Category Archives: Cell Medicine

Collaboration supports precision medicine approach to autoimmune diseases by targeting metabolic hubs to enable target identification, biomarker discovery and patient stratification

CAMBRIDGE, Mass. & MARSEILLE, France, October 27, 2021--(BUSINESS WIRE)--Rheos Medicines, a biopharmaceutical company bringing molecular targeting and precision treatment to autoimmune and inflammatory disease, today announced a research collaboration with the French non-profit research organization CRYOSTEM. The goal of the research collaboration is to provide biological resources from HSCT (Hematopoietic Stem Cell Transplantation) patients in order to evaluate MALT1-targeted therapeutics, including Rheoss lead product candidate, RHX-317, for Graft-versus-Host Disease (GvHD), based on functional immunologic profiling of patients and identification of molecular signatures for MALT1 activity. This collaboration supports a precision medicine approach to enable the treatment of GvHD, by defining the predominant metabolic pathways in the anabolic hub that drive key pathogenic pathways in GvHD patient subsets.

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"CRYOSTEM chose to establish this collaborative research program with Rheos because it aligns with our mission to promote our collection of biological resources to help scientists accelerate innovation and extract new knowledge to allow better prevention, diagnosis and treatment of GvHD as one of the HSCT major complications that is a barrier to effective stem cell transplants for patients," said Professor Rgis PEFFAULT de LATOUR, co-founder and scientific coordinator of CRYOSTEM.

The research program brings together the collaborators two domains of expertise to address the challenge of treating GvHD, a major cause of post-transplant morbidity and mortality in patients who undergo allogeneic HSCT. With its proprietary technology platform, Rheos brings insights from studies showing that MALT1 activity underpins the activation of multiple cell types and signaling pathways within a metabolic hub that is dysregulated in GvHD, as well as approaches to predict and stratify patient response to treatment. CRYOSTEM operates through a national biobanking network bringing together transplant units and Biological Resources Centers to accelerate research in the area of complications of HSCT, housing the first and unique collection in Europe dedicated to HSCT complications. This collection of approximately 200,000 biological samples, taken from patients before and after transplant, support research projects that meet rigorous selection criteria by a world-renowned scientific committee.

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"This research collaboration with the world-class experts at CRYOSTEM will enable us to significantly build on our existing work in immune cells from healthy donors, and now study GvHD patient samples to evaluate the effect of inhibiting a key drug target on the activation state of multiple immune cells and the specific pathways that are dysregulated in GvHD," said Dania Rabah, Ph.D., Chief Scientific Officer of Rheos Medicines. "We believe the data generated under this collaboration can validate our precision medicine approach to identify novel patient subsets in autoimmune and inflammatory diseases, while also informing the clinical development plan for RHX-317, our novel MALT1 inhibitor drug candidate to treat GvHD."

Under the terms of the research collaboration, CRYOSTEM will provide Rheos with biological resources for post-transplant patients in three categories: those who developed acute GvHD, those who developed chronic GVHD, and those who did not develop GvHD. Rheos will evaluate therapeutic targets for GvHD through these study methods:

Measure the effectiveness of MALT1 inhibition against disease-relevant functions of immune cells, comparing results across the three different categories of patient samples to determine sensitivity of MALT1 inhibitor drug response and target validation in chronic GvHD.

Perform multi-omic analyses of patient samples to define signatures reflecting MALT1 therapeutic activity.

Upon successful completion of these initial studies, both parties may agree to expand the research to include larger GvHD patient cohorts and additional evaluation of patient subsets to predict therapeutic response for a potential precision medicine approach to GvHD.

"As with many diseases that have an aberrant immune response, todays treatments for GvHD involve broad immunosuppression, and we lack molecularly-targeted medicines that target disease pathways," said Robert Zeiser, M.D., Head of Tumor Immunology and Immune Modulation and professor at the University of Freiburg Medical Center in Germany. "Rheoss therapeutic approach to target MALT1 for the treatment of GvHD is built on compelling findings that MALT1 activates cellular activity and signaling pathways that are dysregulated in GvHD. I look forward to continued progress with this MALT1 inhibitor that offers a promising new approach for patients with GvHD."

About MALT1

MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a dual-function scaffolding molecule and paracaspase that is expressed preferentially in immune cells. In addition to its role in NF-B mediated lymphocyte activation and proliferation, Rheos has shown that MALT1 activity is central to the anabolic shift that fuels pathogenic functions of immune cells. Inhibiting MALT1 attenuates the activity of multiple immune cell types simultaneously to dampen the inflammatory response in the activated immune system. Because of its role in cellular metabolism, the effects of MALT1 inhibition can be monitored by metabolite signatures, opening an opportunity to monitor disease and evaluate activity of therapeutics in patients and patient subsets.

About CRYOSTEM

CRYOSTEM was initiated in 2010, under the aegis of the SFGM-TC (Socit Francophone de Greffe de Moelle et de Thrapie Cellulaire (https://www.sfgm-tc.com/) to create a multicenter biobank in the field of HSCT. After initially concentrating on Graft-versus-Host Disease (GvHD), CRYOSTEM has broadened its focus to all HSCT complications. Thanks to its network of all the transplant units in France and 28 Biological Resources Centers, CRYOSTEM has established a standardized collection of high-quality biological samples associated with well-annotated clinical data from donors and patients pre- and post-HSCT. Currently, the collection has reached approximately 200,000 available samples coming from nearly 5,900 patients. Since 2015, CRYOSTEM has provided the national and international scientific community with these samples for large-scale research to improve the knowledge of HSCT complications. CRYOSTEM has been funded by the French governments "National Investment Program" and has also received financial support from the French National Cancer Institute (INCa) and patient associations. For more information, please visit http://www.cryostem.org.

