On June 22, 2020 Medigene AG (Medigene, FSE: MDG1), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, reported insights from preclinical studies on its PD1-41BB switch receptor at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II taking place from 22 – 24 June 2020 (Press release, MediGene, JUN 22, 2020, View Source;s%20scientists%20demonstrated%20that%20the,especially%20against%20solid%20tumor%20cells.&text=One%20prominent%20inhibitory%20axis%20exploited,T%20cell%20activity%20in%20tumors. [SID1234561330]). The e-poster is available online today on the first day of the virtual conference as well as on Medigene’s website.

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Medigene’s scientists demonstrated that the PD1-41BB switch receptor significantly improves the functional activity of T cell receptor-modified T cells (TCR-Ts) especially against solid tumor cells. Many solid tumors create a "hostile" microenvironment that suppresses immune cell attack, enabling tumors to survive and grow. To this end, tumor cells employ so-called "checkpoint mechanisms" to impede T cell activity. One prominent inhibitory axis exploited by tumors, the PD1-PDL1 pathway, is known to shut down T cell activity in tumors. Medigene’s PD1-41BB molecule is designed to convert the PD-1 "stop" signal induced by tumor cells to a "go" command by switching signals inside the T cells to activation, thereby overcoming the PD1-PDL1 inhibitory checkpoint blockade.

Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer of Medigene: "In preclinical studies we could show that the addition of the PD1-41BB switch receptor to our TCR-Ts strongly enhances the antigen-specific functions of the TCR-Ts against solid tumors.

"Based on these promising results, we believe that the PD1-41BB switch receptor will ultimately enable our TCR-Ts to be more active in patients with solid tumors which have previously been very difficult to treat due to multiple mechanisms of immunosuppression. Furthermore, exploiting the PD1-PDL1 pathway to increase TCR-T activity through our switch receptor can be done in a targeted, localized manner, thereby avoiding the challenges of systemic side-effects that accompany treatment with existing checkpoint inhibitors."

Presentation Details:

Poster #3231 "The chimeric co-stimulatory receptor PD1-41BB enhances the function of T cell receptor (TCR)-modified T cells targeting solid tumors"

(E-poster with an audio description)

Session Adoptive Cell Therapy 3

Link to abstract https://bit.ly/3g3Q44H

Date 22 June 2020, 9:00 am – 06:00 pm (EDT)

Download www.medigene.com/technologies/abstracts
About Medigene’s PD1-41BB switch receptor:

Checkpoint inhibition via PD1-PDL1 pathway: Solid tumor cells are known to be sensitive to killing by activated T cells. Tumor cells can escape this killing activity by expressing inhibitory molecules, so-called ‘checkpoint proteins’, such as Programmed Death Ligand 1 (PD-L1) on their surface. When this occurs, activated T cells which express PD-1, the natural receptor for PD-L1, are inactivated. The expression of PD-L1 by tumors represents an adaptive immune resistance mechanism that can lead to tumor survival and growth.

The 4-1BB co-stimulatory signaling pathway: Effective T cell immune responses to antigens typically require costimulatory signals to be received alongside the primary antigenic stimulation via the T cell receptor (TCR). The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to positively enhance T cell responses.

Medigene’s PD1-41BB switch receptor takes advantage of the binding of PD-1 on the T cells to PD-L1 on tumors. In the switch receptor, the inhibitory signaling domain of PD-1 has been substituted with the activating signaling domain of 4-1BB. As a result, the switch receptor then delivers an activating signal to the TCR-T cells (not the usually inhibitory signal of PD-1). This enables the PD1-41BB-modified TCR-T cells to proliferate strongly in the presence of PD-L1-positive tumor cells and to mediate greater killing of tumor cells upon repeated exposure. Additionally, signals mediated through the switch receptor also enhance metabolic fitness of TCR-T cells, enabling better function in conditions of low levels of glucose or high levels of the immunosuppressive factor TGF-ß, two conditions that are characteristic of strongly hostile tumor microenvironments.

On June 22, 2020 PureTech Health plc (LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to discovering, developing and commercializing highly differentiated medicines for devastating diseases, reported that new data establishing galectin-9 as a novel target for cancer immunotherapy and providing compelling evidence that therapies targeting galectin-9 may enable the immune system to attack an array of solid tumors (Press release, PureTech Health, JUN 22, 2020, View Source [SID1234561346]). The data were shared in a scientific poster presented at the June session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting.

