Cell Biology

Childhood leukemia treatment 2022: Where we are now and what it takes – EurekAlert

image:Prof. Christina Peters, MD, points out: "We have published highly topical and clinically relevant manuscripts that are of utmost importance for the treatment of children with high-risk acute lymphoblastic leukemia. One of the most burning questions for me is whether we still need stem cell transplantation in the era of modern immunotherapies." view more

Credit: St. Anna Children's Cancer Research Institute

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, generally curable with contemporary chemotherapy. However, if the disease is classified as high-risk ALL and a stem cell transplantation becomes inevitable, total body irradiation is still the treatment of choice prior to transplantation. This was the conclusion drawn from the FORUM study, including 35 countries on five continents (Peters et al., Journal of Clinical Oncology 2020).

"As the largest study on this topic to date, we published the results in the top-ranked Journal of Clinical Oncology. Soon after that, Frontiers invited us the international transplant consortium for ALL to publish a collection of reviews and scientific reports on ALL in children," recalls Christina Peters, Affiliated Clinician at St. Anna Children's Cancer Research Institute (St. Anna CCRI) and Senior Physician at St. Anna Children's Hospital. The editorial board of this Research Topic is formed by Christina Peters together with Assoc.-Prof. Adriana Balduzzi, MD (University of Milano Bicocca, Italy) and Prof. Peter Bader, MD (Goethe University Frankfurt am Main, Germany).

Life at the price of long-term side effects?Although total body irradiation and hematopoietic stem cell transplantation (HSCT) from healthy donors can be life-saving, long-term side effects sometimes have a massive impact on the quality of life of children and young adults. These include organ damage, growth retardation, and the development of secondary cancers. Hence, there was a dire need to clearly outline recent and previously published data, as well as to discuss potential new approaches, as did the aforementioned reviews.

"One of the most burning questions for me is whether we still need stem cell transplantation in the era of modern immunotherapies," Christina Peters points out. In the future, CAR-T cell or antibody therapies directly targeting leukemia cells could replace HSCT, which is addressed by three of the reviews mentioned. Jochen Bchner, MD, PhD, and colleagues are discussing the question of whether and when CAR-T cell therapy could be considered to bridge the time until transplantation and under what conditions it could replace transplantation. Another review, authored by Assoc.-Prof. Tony H. Truong, MD, and colleagues, is dedicated to the question which children should receive a stem cell transplantation at all. Of course, transplantation should only be considered for those patients who would not have a realistic chance of survival with 'milder' therapies. But it is exactly these boundaries that are currently shifting.

More than 59,000 views of our workSo far, the review of Bianca A. W. Hoeben, MD, PhD, and colleagues, which deals with new methods of total body irradiation, has had the most views in this online collection. "In total, we have more than 59,000 views of our Research Topic by now. Accordingly, it seems to be on many people's minds whether and how we can improve transplantation methods to reduce side effects," says Christina Peters. For example, different radiotherapy centers have developed new methods of total body irradiation to achieve a lower irradiation dose in certain organs. There are, however, limitations to shield organs at risk without compromising the anti-leukemic and immunosuppressive effects the latter to preserve a rejection of the transplanted cells.

In addition to the aforementioned long-term effects of irradiation and transplantation, acute side effects of transplantation also play a major role. These include infections during the period in which the immune system reconstitutes (Olga Zajac-Spychala et al.), or complications arising from a donor cells attack against the patient's healthy tissue. The prevention and treatment of the so-called Graft-versus-Host Disease are addressed by six of the articles in this Research Topic (Steven J. Keogh et al., Anita Lawitschka et al., Jacob Rozmus et al., Agnieszka Sobkowiak-Sobierajska et al., Matthias Wlfl et al., Natalia Zubarovskaya et al.).

"The publication of this Research Topic is a huge success for St. Anna CCRI. Together with the valuable contributions of a number of clinicians of St. Anna Children's Hospital, we have published highly topical and clinically relevant manuscripts that are of utmost importance for the treatment of children with high-risk ALL," highlights Christina Peters.

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About the FORUM StudyThe FORUM study demonstrated that patients over four years of age with high-risk ALL in need of a stem cell transplantation live longer and have a lower risk of relapse when they receive total body irradiation instead of chemotherapy in preparation for transplantation. After random assignment of 417 pediatric patients with high-risk ALL, a futility stopping rule was applied because it became apparent that patients receiving chemo-conditioning had a lower chance of cure and survival. FORUM is a randomized, international, multicenter phase III trial designed to investigate whether chemotherapy with fludarabine, thiotepa, and busulfan or treosulfan is non-inferior to total body irradiation plus etoposide as preparation prior to transplantation. The study, led by Christina Peters, is the result of a collaboration among international study groups (AIEOP-BFM-ALL-SG, IBFM-SG, INTREALL-SG, and EBMT-PD-WP).