About Rheos Medicines

Rheos Medicines is a biopharmaceutical company developing novel, small molecule medicines to treat autoimmune and inflammatory diseases with greater precision by targeting the metabolic hubs of the immune system. Using our proprietary MetPM platform, the Rheos team integrates an unmatched knowledge base of immunometabolism networks based on bioinformatic integration of genetic, transcriptomic, epigenomic and metabolomic datasets, including from patient data and samples. We have built a pipeline of novel, differentiated drug programs to address autoimmune and inflammatory diseases by targeting fundamental underpinnings of immune system dysfunction while, at the same time, identifying the molecular signatures for patient stratification and selection. Rheos has assembled leading scientists whose discoveries opened the field of immunometabolism, clinicians with a deep understanding of immune-mediated diseases, and an experienced biotech leadership team. Rheos was founded by Third Rock Ventures and is located in Cambridge, MA. For more information, please visit http://www.rheosrx.com. We invite you to follow us on LinkedIn and @Rheosrx.

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Contacts

FOR RHEOS MEDICINES:

Media: Kathryn MorrisThe Yates Network LLC914-204-6412kathryn@theyatesnetwork.com

Investor: Hannah DeresiewiczStern Investor Relations, Inc.212-362-1200hannah.deresiewicz@sternir.com

FOR CRYOSTEM:

Media: Jean-Mehdi GrangeonKOM AgencyMarseille, Franceinfo@kom-fr.com

Partnership: Emilie RobertAssociation CRYOSTEMMarseille, Franceemilie.robert@cryostem.org

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Rheos Medicines Forms Research Collaboration With CRYOSTEM to Evaluate MALT1Targeted Therapeutics for Graft-versus-Host-Disease - Yahoo Finance

SAN FRANCISCO and SUZHOU, China, Oct. 27, 2021 /PRNewswire/ -- Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, and NeoCura Bio-Medical Technology Co., Ltd. ("NeoCura"), a leading AI-enabled RNA precision medicine biotech company committed to building a global top RNA innovative drug platform, today jointly announced that they have entered into a strategic collaboration agreement to carry out a clinical study in China on the combination therapy of sintilimab from Innovent and individualized neoantigen vaccine NEO_PLIN2101 from NeoCura.

Innovent will collaborate with NeoCura in China to assess the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the combination therapy using sintilimab from Innovent and NEO_PLIN2101 from NeoCura in cancer patients, to advance the clinical development of combination immunotherapy for multiple solid tumors, and prepare to submit the Investigational New Drug (IND) application to the National Medical Products Administration (NMPA) in the near future.

Dr. Liu Yongjun, President of Innovent, stated: "We are impressed by NeoCura's differentiated R&D pipeline and international research team, and we are pleased to enter into this strategic collaboration to explore the clinical value of sintilimab in combination with neoantigen vaccines for solid tumors. Innovent has a robust pipeline with strong capabilities in immunology and cancer biology. Currently, we have five innovative drugs approved and launched in China and will have more than 10 innovative drugs to be launched in the next 2-3 years. Our fully integrated platform has accumulated strong R&D, clinical development and commercialization capabilities and is ideal for partners at home and abroad. We also hope to further explore the new opportunities in expanding indications and enhancing therapeutic efficacy of sintilimab in combination with novel therapies. We look forward to wider and in-depth collaboration between the two parties in the future. "

Dr. Wang Yi, founder of NeoCura, stated: "At present, neoantigen vaccines are a revolutionary emerging therapeutic approach worldwide. NeoCura has been focusing on the R&D of tumor neoantigen vaccines since its establishment, hoping to overcome the challenges of existing immunotherapy in the treatment of solid tumors through the application of new technologies. The collaboration with Innovent will play a synergistic role of personalized neoantigen vaccines and monoclonal antibody drugs and jointly explore the clinical effect of the combination therapy in the treatment of solid tumors, which is expected to improve the objective response rate of cancer immunotherapy and bring new opportunities for cancer combination regimens."

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Eli Lilly and Company. Sintilimab is an immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for four indications, including:

Additionally, Innovent currently has one regulatory submission under review in China for sintilimab, for the first line treatment of esophageal squamous cell carcinoma.

Additionally, four clinical studies of sintilimab have met their primary endpoints:

In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of non-squamous non-small cell lung cancer.

Sintilimab was included in China's National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

About NEO_PLIN2101

NEO_PLIN2101 is a personalized neoantigen vaccine developed by NeoCura, which can be custom made according to the unique tumor gene mutation of each patient. Through high-throughput sample sequencing and AI algorithm epitope prediction, high-quality neoantigen fragments that can be efficiently presented by tumor cells and elicit a potent immune responseare selected from patient's tumor sample. The mRNA vaccine encoded corresponding neoantigen is synthesized in vitro, vaccinated into patients to activate tumor-specific T cells to control tumor growth and reduce tumor burden. Compared to conventional approach, NEO_PLIN2101 has stronger specificity and immunogenicity that can induce anti-tumor immune response in cancer patients.

About Innovent

Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune, metabolic and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK.

Since its inception, Innovent has developed a fully integrated multi-functional platform which includes R&D, CMC (Chemistry, Manufacturing, and Controls), clinical development and commercialization capabilities. Leveraging the platform, the company has built a robust pipeline of 26 valuable assets in the fields of cancer, metabolic, autoimmune disease and other major therapeutic areas, with 5 products TYVYT (sintilimab injection), BYVASDA (bevacizumab biosimilar injection), SULINNO (adalimumab biosimilar injection), HALPRYZA (rituximab biosimilar injection) and Pemazyre (pemigatinib oral inhibitor) officially approved for marketing in China, 1 asset's NDA under NMPA review, sintilimab's Biologics License Application (BLA) acceptance in the U.S., 5 assets in Phase 3 or pivotal clinical trials, and an additional 15 molecules in clinical studies.