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PureTech is developing a first-in-class, fully human monoclonal antibody targeting galectin-9. The product candidate, LYT-200, is expected to enter a first-in-human, Phase 1a/1b study in 2020 in hard-to-treat cancers, including pancreatic, cholangiocarcinoma and certain types of colorectal and liver cancers, which remain insufficiently responsive or resistant to currently approved checkpoint inhibitors. PureTech has previously presented data demonstrating LYT-200’s efficacy in reducing tumor growth and reactivating human effector T cells in preclinical, patient-derived tumor culture models.

"These new data clearly establish the importance of galectin-9 as a therapeutic target, given that its high expression across tumor types correlates with poor patient outcomes. Our analysis of more than 1,000 samples from human breast cancer tumors found that high levels of galectin-9 are associated with shorter time to disease relapse as well as with a tumor microenvironment that lacks cytotoxic CD8+ T cells that would otherwise be able to attack the tumor," said Joseph Bolen, PhD, chief scientific officer at PureTech. "Our first-in-class monoclonal antibody, LYT-200, is designed to target and inhibit galectin-9 and thereby reverse this suppression of the immune system to boost its ability to destroy tumors. We’re proud to be presenting this research at AACR (Free AACR Whitepaper) and look forward to advancing LYT-200 into the clinic later this year, as well as to progressing our work on galectin-9 as a biomarker."

The AACR (Free AACR Whitepaper) poster details a study undertaken by PureTech and its academic collaborators to evaluate the importance of galectin-9 expression in the tissues of cancer patients. The study is believed to include the largest cohort of breast cancer patient samples ever evaluated in this context, as well as robust cohorts of pancreatic and cholangiocarcinoma cases, and it found high expression of galectin-9 across all of these tumor types. Importantly, the highest levels of galectin-9 correlated with shorter time to disease relapse and poor survival. Strong galectin-9 expression was observed on the membranes of tumors with poor prognosis, which indicates this target is attractive for an antibody therapeutic such as LYT-200. In breast cancer, galectin-9 expression was associated with tumors showing worse pathological features, such as high tumor grade and estrogen receptor negativity, as well as features characteristic of an immunosuppressed tumor microenvironment, including the absence of CD8+ T cells. Collectively, these data suggest that galectin-9 could be significant both as a therapeutic target for a range of cancers and as a cancer biomarker, which PureTech intends to explore further for patient stratification.

On June 22, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematologic and oncologic diseases, reported findings on the investigational cyclin-dependent kinase 9 (CDK9) inhibitor alvocidib and TP-1287, an oral prodrug of alvocidib (Press release, Tolero Pharmaceuticals, JUN 22, 2020, View Source [SID1234561362]). These data, highlighting a novel biomarker detection method for CDK9 inhibition and evaluating the anti-tumor activity of alvocidib and TP-1287 in hematologic cancer cells, are being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Meeting II, taking place June 22-24, 2020.

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The virtual poster presents a novel biomarker detection method to assess CDK9 inhibition through reduction of myeloid cell leukemia-1 (MCL-1) expression and of phosphorylation of RNA polymerase II (p-RPB1). Using peripheral blood mononuclear cells (PBMCs) as a surrogate tissue, this method was able to identify CDK9 inhibition in healthy donor PBMCs treated with alvocidib, the active form of TP-1287, ex vivo. This was also identified in a Phase 1 study participant receiving TP-1287 in an ongoing trial in patients with refractory solid tumors. These data may suggest a novel clinical biomarker approach for assessing overall CDK9 inhibition in patients.1

In preclinical studies, TP-1287 and alvocidib also showed potent cell-based activity in vitro and tumor growth inhibition in vivo across multiple hematologic cell lines, including acute myeloid leukemia (AML) and multiple myeloma (MM). Alvocidib was found to suppress p-RPB1 and the transcription of MCL-1, both downstream effectors of CDK9 activation, across cell lines and in normal PBMCs. Separately in a MM xenograft model, TP-1287 was shown to inhibit tumor growth, suppress p-RPB1 and the transcription MCL-1, and induce apoptosis.1

"Together, the results presented at AACR (Free AACR Whitepaper) show the inhibitory downstream effects of TP-1287 and its active form, alvocidib, across multiple AML and MM cell lines and in in vivo mouse models, which can be measured by a novel biomarker detection method," said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. "Given the identification of this novel biomarker detection method to assess CDK9 inhibition, and the ability of TP-1287 to deliver alvocidib in the clinic, these findings support continued evaluation of the potential of CDK9 inhibition and the use of surrogate biomarkers in the ongoing study of TP-1287."