Frontiers Research TopicThe Frontiers in Pediatrics "Research Topic" Allogeneic Hematopoietic Stem Cell Transplantation for Children with Acute Lymphoblastic Leukemia in the Era of Immunotherapy is available for download here: https://www.frontiersin.org/research-topics/19704/allogeneic-hematopoetic-stem-cell-transplantation-for-children-with-acute-lymphoblastic-leukemia-in#overviewThe specific thematic areas envisaged to be addressed in this article collection are the following:

Are HLA-identical siblings still the best available donor for ALL? The challenge of treating older children: what is the best transplant strategy for Adolescents and Young Adults (AYAs)? Tyrosine Kinase Inhibitors (TKIs) for Philadelphia Chromosome positive (Ph+) and Ph-like ALL: could we omit Hematopoietic Stem Cell Transplantation (HSCT)? Bispecific Antibodies before HSCT: less toxicity for better transplant outcome? CAR-T cell therapy: only bridge to transplant? T-cell depletion: Cyclophosphamide after transplantation versus in vitro T-cell depletion Why is Total Body Irradiation so effective in high-risk ALL? Total Body Irradiation forever? New chemotherapeutic options for irradiation-free conditioning Minimal Residual Disease (MRD): Which level of negativity is relevant? Current treatment options for acute Graft-versus-Host-Disease (GVHD) in children Current treatment options for chronic GVHD in children Immunoreconstitution and chimerism: a different story compared to adults? Non-relapse mortality after HSCT: where are we now? High-risk ALL: Transplant indications in 2021 COVID-Infection after allogeneic stem cell transplantation Transplantation for the youngest: better than chemotherapy?

About Christina PetersChristina Peters, MD, is Professor of Pediatrics at the Department of Stem Cell Transplantation of St. Anna Children's Hospital and Affiliated Clinician at St. Anna Childrens Cancer Research Institute in Vienna. She is principal investigator of active studies within the European Society for Blood and Marrow Transplantation (EBMT) and the International Berlin Frankfurt Mnster Study Group (IBFM) for the treatment of pediatric leukemia. Her research interests include allogeneic hematopoietic transplantation in children and adolescents with malignant and non-malignant diseases from related and unrelated donors, infectious and toxic complications after stem cell transplantation, adoptive therapies for hematological malignancies and family oriented rehabilitation for children with life threatening diseases.

Christina Peters chaired the EBMT Pediatric Diseases Working Party between 2008 and 2014. She has authored and co-authored numerous papers in peer-review journals such as The Lancet, The New England Journal of Medicine, or The Journal of Clinical Oncology. Christina Peters acts as a regular reviewer of publications for hematology, pediatric and leukemia journals. She is a member of many professional societies including IBFM, the Center for International Blood and Marrow Transplant Research (CIBMTR), the German and Austrian Society of Pediatric Hematology and the Austrian Gene Therapy Commission. Furthermore, Christina Peters is a member of the Advisory Board of the Austrian Ministry of Health, the Bioethical committee of the Austrian Prime Minister and member of the European Network Pediatric Research at the European Medicines Agency EMA (ENPREMA).

About St. Anna Childrens Cancer Research Institute, St. Anna CCRISt. Anna CCRI is an internationally renowned multidisciplinary research institution with the aim to develop and optimize diagnostic, prognostic, and therapeutic strategies for the treatment of children and adolescents with cancer. To achieve this goal, it combines basic research with translational and clinical research and focus on the specific characteristics of childhood tumor diseases in order to provide young patients with the best possible and most innovative therapies. Dedicated research groups in the fields of tumor genomics and epigenomics, immunology, molecular biology, cell biology, bioinformatics and clinical research are working together to harmonize scientific findings with the clinical needs of physicians to ultimately improve the wellbeing of our patients.www.ccri.at http://www.kinderkrebsforschung.at

About St. Anna Children's HospitalEstablished in 1837 in the former suburb of Schottenfeld, St. Anna was the first children's hospital in Austria and the third independent hospital in Europe dedicated exclusively to the health of children. St. Anna Children's Hospital has evolved into an institution that provides state-of-the-art medical care. Thus, in addition to its performance as a general children's hospital, the Center for Pediatrics and Adolescent Medicine has also been able to establish an excellent reputation throughout Austria and internationally over the past 40 years as a center for the treatment of pediatric hematologic disorders and tumor diseases (cancer).www.stanna.at

Frontiers in Pediatrics

People

Allogeneic Hematopoetic Stem Cell Transplantation for Children with Acute Lymphoblastic Leukemia in the Era of Immunotherapy

The authors declare that the editorial of this Research Topic was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Childhood leukemia treatment 2022: Where we are now and what it takes - EurekAlert

Cell Biology

Photys Therapeutics Debuts with $75 Million Series A Funding to Advance New Class of Bifunctional Molecules for Precision Phosphorylation to Modulate…

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- Phosphorylation-inducing chimeric small molecules (PHICS) are a new class of bifunctional medicines that direct and repair aberrant and dysfunctional proteins

- PHICS enable precise phosphorylation, an important post-translational modification that controls protein function, including activation, stabilization, trafficking, inactivation, and degradation