Innovent has built an international team with advanced talent in high-end biological drug development and commercialization, including many global experts. The company has also entered into strategic collaborations with Eli Lilly and Company, Adimab, Incyte, MD Anderson Cancer Center, Hanmi and other international partners. Innovent strives to work with many collaborators to help advance China's biopharmaceutical industry, improve drug availability and enhance the quality of the patients' lives. For more information, please visit: http://www.innoventbio.com. and http://www.linkedin.com/company/innovent-biologics/.

Note:

Sintilimab is not an approved product in the United States.

BYVASDA (bevacizumab biosimilar injection), HALPRYZA (rituximab biosimilar injection), and SULINNO (adalimumab biosimilar injection) are not approved products in the United States.

TYVYT (sintilimab injection, Innovent)

BYVASDA (bevacizumab biosimilar injection, Innovent)

HALPRYZA (rituximab biosimilar injection, Innovent)

SULINNO (adalimumab biosimilar injection, Innovent)

Pemazyre (pemigatinib oral inhibitor, Incyte Corporation). Pemazyre was discovered by Incyte Corporation and licensed to Innovent for development and commercialization in Mainland China, Hong Kong, Macau and Taiwan.

Disclaimer:

1. This indication hasn't been approved in China. 2. Innovent does not recommend any off-label usage.3. For medical and healthcare professionals only.

About NeoCura

Founded in 2017, NeoCura is committed to building a global top RNA innovative drug platform. NeoCura has built a multi-omics data collection platform and corresponding omics database, empowered by AI and bioinformatics technology for target deep mining and automated drug design for innovative RNA medicine research and development, and built a leading RNA drug manufacturing center in China to support pipeline research and development as well as clinical needs.

NeoCura brings together the world's top scientists, senior industry experts and international first-class academic consultant teams. The core R&D team includes dozens of doctoral/postdoctoral fellows from prestigious schools such as Harvard, Cambridge, Cornell, Peking University, Tsinghua University and Chinese Academy of Sciences. The professional fields cover multiple disciplines including genomics sequencing, AI algorithm, bioinformatics, onco-immunology, vaccine design and drug delivery. Team members have held core R&D positions in top international research institutions or enterprises such as Harvard Medical School, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston Children's Hospital, and the research results have been published on hundreds of articles in international high-portfolio journals such as Nature, Science, and Cell.

NeoCura has independently developed AI bioinformatics platform for deep target mining, RNA medicine platform, automated drug design platform, multi-omics big data collection and analysis platform and target validation platform, aiming to promote RNA drug clinical research in combination with artificial intelligence algorithm plus real-world data validation. Its proprietary NeoCuraTM AI ALPINE tumor neoantigen prediction algorithm has the highest prediction accuracy in the world. Relying on its own R&D expertise and technical advantages, NeoCura has carried out in-depth studies in the tumor neoantigen vaccine, tumor microenvironment modulations, etc., developed personalized neoantigen vaccine for different individuals, established a public neoantigen pool for the high incidence of cancers in China, significantly reduced the cost of neoantigen drug treatment and shortened the preparation cycle. At present, NeoCura has jointly carried out clinical trials with many leading hospitals and will become a new landmark in the field of cancer treatment. With its cutting-edge AI technologies, outstanding innovation capability and robust oncology pipelines, NeoCura is recognized as one of the Most Promising Enterprise in China and Top 10 China AI/Algorithm Pharmaceutical Innovative Enterprise in 2021.

Company website: http://www.neocura.com.cn.

Innovent Forward-Looking Statements

This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", "intend" and similar expressions, as they relate to Innovent, are intended to identify certain of such forward-looking statements. Innovent does not intend to update these forward-looking statements regularly.

These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections and understandings of the management of Innovent with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties and other factors, some of which are beyond Innovent's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, Innovent's competitive environment and political, economic, legal and social conditions.

Innovent, the Directors and the employees of Innovent assume (a) no obligation to correct or update the forward-looking statements contained in this site; and (b) no liability in the event that any of the forward-looking statements does not materialize or turn out to be incorrect.

SOURCE Innovent Biologics

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Innovent and NeoCura Announce Strategic Collaboration to Study the Combination Therapy of Sintilimab and Neoantigen Vaccine NEO_PLIN2101 for Cancer...

Use of comprehensive genomic profiling in patients with advanced nonsmall cell lung cancer (NSCLC) was linked with significant improvements in progression-free survival and overall survival.

Comprehensive genomic profiling (CGP) in the management of advanced nonsmall cell lung cancer (NSCLC) was shown to assist in matching patients with targeted therapies and clinical trials with those matched to these therapies associated with improved survival outcomes. Findings were published in BMC Medicine.

Despite the identification of several new targetable drivers in advanced NSCLC, the standard of care for these populations only includes genetic testing for EGFR, ALK, and ROS1 mutations. Notably, previous research shows use of the broader CGP profiling can better assess for emerging mutations, but research regarding its efficacy has not yet been determined.

Patients carrying alterations other than EGFR, ALK, and ROS1 now have increased access to targeted drugs off label or through a clinical protocol, said the study authors. Therefore, a re-evaluation on the clinical implications of CGP in the current treatment landscape of advanced NSCLC is warranted.

Seeking to further examine the clinical utility of CGP, they prospectively applied the approach to Chinese patients with advanced NSCLC registered in the Precision Medicine Project from October 2016 to October 2019 (N = 1564).

Efficacy of CGP in treatment selection was measured by the proportion of patients receiving a genomic profilingdirected, matched targeted therapy and the proportion of patients being enrolled into a biomarker-selected clinical trial directed by their profiling results.

Those provided with genotype-matched therapy were compared with those who were not matched for progression-free survival (PFS) and overall survival (OS).

In their findings, tumor genomic profiles were established in 1166 participants who underwent CGP:

Compared with patients with a nonmatched therapy, those who were given genotype-matched therapies showed significant improvements in PFS (9.0 vs 4.9 months; P < .001) and OS (3.9 vs 2.5 years; P < .001).

