reduced potency in order to improve tolerability, slow receptor-mediated clearance and prolong the molecule’s half-life," said Dr. Desjarlais.

XmAb 2+1 Bispecific Antibodies

Poster: 2286, "XmAb30819, an XmAb 2+1 ENPP3 x CD3 bispecific antibody for RCC, demonstrates safety and efficacy in in-vivo preclinical studies"
Poster: 5663, "Affinity tuned XmAb 2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models"
Poster: 5654, "Affinity tuned XmAb 2+1 anti-mesothelin x anti-CD3 bispecific antibody induces selective T cell directed cell cytotoxicity of human ovarian cancer cells"
ENPP3, PSMA and MSLN are tumor-associated antigens associated with renal cell carcinoma (RCC), prostate cancer and ovarian cancer, respectively, but they are not restricted to tumors and exhibit base level expression on normal tissues. Xencor has expanded its T-cell redirecting CD3 class of bispecific antibodies to create an XmAb 2+1 bispecific antibody format, utilizing an engineered heterodimeric Fc domain, two identical tumor targeting domains and one CD3 targeting domain. The affinities for antigen binding are reduced, which allows for selective engagement of high antigen-expressing tumor cells over low antigen-expressing normal cells. In preclinical models, XmAb 2+1 bispecific antibodies bound preferentially to tumor cells compared to normal cells and effectively recruited T cells to kill tumor cells selectively. Additional data presented on XmAb 2+1 PSMA x CD3 bispecific antibody candidates and XmAb30819, a first-in-class XmAb 2+1 ENPP3 x CD3 bispecific antibody, demonstrated strong reversal of tumor growth in human-cell engrafted mouse models of disease. Further data presented from preclinical studies of XmAb30819 in non-human primates demonstrated it was well-tolerated with expected pharmacodynamics and an antibody-like half-life.

IL-12-Fc Cytokine

Poster: 5549, "Potency-reduced IL-12 heterodimeric Fc-fusions exhibit strong anti-tumor activity"
IL-12 is a heterodimeric proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. IL-12-Fc fusions were engineered with potency-reduced IL-12 to improve its potential tolerability, slow receptor-mediated clearance and prolong its half-life in vivo. In preclinical models, these potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity concurrent with activation and proliferation of CD8+ T cells, increased PD-1 checkpoint expression and increased levels of interferon gamma in serum. Anti-tumor activity was enhanced when combined with an anti-PD-1 antibody.

The posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

On June 22, 2020 Sutro Biopharma, Inc. (NASDAQ: STRO), a clinical-stage drug discovery, development and manufacturing company focused on the application of precise protein engineering and rational design to create next-generation oncology therapeutics, reported the presentation of new preclinical data for its folate receptor alpha (FolRα) targeting antibody-drug conjugate, STRO-002, at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II from June 22-24, 2020 (Press release, Sutro Biopharma, JUN 22, 2020, View Source;301080795.html [SID1234561369]). The data, being presented by Sutro’s Chief Scientific Officer, Trevor Hallam, Ph.D., demonstrates STRO-002’s immune-modulating properties and potentiation by PD-L1 blockade.

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The results of the study showed that in FolRα positive tumor cells, STRO-002 treatment induced hallmarks of immunogenic cell death, killing tumor cells while activating immune cells, including monocytes. When combined in mouse tumor models with avelumab, an anti-human & mouse PD-L1 monoclonal antibody, the combination treatment enhanced efficacy leading to more complete responses and increased killer T cells, than either agent alone. Importantly, the data suggest that a single dose of STRO-002 when combined with a PD-1/PD-L1 blockade could provide an effective and protective anti-tumor immune response.

"These data suggest that STRO-002 can drive immune-modulatory responses that can cause complete tumor regression, tumor specific T cell activation and adaptive anti-tumor immunity," said Dr. Hallam. "The results here support the clinical evaluation of STRO-002 in combination with anti-PD1 or anti-PD-L1 agents. While we believe STRO-002 as a single agent may demonstrate clinical benefit in certain tumors resistant to checkpoint inhibitor monotherapies, we are excited at the prospect of evaluating potential additional positive impacts on cancer patients that may result from combination treatment regimens involving STRO-002 with other checkpoint inhibitors."

"An important part of our STRO-002 clinical development strategy includes evaluating these data to determine an optimal combination regimen to take into clinical trials," said Sutro Chief Medical Officer, Arturo Molina, M.D. "We anticipate evaluating STRO-002 in combination studies in addition to our single agent studies. We currently expect to initiate a STRO-002 combination clinical trial in 2021."

STRO-002 is an antibody-drug conjugate directed against FolRα, a membrane receptor glycoprotein, which is highly expressed in ovarian cancer and endometrial cancer and is composed of a FolRα antibody conjugated to a tubulin inhibitor hemiasterlin using a cleavable linker.

A Phase 1, open-label, multicenter, dose escalation trial with dose expansion of STRO-002 is ongoing, designed to identify the maximum tolerated dose, the recommended Phase 2 clinical dose, and to evaluate the safety, tolerability, and preliminary anti-tumor activity of STRO-002 in adults with advanced epithelial ovarian cancer, including fallopian or primary peritoneal cancer, and endometrial cancer. The trial is registered with clinicaltrials.gov identifier NCT03748186. Sutro discovered, developed and manufactures STRO-002 using its proprietary XpressCF+ cell-free protein synthesis technology.

