On July 6, 2022 Mnemo Therapeutics, a biotechnology company developing transformational immunotherapies, reported a publication in Nature Communications demonstrating that the histone lysine methyltransferase enzyme Suv39h1 plays not only a key role in T cell persistence, but also in T cell activation and exhaustion (Press release, Mnemo Therapeutics, JUL 6, 2022, View Source [SID1234616521]). This research was conducted at Institut Curie between the lab of Sebastian Amigorena, Ph.D., CNRS research director, head of the Immune Responses and Cancer Team (Immunity and Cancer Unit – Institut Curie/Inserm) and scientific co-founder of Mnemo, and the lab of Eliane Piaggio, Ph.D., Inserm research director and head of the Translational Immunotherapy Team (Immunity and Cancer Unit, Institut Curie/Inserm).

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"T cell exhaustion and lack of persistence are two key challenges that hinder effective and durable immunotherapy treatments for tumors," said Mnemo Chief Executive Officer, Robert LaCaze. "Through Suv39h1 inactivation, Mnemo aims to create therapies with increased durability and activity."

Previous research, exclusively licensed to Mnemo from the lab of Dr. Amigorena, demonstrated that Suv39h1 is a key enzyme involved in the epigenetic regulation of immune cell memory, and that deletion of Suv39h1 results in increased immune cell memory and more durable therapeutic responses. The research demonstrated in the Nature publication goes on to show that this enzyme is a key factor in regulating T cell exhaustion.

"As is known, the potency of current treatments such as immune checkpoint inhibitors (i.e. anti-PD-1) is limited by repeated stimulation of T cells in a tumor rich environment, resulting in T cell exhaustion," said Dr. Amigorena. "The current study showcases that Suv39h1 acts as an epigenetic checkpoint inhibitor that, when coupled with anti-PD-1 treatment, results in increased T cell activity and decreased T cell exhaustion."

Key takeaways from the study include:

Suv39h1 KO CD8+ T cells are more responsive to T-cell receptor (TCR) activation and become highly cytolytic following PD-1 blockade, resulting in increased tumor killing potency.
Deletion of Suv39h1 resulted in higher CD8+ T cell tumor infiltration when coupled with anti-PD-1 treatment.
CD8+ T cells in Suv39h1 KO mice treated with anti-PD-1 displayed the highest level of a protease (GZMb) responsible for T cell induced apoptosis of tumor cells, despite displaying elevated levels of biomarkers associated with exhaustion.
Suv39h1 deletion resulted in increased chromatin accessibility in regions responsible for immune cell signaling and cytotoxicity during anti-PD-1 treatment, compared to WT with anti-PD-1 treatment.
Inhibition of Suv39h1 via small molecules mimicked Suv39h1 deletion in mouse models, reinforcing that this enzyme is playing a direct role in T cell activity.
"Limited potency, durability, and cancer-specific targets impede the efficacy of current immunotherapies, leading to off-target side effects and patient relapse," said Mnemo Co-Founder and Chief Operating Officer, Alain Maiore. "Alongside our EnfiniT Discovery Engine that identifies novel cancer targets, this research demonstrates Mnemo’s commitment to addressing multiple bottlenecks in the efficacy of immunotherapy, as well as bringing solutions to patients."

References: CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas. Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena & Eliane Piaggio.

On July 6, 2022 RefleXion Medical, a therapeutic oncology company pioneering the use of biology-guided radiotherapy (BgRT)* for all stages of cancer, reported the closing of a $125M debt facility, of which $55M is available immediately to repay the company’s existing $50M of debt (Press release, RefleXion Medical, JUL 6, 2022, View Source [SID1234616520]). The remaining $70M of the new facility will be made available upon reaching certain regulatory and commercial milestones. The funds will support the continued commercialization of the RefleXion X1 platform and the introduction of RefleXion’s novel BgRT technology.

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"We have again partnered with Oxford Finance to refinance our existing credit facility to lower our effective interest rate, increase access to additional funding and provide greater financial freedom as we approach the launch of our novel BgRT," said Martyn Webster, chief financial officer at RefleXion Medical. "Among other things, these funds will allow us to expand our installation capacity and build a robust radiopharmaceutical program that will one day expand the clinical indications for BgRT to include advanced prostate and kidney cancers."

"We are pleased to expand our commitment and continue supporting the RefleXion team through development and commercialization of RefleXion’s X1 radiotherapy platform and the introduction of its novel BgRT technology, which we believe has transformative potential for treating metastatic disease," said Christopher A. Herr, senior managing director at Oxford Finance.

Recently RefleXion announced a co-development agreement with Telix Pharmaceuticals to develop a new indication for Telix’s novel prostate surface membrane antigen (PSMA) targeted diagnostic PET radiotracer to include use with BgRT. Earlier this month, the company also hosted its first cancer symposium that included clinicians from 30 of the top cancer care programs in the United States.