After excluding patients with standard targeted therapies, genomic profiling led to a matched targeted therapy in 16.7% (n = 24) and a matched trial enrollment in 11.2% (n = 16) of patients. Contrary to that found in the overall cohort, no PFS (4.7 vs 4.6 months; P = .530) or OS (1.9 vs 2.4 years; P = .238) benefit was observed with the use of genotype-matched targeted therapies in these populations.

In concluding, researchers said that given the low likelihood of benefit from the investigational or off-label use of targeted therapies, applicability of genomic profiling results should be taken with caution in patients without standard-of-care drugs.

Reference

Zhao S, Zhang Z, Zhan J, et al. Utility of comprehensive genomic profiling in directing treatment and improving patient outcomes in advanced non-small cell lung cancer. BMC Med. Published online October 1, 2021. doi:10.1186/s12916-021-02089-z

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Genomic Profiling Linked With Improved Patient Outcomes in Advanced NSCLC - AJMC.com Managed Markets Network

A recent report published in the journal Pharmacological Reviews from Utrecht University reviewed 200 studies revealing that high-quality nutrients in our food have a profound effect on our cells and, in particular, our immune system.

This study demonstrates that specific nutritional components can positively affect inflammatory responses and allergic reactions. To understand how this works it is important to have a basic understanding of the cell. In my opinion, the three key components of the cell are the nucleus which contains the genetic material, the mitochondria which are the fuel packs of the cell producing energy to maintain cell function and the little spoken about but vitally important membrane of the cell which is the interface between the external environment and the inner workings of the cell.

Some research suggests that the membrane is, in fact, the brain of the cell. On the surface of every cell are thousands of receptors which are basically doorways that allow external stimuli to affect different processes occurring within the cell.

There is no doubt that consuming 2 to 3 pieces of fruit and 3 to 5 servings of vegetables per day is a significant health practice that leads to low rates of heart disease and cancer. Tragically, less than 10% of our society practices healthy lifestyles, including the ingestion of the above amount of fruit and vegetables.

Our macronutrients are fat, protein and carbohydrates which basically form the fuel for cell metabolism and in the case of proteins the building blocks for all of our proteins and enzymes.

But, fruit and vegetables also contain a vast array of plant chemicals known as polyphenols, along with a variety of micronutrients which include vitamins, minerals and trace metals. The polyphenols, in particular, have a profound effect on the receptors on our cell surface and therefore maintain vital cell to cell communication and communication between external stimuli and the inner workings of the cell.

The study from Utrecht University demonstrates the vital importance of many of these high-quality natural nutrients in modulating the important processes that occur in our body and dampen down inflammation and allergy. Inflammation is a key component of the generation of our typical modern killers, such as cardiovascular disease, cancer, Alzheimers, Diabetes & respiratory disease which make up over 70% of the deaths around the globe on a yearly basis.

Pharmaceutical drugs work through a similar mechanism but because they are not natural chemicals may often damage many of these natural processes going on throughout our body.

As we age, the vast majority of people living in the modern world develop a variety of chronic complaints requiring pharmaceutical medications but the strong message from my work, reinforced by important trials studies such as this one from Utrecht University demonstrate clearly the value of the effects of high-quality nutrients on cell function.

Hippocrates knew this two and a half thousand years ago and it is somewhat sad that we see medical therapy as a pill or a procedure rather than the vital importance of leading a healthy lifestyle.

IMPORTANT LEGAL INFO This article is of a general nature and FYI only, because it doesnt take into account your personal health requirements or existing medical conditions. That means its not personalised health advice and shouldnt be relied upon as if it is. Before making a health-related decision, you should work out if the info is appropriate for your situation and get professional medical advice.

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Food as medicine: how it works - Starts at 60

Writing in EMBO reports, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumor survival and growth.

The findings appear in the October 26, 2021 issue of the journal, a publication of the European Molecular Biology Organization.

Cancer is driven by multiple types of genetic alterations, including DNA mutations and copy number alterations ranging in scale from small insertions and deletions to whole genome duplication events.

A stained histological slide, magnified 100 times, depicts cancer cells expansively spread through normal breast tissues, including a duct completely filled with tumor cells. Credit: Dr. Cecil Fox, National Cancer Institute

Collectively, somatic copy number alterations in tumors frequently result in an abnormal number of chromosomes, termed aneuploidy, which has been shown to promote tumor development by increasing genetic diversity, instability and evolution. Approximately 90 percent of solid tumors and half of blood cancers present some form of aneuploidy, which is associated with tumor progression and poor prognoses.

In recent years, it has become apparent that cells cohabiting within a tumor microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients), but also to the internal stressor aneuploidy. Both activate a stress response mechanism called the unfolded protein response (UPR), which leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) of cells an organelle that synthesizes proteins and transports them outside the cell.

When this primary transport/export system is disrupted, UPR attempts to restore normal function by halting the accumulation of misfolded proteins, degrading and removing them and activating signaling pathways to promote proper protein folding.

If homeostasis or equilibrium is not re-established quickly, non-tumor cells undergo cell death. Conversely, cancer cells thrive in this chaos, establishing a higher tolerance threshold that favors their survival.

In these circumstances, they also co-opt neighboring cells in a spiral of deceit that progressively impairs local immune cells, said co-senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and a tumor immunologist at Moores Cancer Center with Hannah Carter, PhD, associate professor of medicine and a computational biologist. Zanetti had previously introduced the hypothesis in a Science commentary.

The researchers hypothesized that aneuploidy, UPR and immune cell dysregulation could be linked together in a deadly triangle. In the new study, Zanetti, Carter and colleagues analyzed 9,375 human tumor samples and found that cancer cell aneuploidy intersects preferentially with certain branches of the signaling response to stress and that this finding correlates with the damaging effects of aneuploidy on T lymphocytes, a type of immune cell.

This was an ambitious goal not attempted before, said Zanetti. It was like interrogating three chief systems together chromosomal abnormalities in toto, signaling mechanisms in response to endogenous stress and dysregulation of neighboring immune cells just to prove a bold hypothesis.