- Led by a strong foundational management team of respected industry veterans with deep experience in successful drug discovery and corporate development

BOSTON--(BUSINESS WIRE)--Photys Therapeutics, the pioneer in the development of phosphorylation-inducing chimeric small molecule medicines (PHICS), founded by Longwood Fund and Dr. Amit Choudhary of Brigham and Womens Hospital and the Broad Institute of MIT and Harvard, today announced a $75 million Series A financing led by MPM Capital and joined by Omega Funds, Longwood, 8VC, Arkin Bio, Mass General Brigham Ventures, MRL Ventures Fund, the therapeutics-focused corporate venture fund of Merck & Co., Eli Lilly and Company, and Heritage Medical Systems. Through induced proximity, PHICS enhance the pairing of specific kinases, the enzymes responsible for protein phosphorylation, with disease target proteins, unlocking a new approach to treatment of underserved diseases.

Many current chimeric and bifunctional modalities focus on protein degradation, which limits their range of addressable diseases, said Edward Holson, PhD, co-founder and Chief Scientific Officer, Photys. Photys expands this functionality, using PHICS to recruit kinases and induce phosphorylation, a key post-translational modification that controls many protein functions, including activation, stabilization, localization, trafficking, degradation, and inactivation.

The foundational biology of kinases is well-understood, and decades of screening has yielded potent kinase binders, said Brian Fenton, Chief Executive Officer. Our approach builds on this foundation and leverages the diversity of kinase function towards treating cancer and other critical immune, metabolic, and rare diseases.

Dr. Choudharys transformational research has provided Photys with a roadmap to expand the native function of kinases to treat disease, said David Steinberg, Chairman and Founding CEO of Photys, and General Partner at Longwood Fund. We look forward to building on his unique insights to establish a broad pipeline of therapeutics that can potentially enhance and extend the lives of patients.

Dr. Lizzie Ngo, Longwood Fund Principal, acted as a co-founder alongside Dr. Choudhary, Mr. Steinberg, and Dr. Holson. Dr. Ngo and Mr. Steinberg also joined the Board of Directors along Luke Evnin, PhD, co-founder and Managing Director of MPM Capital; Alon Lazarus, PhD, Investment Manager, Arkin Bio; Briggs Morrison, MD, President, Head of R&D, and board member at Syndax Pharmaceuticals and Executive Partner at MPM Capital; and Otello Stampacchia, PhD, founder of Omega Funds.

Dr. Holson is a co-founder and Chief Scientific Officer (CSO) of Photys. Dr. Holson has worked in drug discovery for over 20 years as a scientist, founding director, CSO and scientific advisor across multiple organizations, including Amathus Therapeutics, Atlas Venture, KDAc Therapeutics, the Broad Institute of MIT and Harvard, and Merck & Co.

Brian Fenton was named President and CEO of Photys in September of this year and brings over three decades of biopharma leadership experience. He previously served as Chief Business Officer at Translate Bio and spent several years working in the Rare Disease Business Development Group at Shire Pharmaceuticals. He has successfully identified, led, and executed multiple strategic transactions during his career in corporate development. Mr. Fenton earned his BA in Biochemistry from University of Massachusetts, Amherst, MS in Chemical Engineering from University of Virginia, and MBA at Worcester Polytechnic Institute. The Photys Scientific Advisory Board consists of scientific founder Dr. Amit Choudhary; Eric Fischer, PhD, Independent Investigator at Dana-Farber Cancer Institute; Tony Hunter, PhD, Professor and Renato Dulbecco Chair in Cancer Research at the Salk Institute; Angela Koehler, PhD, Associate Professor of Biological Engineering, Koch Institute, Institute Fellow at the Broad Institute of MIT and Harvard and Co-Director of the Swanson Biotechnology Center High-Throughput Screening Facility; Dan Nomura, PhD, Professor of Chemical Biology in the Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology at the University of California, Berkeley and Adjunct Professor in the Department of Pharmaceutical Chemistry at UCSF; and Wendy Young, PhD, Executive Partner at MPM Capital.

About Photys Therapeutics

Photys Therapeutics, founded by Longwood Fund and Dr. Amit Choudhary of Brigham and Womens Hospital and the Broad Institute of MIT and Harvard, is advancing Phosphorylation Inducing Chimeric Small Molecules (PHICS), a proprietary new class of bifunctional medicines that direct and repair protein phosphorylation to treat a range of diseases including cancer, immune, metabolic, and rare diseases.

Post-translational modifications, particularly phosphorylation, are ubiquitous throughout the human proteome and play a central role in cellular function. Through induced proximity, PHICS enhance the pairing of specific kinases, the enzymes responsible for protein phosphorylation, with disease target proteins. PHICS can induce precise phosphorylation at native and/or non-native sites, modulating key functions including activation, stabilization, trafficking, localization, phospho-antigen presentation, inactivation, degradation and interactions of proteins. Harnessing well-established biology and chemistry in kinases and bifunctionals in new ways, the PHICS approach unlocks diverse classes of targets.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220908005074/en/

Media:Mariesa Kemble[emailprotected]

Source: Photys Therapeutics

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Photys Therapeutics Debuts with $75 Million Series A Funding to Advance New Class of Bifunctional Molecules for Precision Phosphorylation to Modulate...