Presentation Details:

Title: STRO-002, an anti-FolRα ADC, demonstrates immune-modulating properties
and potentiates PD-L1 blockade
Abstract Number: 2250
Session Title: Immune Mechanisms Invoked by Therapies 2
Date/Time: June 22, 2020, 9:00 a.m. – 6:00 p.m. EDT
Presenter: Trevor Hallam, Ph.D.

The e-poster presentation can be found on the AACR (Free AACR Whitepaper) website and is also accessible through the Clinical/Scientific Presentation and Publication Highlights page of the News section of Sutro Biopharma’s website at www.sutrobio.com on the day of the poster presentation.

Additionally, on June 24th Sutro’s partner Merck KGaA, Darmstadt, Germany, will be presenting preclinical data from the collaboration’s pre-Development Candidate, M1231, a first-in-class bispecific antibody-drug conjugate targeting EGFR and MUC1.

Presentation Details:

Title: M1231: A first-in-class bispecific antibody-drug conjugate targeting EGFR
and MUC1
Abstract Number: 5686
Session Title: Emerging Mechanisms of Resistance to Targeted Therapies
Date/Time: June 24, 2020, 10:05 a.m. – 10:15 a.m. EDT
Presenter: Jan Anderl, Ph.D.

On June 22, 2020 TG Therapeutics, Inc. (NASDAQ: TGTX), reported preclinical data presentation for TG-1701, the Company’s highly selective, BTK inhibitor, at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, being held virtually (Press release, TG Therapeutics, JUN 22, 2020, View Source [SID1234561282]).

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer stated, "We are encouraged by the preclinical data presented today which showed TG-1701 to be just as active and more selective for BTK than ibrutinib, a currently approved BTK inhibitor. Importantly, we are pleased to see the additive anti-tumor inhibition seen when TG-1701 was combined with umbralisib plus ublituximab (U2), supporting our combinatorial approach to development. The proprietary triple combination regimen of U2 + TG-1701 has shown strong responses clinically in an ongoing Phase 1 study, and we look forward to continuing this research and presenting updated data on TG-1701 as a monotherapy and as a triple regimen with U2."

Highlights from the data presentation are included below.

Title: TG-1701, a novel irreversible Bruton’s kinase (BTK) inhibitor, does not inhibit anti-CD20-driven ADCC and ADCP in vitro, and cooperates with the glycoengineered anti-CD20 mAb, ublituximab, in in vivo mantle cell lymphoma models

In vitro and in vivo studies were undertaken to evaluate the activity of TG-1701 alone and in combination with ublituximab and umbralisib in models of lymphoma
TG-1701 showed greater selectivity for BTK than, and similar activity to, ibrutinib in mantel cell lymphoma (MCL) models
TG-1701, in contrast to ibrutinib, did not block ublituximab-driven antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cell phagocytosis (ADCP) in vitro
In vivo xenograft studies suggested that TG-1701 synergized with the U2 combination, resulting in greater anti-tumor activity than either TG-1701 or U2 alone

On June 22, 2020 Onconova Therapeutics, Inc. (NASDAQ: ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with an initial focus on myelodysplastic syndromes (MDS) reported an investigator-initiated Phase 1/2a trial of oral rigosertib plus nivolumab in advanced metastatic KRAS mutated (KRAS+) lung adenocarcinoma has begun enrolling patients (Press release, Onconova, JUN 22, 2020, View Source [SID1234561322]).

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"Over half of non-small cell lung cancers are classified as lung adenocarcinomas; of these, the largest subset has a KRAS mutation as the predominant genetic driver," said Dr. Steven Fruchtman, President and CEO, Onconova Therapeutics. "Despite discovering the KRAS mutation over 30 years ago, little progress has been made in KRAS+ directed treatments. The work under Dr. Rajwanth Veluswamy’s leadership at the Icahn School of Medicine is an important step towards determining if rigosertib, as a RAS-mimetic, can change that."

The investigator-initiated trial is an open-label, dose-escalating Phase 1 study followed by a Phase 2a dose-expansion phase to study the combination of oral rigosertib and nivolumab in metastatic KRAS+ lung adenocarcinoma patients who have progressed on standard frontline treatment. The study will assess safety and efficacy. Additional details are available on www.clinicaltrials.gov (NCT04263090).

"The novel combination of rigosertib with an anti-PD-1 antibody targets two of the most important oncogenic pathways in cancer biology," said Dr. Rajwanth Veluswamy, Assistant Professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai. "This study will evaluate the safety and tolerability of this combination in KRAS mutated NSCLC in which patients have failed frontline immunotherapy. The study will explore efficacy of the combination in this common lung cancer subset and will also determine if rigosertib may restore sensitivity to the PD-1 blockade."

About Rigosertib

Rigosertib, Onconova’s lead candidate, is a proprietary Phase 3 small molecule. A key publication in a preclinical model reported rigosertib’s ability to block cellular signaling by targeting RAS effector pathways (Divakar, S.K., et al., 2016: "A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling." Cell 165, 643). Onconova is currently in the clinical development stage with oral and IV rigosertib, including clinical trials studying single agent IV rigosertib in second-line higher-risk MDS patients (pivotal Phase 3 INSPIRE trial) and oral rigosertib plus azacitidine in HMA naive and refractory higher-risk MDS patients (Phase 2). Patents covering oral and injectable rigosertib have been issued in the US and are expected to provide coverage until at least 2037.