We knew the task would be challenging, added Carter, and that we would need to create and refine new analytical tools to test our hypotheses in heterogeneous human tumor data, but it was a worthwhile risk to take.

The findings, they said, show that the stress response in cancer cells serves as an unpredicted link between aneuploidy and immune cells to diminish immune competence and anti-tumor effects. It also demonstrates that molecules released by aneuploid cells affect another type of immune cells macrophages by subverting their normal function to turn them into tumor-promoting actors.

The findings offer new opportunities to understand tumor progression as a balance between the progressive accumulation of chromosomal abnormalities during tumor evolution and the progressive decay of anti-tumor immunity, said the authors, with the signaling response to stress gauging and regulating the relationship.

In practical terms, they said, a new aneuploidy score defining the burden of chromosomal abnormalities, developed for the study, could set a new paradigm for assessing the biological stage of tumor progression in patients and be used to extrapolate immune status.

It may also inform on new opportunities for pharmacological or genetic interventions that interfere with specific branches of the UPR as the mediator of aneuploidy-driven local immune dysregulation. This non-immunological approach could make immunotherapy of cancer more efficient, said Zanetti.

Co-authors include: Su Xian, Magalie Dosset, Gonzalo Almanza, Stephen Searles, Paras Sahani, T. Cameron Waller, Kristen Jepsen and Hannah Carter, all at UC San Diego.

Funding for this research came, in part, from the National Institutes of Health (grant RO1 CA220009), Mark Foundation Emerging Leader Award and the National Cancer Institute (grant T32CA121938).

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Tumor Reasons Why Cancers Thrive in Chromosomal Chaos - UC San Diego Health

San Diego research centers receive $15 million to train next generation of scientists

San Diego Community News Group

Three San Diego research institutions have been awarded nearly $15 million from the California Institute of Regenerative Medicine (CIRM) to train the next generation of scientists in regenerative medicine, a field of research that holds great promise for generating transformative medicines.

Scripps Research, University of California San Diego, and Sanford Burnham Prebys each received grants of around $5 million from CIRM to support the training of graduate students, postdoctoral trainees, and clinical trainees.

The CIRM awards will also foster interdisciplinary regenerative medicine collaborations among the three San Diego recipient institutions and support outreach science activities in the broader San Diego community. The funding also will support educational programs for K-12 students and undergraduates on topics related to regenerative medicine that are intended to reduce disparities and disproportionate access to science.

"CIRM has provided critical leadership spearheading regenerative medicine and stem cell research," says Peter Schultz, president and CEO of Scripps Research. "This forward-looking investment in training the next generation of scientists will help ensure continued progress toward realizing the tremendous promise of regenerative medicine."

Schultz will head the Scripps Research program which received $4,931,353 to train scientists in disciplines and techniques central to stem cell biology and regenerative medicine. These include cellular processes involved in human embryonic and adult stem cell self-renewal and differentiation and the development of novel drugs to target related pathways.

University of California San Diego received $4,992,446 to train the next generation of stem cell biologists, driving advances ranging from the unraveling of fundamental mechanisms of cell function to the development of new therapies. The UC San Diego training program will be led by Alysson R. Muotri, PhD, professor of pediatrics and cellular and molecular medicine at UC San Diego School of Medicine, and Sheldon Morris, MD, primary care physician at UC San Diego Health.

This grant comes at a time when stem cell research in San Diego has matured, thanks to strong support over the years from visionaries such as CIRM and philanthropist T. Denny Sanford, Muotri said. The only way to keep up this momentum is to have professionals that understand how to use and apply stem cell and gene therapies. We are building the next generation of researchers and clinicians to do this.

Sanford Burnham Prebys received $4,931,353 to launch a multidisciplinary stem cell training program. The grant will provide funds for competitive awards for PhD students, postdocs and clinical fellows in stem cell, gene therapy and regenerative medicine fields at the institute. The training program will be led by Evan Snyder, MD, PhD, professor and director of the Center for Stem Cells & Regenerative Medicine, as well as professors/directors Pier Lorenzo Puri, MD, and Alessandra Sacco, PhD, in the Development, Aging and Regeneration Program Center at Sanford Burnham Prebys.

Sacco says stem cell research holds tremendous promise for medical treatments, and that CIRMs support will allows scientists to learn more about the process through which science becomes medicine.

We are exceptionally grateful that CIRM is supporting this important program, says Sacco. This award helps the next generation of stem cell and regenerative medicine scientists who will work across boundaries and between disciplines to become capable of translating basic discovery science into clinical research for patient benefit.

This years awards build on an earlier Research Training program through which CIRM supported training in regenerative medicines from 2006-2016 and trained 940 CIRM Scholars including 321 doctoral students, 453 postdocs and 166 MDs.

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San Diego research centers receive $15 million to train next generation of scientists - Three San Diego research institutions have been awarded nearly...

Kawasaki disease (KD) is rare, with fewer than 6,000 diagnosed cases per year in the United States. It is most common in infants and young children and causes inflammation in the walls of some blood vessels in the body. KD is a common cause of acquired heart disease in children around the world, causing coronary artery aneurysms in a quarter of untreated children.

Multisystem inflammatory syndrome in children (MIS-C) is also rare, a life-threatening illness that follows exposure to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). MIS-C is characterized by the acute onset of fever and variable symptoms, including rash, cardiovascular complications, shock and gastrointestinal symptoms, including abdominal pain, diarrhea and vomiting.

KD and MIS-C share several clinical features and immune responses. Both conditions are treated with intravenous immunoglobulin (IVIG), a therapeutic containing antibodies purified from blood products. Antibodies in the blood protect us from a number of viral, bacterial and fungal pathogens, but when administered as IVIG, can also suppress excessive inflammation. How it does this is an ongoing area of research worldwide.