Cell Biology

New in-silico-designed protein ‘probes’ could pave the way to early diagnosis of neurodegenerative diseases – EurekAlert

image:Zoom-in on single cultured mammalian cells in which TDP-43 has been induced to aggregate. In this system, the cells produce TDP-43 fused to a green fluoresce molecule, to be able to detect whether the protein forms insoluble granules (green fluorescent dots). The RNA probe is labelled with a red fluorescent tag. The yellow colour, given by the overlap between the green of TDP-43 and the red of the RNA probe, signifies that the probe can search and find its protein target in live cells, suggesting that it could be use as a detection tool to track the progress of TDP-43 aggregation in disease.Blue: nuclei; green: TDP-43; red: RNA probe; yellow: TDP-43+RNA probe. view more

Credit: IIT-Istituto Italiano di Tecnologia

Genoa (Italy) - 8 September 2022 - A team of researchers from the IIT-Istituto Italiano di Tecnologia (Italian Institute of Technology) has designed in silico molecular probes able to track the progress of a protein that misbehaves in different neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD). The probes can be used to study the behavior of the target protein in cell and were tested in collaboration with Sapienza University of Rome, Centre for Genomic Regulation n Barcellona, University of Edinburgh and Kings College London. The research study has been published in Nature Communications.

Created by the RNA Systems Biology group at IIT in Genoa, the probes consist of computer-designed RNA molecules that bind to a neurodegeneration-associated protein named TDP-43. This protein is present in numerous cases of Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD), where it aggregate creating insoluble protein blobs in neural cells, altering their metabolism and function.

The research team was inspired by the protein's natural interactions with RNA molecules to design molecular probes, which are called aptamers, literally molecules made to fit one single target. Their main goal was to obtain a novel approach for tracking the aggregation of neurodegeneration-associated proteins at the very first steps of the process.

"Using our own algorithms, we designed RNA aptamers specific for TDP-43 and used themtogether with advanced microscopy techniques to follow the protein transition towards its aggregated forms explains Gian Gaetano Tartaglia, principal investigator of the RNA System Biology Lab. We can identify TDP-43 aggregates as small as 10 nanometers which, to our knowledge, is the best resolution achieved so far when visualising protein aggregates".

These aptamers could be used to study, at the molecular level, the phenomenon of abnormal protein aggregation typical of several neurodegenerative diseases and would, therefore, pave the way for the development of early diagnosis tools for these disorders.

"We showed that the RNA aptamers can also be used to track TDP-43 in live cells and in real time, detecting all forms of the protein, from the physiological soluble one to the insoluble state, passing by aggregates of intermediate sizes undetectable by standard approaches," adds Elsa Zacco, lead researcher on the project.

The study was carried out by IIT researchers Elsa Zacco, Alexandros Armaos and Gian Gaetano Tartaglia (also at Sapienza University of Rome), with the participation of the groups led by Mathew Horrocks at University of Edinburgh and Annalisa Pastore at Kings College London.

Nature Communications

Experimental study

Cells

Probing TDP-43 condensation using an in silico designed aptamer

23-Jun-2022

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New in-silico-designed protein 'probes' could pave the way to early diagnosis of neurodegenerative diseases - EurekAlert

Cell Biology

Alpha Tau Announces the Acceptance in Major Peer-Reviewed Journals (International Journal of Radiation Oncology, Biology, Physics, and Frontiers in…

Study on combination with anti-PD1 therapy published by International Journal of Radiation Oncology, Biology, Physics, known in the field as the Red Journal, the official journal of the American Society for Radiation Oncology (ASTRO)

Study on combinations with chemotherapy and anti-angiogenic therapy in human glioblastoma multiforme xenografts accepted for publication by Frontiers in Oncology, in its Radiation Oncology section

JERUSALEM, Sept. 08, 2022 (GLOBE NEWSWIRE) -- Alpha Tau Medical Ltd. ("Alpha Tau") (Nasdaq: DRTS and DRTSW), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, announced today the acceptance of two landmark pre-clinical studies in major peer-reviewed journals, both demonstrating the significant potential synergies between Alpha DaRT therapy and standard-of-care solid tumor therapies used today.

We are very excited to have these fantastic results recognized by two leading journals in our field, said Alpha Tau CEO Uzi Sofer. The potential synergy between Alpha DaRT and immunotherapies continues to be a strong area of focus for Alpha Tau, both in our ongoing pre-clinical work as well as in our endeavors to run multiple human clinical trials examining such combinations, including the trial currently underway combining Alpha DaRT with pembrolizumab in recurrent unresectable or metastatic head & neck squamous cell carcinoma patients. Similarly, the promising results for GBM patients are a key priority for Alpha Tau, as we continue to focus on advancing our solution for this deadly disease as quickly as possible. Armed with our Breakthrough Device Designation from the FDA in recurrent GBM, we have been progressing swiftly in large animal studies using our specially designed radial applicator for use in the brain, with the intent to begin a human clinical study in the near future.