Below are the details for the presentation:

Abstract Title

Details

Author

Pharmacodynamic biomarker strategies
for CDK9 inhibition

Abstract# 5813

June 22, 2020

9 a.m. ET

Poster Presentation

Yuta Matsumura, Tolero
Pharmaceuticals

About TP-1287

TP-1287 is an investigational oral cyclin-dependent kinase 9 (CDK9) inhibitor under evaluation in a Phase 1 study in patients with advanced solid tumors (NCT03604783). TP-1287 has shown favorable oral bioavailability in preclinical models.

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the ongoing Phase 2 Zella 202 study in patients with acute myeloid leukemia (AML) who have either relapsed on or are refractory to venetoclax in combination with azacitidine or decitabine (NCT03969420). Alvocidib is also being evaluated in Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with azacitidine or decitabine (NCT03593915), and in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.2 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.3 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.2,4 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).5,6 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.5 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.2

On June 22, 2020 Chimerix (NASDAQ:CMRX), a biopharmaceutical company focused on accelerating the development of medicines to treat cancer and other serious diseases, reported the appointment of Allen Melemed, M.D., M.B.A., as Chief Medical Officer (Press release, Chimerix, JUN 22, 2020, View Source [SID1234561433]).

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"We are delighted to welcome Dr. Melemed as a key member of our management team. We look forward to leveraging his considerable clinical and regulatory experience as a distinguished pharmaceutical executive. His vast experience bringing oncology therapeutics through development and approval across multiple modalities will be invaluable as we initiate our dociparstat sodium (DSTAT) Phase 3 trial in first line acute myeloid leukemia (AML), our ongoing Phase 2/3 trial to combat acute lung injury (ALI) in COVID-19 patients, and finalize our rolling New Drug Application (NDA) for brincidofovir (BCV) as a medical countermeasure for smallpox," said Mike Sherman, Chief Executive Officer of Chimerix.

"I am particularly pleased to be joining Chimerix at such an important juncture in its growth trajectory. DSTAT’s potential to improve survival in newly-diagnosed AML patients is critically important in a disease where five-year survival rates remain far too low, particularly in older populations. Furthermore, DSTAT’s broad mechanism to manage inflammation and hematologic disorders offers promise to treat ALI in COVID-19 patients and underpins its mechanism of action in ALI beyond the current pandemic. I look forward to working with the team to advance our pipeline of important therapies and to bringing these life-saving treatments to patients in need," said Dr. Melemed.

Dr. Melemed joins Chimerix from Eli Lilly and Company, where he spent more than 20 years dedicated to the clinical development and approval of oncology medicines across a broad range of tumor types including VERZENIO, CYRAMZA, LARTRUVO , ALIMTA and RETEVMO among others. Most recently, he served as a Distinguished Medical Fellow and Senior Director of Regulatory Affairs Oncology, North America. In addition to his role at Eli Lilly, Dr. Melemed was an attending physician in pediatric oncology at Indiana University (IU) School of Medicine, Riley Children’s Hospital from 1996 to 2012.

Dr. Melemed holds a B.S. in Genetics and Cell Biology from the University of Minnesota and a M.D. from the University of Minnesota School of Medicine. In addition, he completed his residency in pediatrics at the University of Wisconsin, Madison and fellowship in pediatric hematology/oncology at IU School of Medicine. He earned an M.B.A. from the University of Chicago Booth School of Business. Dr. Melemed has authored dozens of scientific and clinical publications.

On June 22, 2020 Ankrin Therapeutics has been awarded 2.4 million DKK from Innovation Fund Denmark’s ‘Innobooster’ program (Press release, Ankrin Therapeutics, JUN 22, 2020, View Source [SID1234572466]). The Grant will support Ankrin’s discovery programs targeting so-called homologous recombination (HR), a critical DNA damage response (DDR) mechanism in cancer cells. Ankrin’s novel concept provides a new approach to inhibit HR with potential to treat a broad spectrum of cancers.

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