In a pair of new studies, published online October 26 and August 31, 2021, two collaborating teams of researchers at University of California San Diego School of Medicine examined the use of IVIG in two groups; one group used a second dose of IVIG in children with KD who do not respond to the first dose of the drug, and the other group used IVIG as an effective treatment for MIS-C.

Our research teams looked further into KD to improve treatment, and then used what we know about that disease to advance science in another illness, said senior author Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Childrens Hospital-San Diego.

In a paper published in the October 26, 2021 online edition of the Lancet: Child and Adolescent Health, researchers found treating IVIG-resistant KD patients with infliximab, a targeted anti-inflammatory drug, was more effective than a second dose of IVIG.

In an earlier paper, published in the August 31, 2021 online edition of The Journal of Clinical Investigation, researchers found why IVIG is a successful treatment for MIS-C.

IVIG is the standard of care for KD and can alleviate symptoms and stabilize patients within hours of administration. However, 10 to 20 percent of children have recurrence of fever after initial therapy and are at an increased risk of coronary artery aneurysms. Historically, a second dose of IVIG has been advocated for treatment of IVIG-resistant KD.

In a national, randomized clinical trial, known as KIDCARE, involving 30 clinical sites and 103 children, researchers looked at a second dose of IVIG versus infliximab in children with KD who did not respond to the first dose of IVIG. They found those treated with infliximab had shorter duration of fever, reduced need for additional therapy, less severe anemia and shorter hospitalizations.

Jane C. Burns, MD, is a professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Childrens Hospital-San Diego.

Researchers in this field have been trying to answer the question of what we should use when the first dose of IVIG does not work since the 1980s, said Burns.

This clinical trial was designed to find out the safest and most effective way to stop the fever and get these children out of the hospital. Our results show that infliximab is the best treatment that does the job safely and quickly.

Additionally, IVIG administration can take up to 12 hours while infliximab requires two.

Trials of infliximab for KD treatment began in the early 2000s in San Diego. Researchers found that the target of infliximab, a pro-inflammatory molecule called TNF, was markedly elevated in the bloodstream of KD patients. This suggested that infliximab, a monoclonal antibody that neutralizes TNF, might be an effective treatment.

We are on the forefront of advances in treatment for KD patients and this finding is another example of how our team moves innovative research from the lab to the patient bedside, said Burns.

Next steps include clinical trials to determine the best treatment for children with KD who come to the hospital already showing damage to the coronary arteries.

MIS-C was first identified in children in April 2020 and is a rare complication of the coronavirus SARS-CoV-2, which causes COVID-19. The inflammation caused by the condition affects several organs and progresses over time. Symptoms are usually seen between two and six weeks after initial infection, which may in fact not cause any symptoms at all.

Both KD and MIS-C share a robust activation of the innate immune system, termed the first responder arm of the immune system. In contrast to KD, however, additional anti-inflammatory therapies, such as steroids or biologic therapies are often needed to further reduce inflammation with MIS-C.

In a recent study, researchers examined what IVIG does to white blood cells (WBC) in MIS-C and KD. Neutrophils are a type of WBC that prevent serious infections by killing invading bacteria and fungi.

Using cell samples from children with MIS-C or KD, researchers found that neutrophils laden with IL-1b, a key mediator of the inflammatory response, are generated in large numbers and play an active role in inflammation in patients. Exposing these patient cells to IVIG in the laboratory, researchers showed that IVIG targets and kills those neutrophils, thus, reducing inflammation.

Ben Croker, PhD, is an associate professor in the Department of Pediatrics at UC San Diego School of Medicine.

This finding is important because it shows how and why IVIG is successful in rapidly reducing inflammation in kids. It targets a different part of the immune response to steroids, which can also suppress inflammation, said Ben Croker, PhD, associate professor in the Department of Pediatrics at UC San Diego School of Medicine.

Initially, we borrowed from the KD playbook to treat MIS-C because of the similarities between the two diseases. We were challenged to treat a severe reaction (MIS-C) to a novel virus no one on the planet had seen two years ago. Our studies now support an important role for IVIG as a therapy for these patients, said Burns.

Croker noted that these findings pave the way for the next discovery, which will be understanding the mechanism by which IVIG accomplishes its killing mission so that it could be replaced with a less expensive, more readily available treatment.

Co-authors include: Samantha Roberts, Adriana Tremoulet, Feng He, Beth Printz and Sonia Jain, all with UC San Diego; Negar Ashouri with CHOC Childrens Hopsital; Supriya Jain, Maria Fareri Children's Hospital; David Michalik, Miller Children's Hospital Long Beach; Kavita Sharma, Children's Health, University of Texas Southwestern Medical Center; Dongngan Truong, University of Utah/Primary Childrens Hospital; James Wood, Indiana University School of Medicine; Katherine Kim, University of California Davis; and the KIDCARE Multicenter Study Group.

Funding for the KIDCARE study came from Patient Centered Outcomes Research Institute (PCORI).

Co-authors include: Yanfang Peipei Zhu, Isaac Shamie, Jamie Casey Lee, Weiqi Peng, Shiela Angulo, Linh Le, Yushan Liu, Huilai Miao, Hainan Xiong, Cathleen Pena, Elizabeth Moreno, Eric Griffis, Stephanie Labou, Alessandra Franco, Lori Broderick, Hal Hoffman, Chisato Shimizu, Nathan Lewis, John Kanegaye, Adriana Tremoulet, and the Pediatric Emergency Medicine Kawasaki Disease Research Group, all with UC San Diego; and Cameron Nowell with Monash Institute of Pharmaceutical Sciences in Australia.

Funding for this research came, in part, from the National Institutes of Health (grants R61HD105590, RO1HL124209, RO1HL140898-03S1), Patient Centered Outcomes Research Institute (CER1602-3447), the American Asthma Foundation, the American Heart Association, the Novo Nordisk Foundation provided to the Technical University of Denmark (NNF20SA0066621), NIGMS (R35 GM119850) and the American Academy of Allergy, Asthma and Immunology Foundation.