Ronen Segal, CTO at Alpha Tau, added, These two significant studies continue to build on the ever-growing body of evidence that the Alpha DaRT may offer not only a compelling local radiation therapy solution, but also provide a broader systemic benefit through interaction with the immune system, and our incorporation of more advanced immunological analyses has improved our understanding of these amazing mechanisms. We also are impressed by the synergies we see with other mechanisms such as anti-angiogenesis and continue to explore those in parallel as well.

The first study, published in the International Journal of Radiation Oncology, Biology, Physics (known as the Red Journal) examines the transcriptional profile activated by Alpha DaRT, and its potential to enhance responsiveness to immune checkpoint inhibition of the programmed cell death protein 1 (PD-1) blockade. These results demonstrate potential synergies with immune stimulation in mice and support the further exploration of the Alpha DaRT as a compelling local radiation therapy with the potential to induce antitumor immunity.

In this pre-clinical study, Squamous Cell Carcinoma (SCC) tumor-bearing mice were treated with Alpha DaRT in combination with an anti-PD1 therapy (aPD-1). This group was compared to groups of mice treated with either Alpha DaRT or aPD-1 as a monotherapy, as well as to a control group. The efficacy of the treatment was evaluated over time, and the immune level of activation was analyzed through immunophenotyping and immunohistochemical staining sixteen days after Alpha DaRT source insertion.

The group treated with Alpha DaRT in combination with aPD-1 demonstrated delayed tumor development, higher T-effector cell infiltration with enhanced cytotoxic potential, and reduced systemic Myeloid-Derived Suppressor Cells (MDSCs) than either monotherapy alone. Gene expression and gene set enrichment analysis of mRNA levels seven days after Alpha DaRT insertion indicated that Alpha DaRT upregulated indicators of cell death, interferon signaling and myeloid related transcription, while downregulating indicators of DNA repair and cell proliferation. Moreover, immunophenotyping analysis at this timepoint showed that Alpha DaRT induced dendritic cell activation and affected the distribution of MDSC populations. Altogether, those findings demonstrated that the Alpha DaRT may offer tumor cell destruction via additional pathways beyond the immediate local impact of generating double-strand DNA breaks in tumor cells.

This studys authors conclude that Alpha DaRT can promote a hot tumor microenvironment and changes in immune suppression that lead to a potentiation of aPD-1 blockade-induced effector T-cell function and improved treatment efficacy. The authors observe that this study provides a rationale for investigating the combination of Alpha DaRT and aPD-1 clinically in SCC patients.

The full publication can be seen here: https://www.sciencedirect.com/science/article/pii/S0360301622031881

The second study, accepted for publication by Frontiers in Oncology in its Radiation Oncology section, examines the use of Alpha DaRT in treating human glioblastoma multiforme (GBM) xenografts, together with Temozolomide (TMZ), a standard-of-care chemotherapy, or Bevacizumab, a standard-of-care antiangiogenic therapy, both commonly used in treating GBM.

The results demonstrated that the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone, and the surviving fraction of cancer cells treated by TMZ in combination with alpha irradiation was lower than alpha- or x-ray irradiation as monotherapies, or than by x-ray combined with TMZ. In addition, the treatment of GBM-bearing mice with Alpha DaRT and TMZ delayed tumor development more efficiently than the monotherapies. The studies further confirmed that, unlike other radiation types, alpha radiation did not increase the secretion of VEGF, a potent angiogenic factor that promotes tumor growth.

With respect to the combination of Alpha DaRT with anti-angiogenic therapy, Bevacizumab treatment introduced several days after Alpha DaRT implantation improved tumor control, compared to Bevacizumab or Alpha DaRT as monotherapies. The combination was also shown to be superior when starting Bevacizumab administration prior to Alpha DaRT implantation in large tumors relative to the size of the Alpha DaRT source. Bevacizumab induced a decrease in the endothelial cell marker CD31 staining in conjunction with the Alpha DaRT treatment, and increased the diffusive spread of Radium-224 daughter atoms in the tumor tissue, while decreasing their clearance from the tumor through the blood.

A summary abstract of the publication can be seen here:https://www.frontiersin.org/articles/10.3389/fonc.2022.888100/abstract

About Alpha DaRT

Alpha DaRT (Diffusing Alpha-emitters Radiation Therapy) is designed to enable highly potent and conformal alpha-irradiation of solid tumors by intratumoral delivery of radium-224 impregnated sources. When the radium decays, its short-lived daughters are released from the sources and disperse while emitting high-energy alpha particles with the goal of destroying the tumor. Since the alpha-emitting atoms diffuse only a short distance, Alpha DaRT aims to mainly affect the tumor, and to spare the healthy tissue around it.