On July 6, 2022 Global Coalition for Adaptive Research (LARKSPUR, CA), Biohaven Pharmaceutical Holding Company Ltd. (NYSE: BHVN), and Vigeo Therapeutics — The Global Coalition for Adaptive Research (GCAR) in collaboration with Biohaven and Vigeo Therapeutics, reported the activation of Biohaven’s troriluzole and Vigeo’s VT1021 in GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment) (Press release, Biohaven Pharmaceutical, JUL 6, 2022, View Source [SID1234616519]). GBM AGILE is a revolutionary patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent glioblastoma (GBM) – the deadliest form of brain cancer.

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Biohaven’s troriluzole and Vigeo’s VT1021 are entering the GBM AGILE trial, which initially opened in July 2019 and has screened over 1200 patients to date. Troriluzole and VT1021 will enroll patients with newly-diagnosed and recurrent glioblastoma.

Dr. Michael Lim, Chair of the Department of Neurosurgery at Stanford University and Dr. Michael Weller, Director Department of Neurology, University Hospital Zurich, Switzerland will serve as arm Principal Investigators for troriluzole’s evaluation in GBM AGILE. VT1021 will be led by arm Principal Investigators, Dr. Howard Colman, Professor, Huntsman Cancer Institute and Department of Neurosurgery, University of Utah, and Dr. Tom Mikkelsen, Medical Director, Precision Medicine Program & Clinical Trials Office, Henry Ford Health.

"GBM AGILE is a ground-breaking trial that enables us to simultaneously and dynamically study the effects of multiple new drug candidates in an optimized learning environment. The trial’s nimble model allows us to more efficiently and rapidly identify effective therapies for GBM patients," said Dr. Michael Lim, who also serves as a member of the GBM AGILE Arm Identification and Selection Committee. "We are excited to include troriluzole and VT1021 in GBM AGILE. These investigational drugs have the potential to support improved outcomes for GBM patients, who desperately need more effective treatment options."

GBM AGILE is an international, innovative platform trial designed to more rapidly identify and confirm effective therapies for patients with glioblastoma through response adaptive randomization and a seamless phase 2/3 design. The trial, conceived by over 130 key opinion leaders, is conducted under a master protocol, allowing multiple therapies or combinations of therapies from different pharmaceutical partners to be evaluated simultaneously. With its innovative design and efficient operational infrastructure, data from GBM AGILE can be used as the foundation for a new drug application (NDA) and biologics license application (BLA) submissions and registrations to the FDA and other health authorities.

The new interventions are opening first at Henry Ford Health Cancer in Detroit under Henry Ford site Principal Investigator Dr. Tom Mikkelsen and will subsequently open at more than 40 trial sites across the United States with additional global sites to follow.

"Glioblastoma is a devasting disease with few effective treatment options and no cure. Currently the average survival rate is estimated to be only eight months," noted Dr. Mikkelsen. "We are enthusiastic to be the first site to activate troriluzole and VT1021 in the GBM AGILE study. We are committed to finding our patients the best possible treatments."

Biohaven’s troriluzole is a novel, orally administered small molecule that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. Troriluzole is thought to restore glutamate homeostasis by enhancing glutamate cycling, decreasing presynaptic glutamate release, and augmenting the expression and function of excitatory amino acid transporters (i.e., EAAT2) located on glial cells that play a key role in clearing excess glutamate from the synapse. Troriluzole was selected for inclusion in GBM AGILE, based on compelling evidence showing deregulation of glutamate in glioblastoma. The therapeutic potential of troriluzole in glioblastoma and other oncology indications is supported by several recent clinical and translational research studies conducted with troriluzole and its active moiety.

"The initiation of this pivotal trial of troriluzole for glioblastoma is an exciting milestone," commented Dr. Vlad Coric, Chairman and Chief Executive Officer of Biohaven. "We are extremely proud to be joining the highly innovative GBM AGILE trial. We look forward to collaborating with the Principal Investigators, Drs. Lim and Weller, the team at GCAR, and the GBM AGILE trial sites in order to rapidly advance the development of troriluzole in combination with standard of care therapies as a novel treatment for people suffering from glioblastoma, which is amongst the most recalcitrant and lethal of all cancers."

Vigeo’s 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 in tumor and endothelial cells, 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 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. With its novel mechanism of action and clinical data from a Phase 2 expansion study in recurrent GBM patients, VT1021 is undergoing further studies to determine its effect in treating the disease, given that CD36 and CD47 are found to be highly expressed in tumor cells compared to normal brain tissue. Vigeo is developing VT1021 as a therapeutic agent across a range of cancers, with a current focus on solid tumors.

"VT1021 has seen remarkable patient response, with a great safety profile, in our earlier clinical trials. We are excited that VT1021 is included as part of this global, multi-site effort to treat such a devastating disease," said Jim Mahoney, Chief Executive Officer, Vigeo Therapeutics. "The opportunity to work with these distinguished Principal Investigators and to test our drug in both newly diagnosed and recurrent GBM patient populations are key factors in our decision to join AGILE."