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Same Treatment Tested for Kids with Kawasaki Disease and Rare COVID-19 Reaction - UC San Diego Health

1. Intracranial response rate of 55% was reported in patients receiving cabozantinib with progressing brain metastases with no concomitant brain-directed local therapy

2. Cabozantinib was well-tolerated with common adverse events such as fatigue, diarrhea and palmar-plantar erythrodysesthesia

Evidence Rating Level: 2 (Good)

Study Rundown: Patients with metastatic renal cell carcinoma (RCC) may develop brain metastases, increasing their morbidity and mortality. Currently, the standard treatment of care includes local therapies targeting metastases (e.g., stereotactic radiosurgery, whole-brain radiotherapy). RCC patients with brain metastases were poorly represented in other clinical trials and the aim of this study was to characterize cabozantinib monotherapy in the treatment of progressive brain metastases. This study aimed to evaluate the efficacy and safety of cabozantinib for the treatment of brain metastases in patients with metastatic RCC. Patients were divided into two cohorts. Cohort A comprised of patients with progressing brain metastases who did not receive brain-directed local therapy concomitantly. Cohort B comprised of patients with stable brain metastases who received brain-directed local therapy concomitantly. Cabozantinib showed a notable intracranial response rate of 55% and 47% in cohorts A and B, respectively. Commonly reported adverse events included fatigue, diarrhea and palmar-plantar erythrodysesthesia. Limitations to the study include having a low number of patients in each cohort and the lack of information regarding other concomitant medications that the patients may be on, which could influence the safety profile of cabozantinib. Overall, this study demonstrated that cabozantinib could be an effective treatment for patients with brain metastases from RCC, particularly patients with progressive brain metastases. However, further investigation is required to confirm the findings and establish a more comprehensive efficacy and safety profile of cabozantinib in patients with brain metastases, including in combination with other therapies.

Click to read the study in JAMA Oncology

Relevant Reading: Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population

In-Depth [retrospective cohort]: This was a multicenter, international, retrospective cohort study of 88 patients at 15 academic centers in the United States, Belgium, France, and Spain. Patients were eligible if they had brain metastases from RCC and received cabozantinib between January 2014 and October 2020. The patients were divided into 2 cohorts. Cohort A included patients with progressing brain metastases at the start of cabozantinib who were not receiving concomitant brain-directed local therapy. Cohort B included patients with stable brain metastases at the start of cabozantinib who were receiving brain-directed local therapy concomitantly. The study examined the intracranial and extracranial objective response rates (ORRs) as well as the safety profile of cabozantinib. The intracranial ORR for Cohort A and B were 55% (95% confidence interval [CI]: 36%-73%) and 47% (95% CI: 33%-61%), respectively. 32% of the patients in Cohort A experienced stable disease compared to 42% of patients in Cohort B. 13% of the patients in Cohort A and 11% of patients in Cohort B experienced progressive disease. The extracranial ORR for Cohort A and B were 48% (95% CI: 31%-66%) and 38% (95% CI: 25%-52%), respectively. The median overall survival was 16.0 months (95%CI, 12.0-21.9months). Commonly reported adverse events included fatigue (77%), diarrhea (46%) and palmar-plantar erythrodysesthesia (32%). There were no reported deaths and neurological toxic effects (e.g., seizure, brain hemorrhage, stroke).

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Cabozantinib is associated with an intracranial response in the treatment of brain metastases from renal cell carcinoma - 2 Minute Medicine

In this companion article, Dr. Jared Weiss provides key insights into recent advancements in the standard of care for extensive-stage small cell lung cancer and examines challenges affecting treatment.

While patients with small cell lung cancer can be responsive to initial treatment with chemotherapy, relapse is an important consideration for clinicians. Many patients will also present with advanced disease at diagnosis, so it is essential that clinicians continue to optimize the management of extensive-stage small cell lung cancer (ES-SCLC).

The treatment of ES-SCLC has included the use of platinum chemotherapy (cisplatin, carboplatin) in combination with etoposide. However, in 2019, the IMpower133 clinical trial led to the approval of atezolizumab in combination with etoposide and carboplatin in the first-line setting. Combination therapy with durvalumab, etoposide, and platinum chemotherapy was also approved in the first-line setting with the CASPIAN clinical trial in 2020. Although these new treatment approaches have advanced the standard of care in ES-SCLC, there continue to be challenges affecting optimal patient management and important areas of unmet need that must be addressed.

In this new Precision Medicine Perspectives in Small Cell Lung Cancer series, experts in the management of ES-SCLC reflect on the current therapeutic landscape and highlight some challenges affecting optimal treatment. In the first interview of the series, Jared Weiss, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina provides an overview of recent advancements in the standard of care and underscores the importance of utilizing effective therapeutic approaches while also mitigating and managing the toxicity associated with treatment.

TARGETED ONCOLOGY: What do you consider the biggest challenges in treating ES-SCLC?

WEISS: In my opinion, the unambiguously greatest challenge in treating extensive-stage small cell lung cancer is the lack of therapeutic efficacy. I've been frustrated with extensive-stage small cell lung cancer treatment for some time, as I think many have. It's very frequent that we get these rapid, dramatic, and even complete responses. You have a high log cell kill, you're close to cure, and then you don't get there. This was true even in the era before modern therapeutics. Even back in the era of CAV (cyclophosphamide, doxorubicin, vincristine), we would get complete responses that were not curative. For a long time, we've recognized that, in terms of cell count number, we're getting close to a cure, yet we just about never get there. We're so close, yet for decades have never crossed that finish line.

Even if you step back and say that we don't cure most stage 4 cancers and that we should be a little more realistic, even still, the duration of control that we get is grossly inadequate, and our survival is grossly inadequate. Along the way, our patients suffer not just from the adverse effects of what we do to themalthough I would list that as another really important unmet needthey also suffer from the effects of our therapy, so we need therapies that are more effective. Ideally, curing some or really all patients, we need treatments that are less toxic.