About Alpha Tau Medical Ltd.

Founded in 2016, Alpha Tau is an Israeli medical device company that focuses on research, development, and potential commercialization of the Alpha DaRT for the treatment of solid tumors. The technology was initially developed by Prof. Itzhak Kelson and Prof. Yona Keisari from Tel Aviv University.

Forward-Looking Statements

This press release includes "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. When used herein, words including "anticipate," "being," "will," "plan," "may," "continue," and similar expressions are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon Alpha Tau's current expectations and various assumptions. Alpha Tau believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. Alpha Tau may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation: (i) Alpha Tau's ability to receive regulatory approval for its Alpha DaRT technology or any future products or product candidates; (ii) Alpha Tau's limited operating history; (iii) Alpha Tau's incurrence of significant losses to date; (iv) Alpha Tau's need for additional funding and ability to raise capital when needed; (v) Alpha Tau's limited experience in medical device discovery and development; (vi) Alpha Tau's dependence on the success and commercialization of the Alpha DaRT technology; (vii) the failure of preliminary data from Alpha Tau's clinical studies to predict final study results; (viii) failure of Alpha Tau's early clinical studies or preclinical studies to predict future clinical studies; (ix) Alpha Tau's ability to enroll patients in its clinical trials; (x) undesirable side effects caused by Alpha Tau's Alpha DaRT technology or any future products or product candidates; (xi) Alpha Tau's exposure to patent infringement lawsuits; (xii) Alpha Tau's ability to comply with the extensive regulations applicable to it; (xiii) the ability to meet Nasdaq's listing standards; (xiv) costs related to being a public company; (xv) changes in applicable laws or regulations; (xix) impacts from the COVID-19 pandemic; and the other important factors discussed under the caption "Risk Factors" in Alpha Tau's annual report filed on form 20-F with the SEC on March 28, 2022, and other filings that Alpha Tau may make with the United States Securities and Exchange Commission. These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management's estimates as of the date of this press release. While Alpha Tau may elect to update such forward-looking statements at some point in the future, except as required by law, it disclaims any obligation to do so, even if subsequent events cause its views to change. These forward-looking statements should not be relied upon as representing Alpha Tau's views as of any date subsequent to the date of this press release.

Investor Relations Contact

IR@alphatau.com

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Cell Biology

More Effective Cancer Immunotherapy: Stanfords New Method To Find Antigens That Trigger Specific Immune Cells – SciTechDaily

Scientists have developed a new method to faster and more accurately predict which antigens will lead to a strong immune response. This could help researchers develop more effective cancer immunotherapies.

A cells secrets can be revealed by its surface. It is decorated with tens to hundreds of thousands of molecules that help immune cells determine friend from foe. Some of those protruding molecules are antigens that trigger the immune system to attack. However, it can be difficult for scientists to identify those antigens, which often vary across individuals, in the molecular forest.

A team of Stanford scientists has developed a new method to faster and more accurately predict which antigens will lead to a strong immune response. Their approach could help researchers develop more effective cancer immunotherapies. The study was led by Polly Fordyce, an Institute Scholar at Sarafan ChEM-H, and will be reported today (September 5, 2022) in the journal Nature Methods.

T cells, a class of immune cells, crawl along and squish past other cells as they patrol the body. They use T cell receptors to molecularly read peptides, or short pieces of proteins which are cradled within larger proteins called major histocompatibility complexes (pMHCs) that project from cell surfaces. Healthy host cells display an array of pMHCs that do not trigger an immune response. However, once T cells recognize disease-indicating peptides, they become activated to find and kill cells bearing these foreign signatures. Understanding how T cells sensitively differentiate these antigenic peptides from host peptides to avoid mistakenly killing host cells has long been a mystery.

A T cell can detect a single antigenic peptide amongst a sea of 10,000 or 100,000 non-antigenic peptides being displayed on cell surfaces, said Fordyce, assistant professor of bioengineering and of genetics.

The key to selectivity is in the T cell crawl. T cells sliding puts stress on the bonds between receptors and peptides, and most of the time, that extra stress is enough to break that bond. But sometimes, it has the opposite effect. Chris Garcia, co-author of the study and professor of molecular and cellular physiology and of structural biology, and others had previously shown that the most antigenic peptides are those whose interactions with T cell receptors grow stronger in response to sliding.

Its kind of like a Chinese finger trap, said Fordyce. When you pull a bit at the receptor-antigen interaction, the binding actually lasts longer.

Identifying the best antigen-receptor pairs requires simultaneously applying that sliding, or shear, force between a peptide and a T cell and measuring T cell activation. Ideally, this would be done thousands of times to get repeatable data for many possible peptide/T cell receptor pairs. However, existing methods are time-intensive and can result in measuring only one peptide with hundreds of T cells in a day.

Postdoctoral scholar Yinnian Feng, the studys first author, developed a trick that allows the team to measure 20 unique peptides interacting with thousands of T cells in less than five hours.