On July 6, 2022 Pyramid Biosciences, Inc., a clinical-stage biotechnology company developing a portfolio of precision therapies targeting a range of serious diseases, reported that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for PBI-200, a next-generation, highly brain penetrant inhibitor of the neurotrophic tyrosine receptor kinase (NTRK) currently in clinical development for the treatment of NTRK fusion-positive solid tumors (Press release, Pyramid Biosciences, JUL 6, 2022, View Source [SID1234616516]).

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"Oncogenic NTRK gene fusions are found in a broad range of cancers," said Pyramid Biosciences CEO Brian Lestini, MD, PhD. "Orphan designation for drugs in development such as PBI-200 are important to ensure continued innovation to address unmet needs for these patients, including primary and metastatic brain tumors."

"We are extremely pleased that the orphan designation was granted, and we look forward to continued enrollment in our global Phase 1/2 clinical trial of PBI-200," said Pyramid Biosciences co-founder and COO Jordan Leef.

The FDA’s Office of Orphan Drug Products grants orphan drug designation to support the development of medicines for underserved patient populations or rare disorders, that affect fewer than 200,000 people in the United States.

About PBI-200

PBI-200 is an oral, highly potent, and selective inhibitor of TRK kinase that is currently in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases. In some patients, the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. PBI-200 was discovered and developed by Pyramid Biosciences to overcome a wide range of on-target resistance mutations that have been described with first-generation TRK inhibitors. In addition, preclinical studies have shown that PBI-200 achieves high levels of penetration into brain, which translated into superior efficacy in intracranial xenograft models compared to other TRK inhibitors, as well as a favorable safety profile.

The global Phase 1/2 trial of PBI-200 (PBI-200-101) is a multicenter, open-label study in subjects with NTRK fusion-positive advanced or metastatic tumors including primary and metastatic CNS tumors. The trial consists of a dose-escalation phase, followed by a multicohort expansion at the recommended Phase 2 dose. Additional information can be found at: View Source (NCT04901806).

On July 6, 2022 Turnstone Biologics Corp., a clinical-stage biotechnology company developing next-generation immunotherapies to treat and cure solid tumors, and Moffitt Cancer Center ("Moffitt"), a world leader in advancing cellular immunotherapies for the treatment of cancer, reported the formation of a broad strategic alliance, deepening their existing multi-year research collaboration (Press release, Turnstone Biologics, JUL 6, 2022, View Source [SID1234616515]). As part of this expanded partnership, Turnstone will have priority access to Moffitt’s scientific research, manufacturing, and clinical capabilities for the development of novel tumor infiltrating lymphocyte ("TIL") therapies. The parties also announced U.S. Food and Drug Administration ("FDA") clearance of an Investigational New Drug ("IND") application for a Moffitt-sponsored Phase 1 clinical study of TIDAL-01, Turnstone’s lead TIL therapy candidate, in cutaneous and non-cutaneous melanoma. The trial is expected to commence later this year.

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"Our landmark strategic alliance with Turnstone underscores Moffitt’s commitment to bold research initiatives and groundbreaking clinical studies for the benefit of cancer patients who have limited or no effective treatment options," said Patrick Hwu, M.D., President and CEO, Moffitt Cancer Center. "Cell therapy is a key area of focus at Moffitt, and we are impressed by Turnstone’s novel approach to TIL therapy. Our combined team has made strong progress as part of our ongoing partnership, particularly with the IND clearance of TIDAL-01. We look forward to initiating the clinical study in melanoma and continuing to grow this valuable relationship with Turnstone."

Selected TILs represent the foundational therapeutic modality driving Turnstone’s cancer immunotherapy pipeline and leverage decades of work anchored in academia that have demonstrated the promise of this approach. By identifying, selecting, and expanding the most potent subsets of patient specific tumor-reactive T-cells, Turnstone aims to improve and broaden the clinical efficacy of TILs and overcome the limitations of current treatments to achieve positive outcomes in harder to treat, lower mutational burden, cancers. TIDAL-01 builds on the historical clinical success of Selected TIL treatment protocols and is the initial focus of the Turnstone-Moffitt collaboration as the parties advance the program into a Phase 1 clinical study.

Under the terms of the agreement, Moffitt will grant Turnstone prioritized clinical trial activation, enhanced patient screening and data sharing, full access to Moffitt’s cellular therapies research and development infrastructure and expanded molecular data sets and biospecimens for research. Moffitt will also provide extended governance support and allocated GMP manufacturing capacity for Turnstone product candidates. Turnstone will contribute resources and expertise to the partnership and fund research and development activities at Moffitt. Additional financial terms were not disclosed.

"This industry-leading partnership with Moffitt is a direct result of our unwavering efforts to develop promising new cancer medicines in the most innovative and impactful ways possible," said Sammy Farah, Ph.D., M.B.A., President and CEO, Turnstone Biologics. "We believe Moffitt’s translational insights and clinical execution capabilities coupled with our next-generation Selected TIL technology will accelerate the development of our differentiated TIL therapies and increases our opportunity to create curative outcomes for patients with solid tumors."