To make a simplified system that mimics cells with dangling peptides, they constructed small spherical beads from a material that expands upon heating and attached a few molecules of a given peptide-studded pMHC to their surfaces. After depositing a T cell atop each bead and waiting long enough for receptors to bind to the peptides, they then very slightly heated the bead. The beads expansion increases the distance between tether points, and the corresponding stretching of the T cell mimics the force it would experience sliding along cells in the body. After exerting that force, the team then measured how active the T cells were.

They could do hundreds of individual experiments in parallel by using beads that are each labeled with a unique color, making it possible to track multiple different pMHCs. They took two sets of pictures tiling across each slide after each run: one set that tells them which pMHC a given bead is displaying and another that tells them how active each T cell atop that bead is. Cross-referencing those images tells them which antigens led to the strongest T cell responses.

In this demonstration of their platform, the research team showed, with 21 unique peptides, that their results confirmed known activating and non-activating peptides for one T cell receptor and uncovered a previously unknown antigen that induced a strong T cell response. Working with the Garcia lab, they have also already begun to address a challenge in immunotherapy: the T cell receptors that form the highest affinity interactions with antigens in the lab are often also activated by non-antigenic peptides in the body. This is a dangerous side effect that leads to the killing of healthy cells.

Using their technology, the team of researchers characterized T cell receptors engineered to specifically recognize tumor antigens without off-target reactivity. In future work, they plan to build libraries of over 1,000 peptides to uncover novel antigens.

The scientists hope that this approach, which is quick and requires few cells, or an optimized form of it could one day be used to improve personalized immunotherapies.

This platform can help improve efforts to engineer T cells that specifically target cancer cells, as well as determine which antigens are capable of potently activating a patients own T cells to more effectively target cancer cells, said Fordyce.

Reference: Bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation 5 September 2022, Nature Methods.DOI: 10.1038/s41592-022-01592-2

Fordyce is a member of Stanford Bio-X, SPARK, and the Wu Tsai Neurosciences Institute, and is a Chan Zuckerberg Biohub investigator. Garcia is a member of Stanford Bio-X, the Stanford Cancer Institute, the Wu Tsai Neurosciences Institute, and a Howard Hughes Medical Institute investigator.

Xiang Zhao and Adam K. White are also authors of the paper.

The work was funded by a Stanford Bio-X Interdisciplinary Initiatives seed grant and the National Institutes of Health.

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More Effective Cancer Immunotherapy: Stanfords New Method To Find Antigens That Trigger Specific Immune Cells - SciTechDaily

Anatomy

Kate Walshs Addison Returns to Greys Anatomy Season 19 in Recurring Role (EXCLUSIVE) – Variety

Kate Walsh is set to recur in the upcoming 19th season of Greys Anatomy, returning as Dr. Addison Montgomery, the character shes played since the Season 1 finale of the medical drama in 2005. Walshs Addison was also the central character on Private Practice the first Greys spinoff which ran for six seasons on ABC, from 2007 to 2013.

Walsh appeared on Greys last season in a multi-episode arc, in which Addison returned to Grey Sloan Memorial in order to perform a uterine transplant on a patient, who later miscarried. During her Season 18 appearances, Addison grieved the death of her ex-husband Derek (Patrick Dempsey) with his sister Amelia (Caterina Scorsone) and his widow Meredith (Ellen Pompeo).

In an interview last year, Walsh was enthusiastic about returning to Greys to play Addison for the first time since Private Practice had ended, saying I was very satisfied and delighted by it. She also left the door open for more. Nobody knows what the future holds, Walsh said at the time. But for now, this is what weve got planned: just to have Addison pop in and well see what happens, what transpires.

Addison will indeed be popping back in: Her first appearance will be in the third episode of the new season.

Season 19 of Greys Anatomy premieres on ABC on Oct. 6, and Pompeo around whom the show has revolved since its 2005 premiere will for the first time have a reduced role as Meredith. As was announced in August, though Merediths narration will continue to begin and end every episode, Pompeo (also an executive producer) will appear in only eight episodes this season. Under her Calamity Jane production company, she is producing and starring in an upcoming untitled limited series for Hulu.

Pompeo is irreplacable, of course, but a slew of cast members have been added to Greys to play the new surgical interns at the hospital, including Harry Shum Jr., Adelaide Kane, Alexis Floyd, Niko Terho and Midori Francis.

Greys created by Shonda Rhimes, and run by executive producer Krista Vernoff continues to be ABCs No. 1 scripted series.

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Kate Walshs Addison Returns to Greys Anatomy Season 19 in Recurring Role (EXCLUSIVE) - Variety

Anatomy

Grey’s Anatomy season 19: How will Teddy, Owen return? – CarterMatt

As we prepare for the arrival ofGreys Anatomyseason 19 on ABC next month, we know there are a lot of big questions. Its pretty unavoidable that there would be, all things considered.

Inevitably, one of the biggest mysteries at the moment has to be the status of one Ellen Pompeo, given that shes only going to be in a handful of episodes this season. Yet, there is also more than that going on, and this is where we look towards Teddy and Owen. Whats going to happen to the two of them?

The last that we saw Kevin McKidd and Kim Ravers characters, the two of them were fleeting Seattle after Bailey was forced to call the police. However, there is going to be a six-month time jump and in that span of time, things have been worked out enough for the two to come back but there are still some major problems.

According to a report from TV Insider, Teddy and Owen will be around, and Owen is still even going to have his medical license. However, there are some big problems here, starting with the fact that their relationship is torn apart; also, they are effectively bankrupt. Whether it be a possible legal defense or traveling out of the city, whatever money the two had has been whittled completely away. This is a whole new challenge for the two of them, and were sure that will be center stage for the two of them for a while.

As for what else is happening around the two of them, we know that a lot of the marketing for this season so far has been about the new residents as a matter of fact, you can head over here to learn a little bit more about some of them. We hope that theyre interesting, especially since this show faces some of its biggest challenges yet entering this season. Are people still going to watch the show without Meredith? Were going to find out over time.

Be sure to share right now in the comments! Once you do just that, come back for other updates you dont want to miss. (Photo: ABC.)

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Grey's Anatomy season 19: How will Teddy, Owen return? - CarterMatt

Anatomy

Centinel Spine Announces First Commercial Use of prodisc Cervical Total Disc Replacement Portfolio that Allows the Disc to be Matched to Patient…

West Chester, PA,September 7, 2022 /OrthoSpineNews/ Centinel Spine, LLC, a leading global medical device company addressing cervical and lumbar spinal disease through anterior surgical access, today announced the first implantation of its prodiscCVivoCervical Total Disc Replacement (TDR) product. In July, the company received U.S. Food and Drug Administration approval for 1-level indications for prodiscC Vivo, prodiscC SK,and prodiscC Nova. Along with the currently available prodiscCimplant, which remains the most studied TDR technology, Centinel Spine now has the broadest offering of cervical TDR solutions in the world to address surgeon preference and individual patient anatomy.

The first prodisc C Vivo procedure was performed in Dallas-Fort Worth, TXby orthopedic spine surgeon Jason Tinley, MD, founder of DFW Center for Spinal Disorders.

This patient had severe left-sided neck pain radiating into the forearm and thumb and a left C5/6 disc herniation, said Dr. Jason Tinley. Having the intraoperative options of a convex dome with spikes (prodisc C Vivo) versus a flat endplate component with keel (prodisc C) gave me the modularity to maximize endplate contact and stability, thus decreasing bone removal, risk of heterotopic ossification, subsidence, or implant failure. Ultimately, this allows me to best restore motion while also minimizing risk, Dr. Tinley adds.

Centinel Spine CEO Steve Murray stated, This is a historic milestone for the company, and we appreciate the support from our surgeon partners. Total disc replacement is one of the fastest growing global segments in all of orthopedics, and we continue innovating in this area to advance patient care. With our recent regulatory achievements, we are now able to offer surgeons a unique range of options to match the disc to patient anatomy.

The prodisc C Vivo system has been in clinical use internationally since 2009 and is currently one of the most frequently implanted TDR devices outside of the U.S. The device has keel-less fixation and combines a unique anatomically-designed superior endplate with lateral spikes to optimize fit and provide immediate fixation.Similar to all prodisc products, the prodisc C Vivo device incorporates prodisc CORE technology, the basis behind the predictable clinical outcomes of the prodisc platform after 30 years and over 225,000 implantations worldwide*.

* Data on file

About Centinel Spine, LLCCentinel Spine, LLC is a leading global medical device companyaddressing cervical and lumbar spinal disease through anterior surgical access. The company offers a continuum of trusted, brand-name, motion-preserving and fusion solutions backed by over 30 years of clinical successproviding the most robust and clinically-proven technology platforms in the world for total disc replacement (prodisc) and Integrated Interbody fusion (STALIF).

Centinel Spine continues to advance its pioneering culture and corporate mission to become a catalyst of change in the spine industry and alter the way spine surgery is perceived. Centinel Spine remains the only company with comprehensive motion-preserving and fusion solutions for both cervical and lumbar anterior column reconstruction.

For more information, please visit the companys website atwww.CentinelSpine.comor contact:

Centinel SpineVarun GandhiChief Financial Officer900 Airport Road, Suite3BWest Chester, PA19380Phone: 484-887-8871Email:v.gandhi@centinelspine.com

MediaSean LeousICR WestwickePhone: +1.646.677.1839sean.leous@westwicke.com

SOURCE Centinel Spine, LLC

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Centinel Spine Announces First Commercial Use of prodisc Cervical Total Disc Replacement Portfolio that Allows the Disc to be Matched to Patient...

Anatomy

‘Celebrity Wheel of Fortune’ returns with Snoop Dogg, ‘Grey’s Anatomy’ vet – Entertainment Weekly News

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Celebrity Wheel of Fortune returns with Snoop Dogg, Grey's Anatomy vet, Jenifer Lewis, and more

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