TARGETED ONCOLOGY: How do these challenges affect a patient's treatment plan?

WEISS: When thinking about how to treat a patient, we have to recognize that small cell lung cancer tends to present very symptomatically. It likes to grow in the central area of the chest with a lot of lymphadenopathy, so you get central chest syndromes. You get pain, and you get trouble breathing from clipping off the central airways and the central vessels, so there's often an urgency to treat small cell lung cancer. Of the solid tumors, it is the one that I treat the most inpatient. This is probably true for most consultative physicians.

The good part of this, though, is that the chemotherapy works. If you have a patient in the hospital, even in an extreme situation like on a ventilator, when you give them a cycle of chemotherapy, days later, they're doing much better. The major treatment consideration is efficacy. Fortunately, in the short run, efficacy is quite good.

Then of course, another consideration is toxicity minimization. If you look at the historic evolution of cytotoxic chemotherapy in the preimmunotherapy era and look at the front-line evolution from CAV to platinum and etoposide and the second-line evolution from CAV to topotecan, we really don't have an improvement in survival. What we have is an improvement in toxicity profile and patient convenience profile; this matters, even if we wanted more out of it. Then of course, as we entered the immunotherapy era, there is finally an advantage in survival. Not as much as we'd like, but real.

These historic considerations are the same that we face in clinic every day. What do we need to address our patients immediate needs? What's the best regimen to give them long-term control? And of course, how can we minimize the adverse effects of therapy? Small cell treatment is toxic; the most common toxicities are myelosuppression and their downstream sequalae, like fatigue. There is need for supportive care interventions because our patients are very much suffering from the treatment in addition to suffering from the disease.

TARGETED ONCOLOGY: Regarding recent approvals, first line use of atezolizumab, carboplatin, and etoposide gained approval in 2019, and then durvalumab, carboplatin or cisplatin, and etoposide gained approval in 2020. How have these approvals changed decision-making for first-line therapy for ES-SCLC?

WEISS: First-line treatment of extensive-stage small cell lung cancer changed dramatically in 2019 with the approval of atezolizumab. For a very long time until then, the evolution of frontline regimens never improved survival. Enter IMpower-133: This was a randomized study of carboplatin and etoposide, plus either placebo or the PD-L1 inhibitor atezolizumab. We have an improvement in progression-free survival, we have an improvement in overall survival, and there was not much extra toxicity. There were some immune-related adverse events that you see with the addition of atezolizumab, of course, but looking at the safety profile globally, there was not a terribly big increase.

The same was pretty much replicated in 2020 in the CASPIAN study with the addition of the PD-L1 inhibitor durvalumab to platinum and etoposide. This was a 3-arm randomized study; the third arm had the CTLA-inhibitor tremelimumab. That really didn't improve outcomes any further, so I'll focus on what was approved, deservedly: the addition of durvalumab.

If you look at the forbidden but omnipresent cross-trial comparisons, the curves were nearly superimposable from IMpower-133, which to me reflects that the agents are more similar than different and that both companies conducted their trials fairly and appropriately. There were minor differences in inclusion criteria and enrolled patients, but the main meaning of having 2 trials with similar safety, PFS (progression-free survival), and OS (overall survival) is that it is true. In science, we like to have everything confirmed with another case study. The addition of the PD-L1 inhibitor, the approved ones being atezolizumab or durvalumab, to standard platinum and etoposide improved survival in extensive-stage small lung cancer. This, of course, has changed the standard of care. In the US and other countries that can afford it, the absolute unambiguous standard of care for patients eligible for a checkpoint inhibitor is platinum, etoposide, and a checkpoint inhibitor.

TARGETED ONCOLOGY: What do you consider the most significant unmet needs in the management of ES-SCLC?

WEISS: We've spoken already about the unmet need of actually curing people, and even if we can't do that, of having more durable control with the drugs. We have spoken about the unacceptable toxicity profile of our current standards of care. The 1 additional theme that I might mention for unmet needs is dealing with the patient and their systems as a whole.

While I love my smokers and non-smokers the same and have no desire to stigmatize anybody, we do need to recognize that smoking brings with it smoking-associated comorbidities. In addition to decreased socioeconomic resources, the patients bodies come to their cancer more beaten up with things like COPD (chronic obstructive pulmonary disease) and more limited blood counts. They're less able to tolerate and benefit from the standard of care in addition to the greater difficulty in traveling to academic centers and getting trials. Optimal care of the patient with extensive-stage small cell lung cancer involves not only less toxic therapy, better supportive care, and therapies that work better, but it also requires an extensive network to support the patient to be able to get those more advanced standards of care applied to them.

Additionally, lung cancer is a heavily stigmatized cancer that disproportionately affects patients with fewer financial resources and social capital to bring to their treatment. If you contrast this, for example, with a patient with estrogen receptor positive breast cancer, or a patient with HPV (human papillomavirus)-positive head and neck cancer, these are patients who can afford to travel for trials, who can get many opinions. In contrast, many of my patients with small cell lung cancer have trouble paying for the tank of gas to get to the doctor's visit.

TARGETED ONCOLOGY: Chemotherapy-induced myelosuppression (CIM) can result from some treatment regimens. How significant of an issue is CIM and to what extent does it affect a patients treatment course?

WEISS: The problem is actually quite common if you look at the toxicity tables of the regimens that have defined our standard of care. If you look at IMpower-133, if you look at CASPIAN, if you look at the phase I basket results of lurbinectedin, and if you look at any of the dozen or so topotecan trials, what you can see is that the majority of patients are experiencing adverse events. The most common of these are myelosuppressive events, which until very recently we couldn't do a whole lot about.

Chemotherapy-induced myelosuppression is a major harm to treatment. While dose density doesn't have a great impact on survival in small cell lung cancer the way it does in breast cancer or some lymphomas, there are meaningful harms to needing to delay and reduce doses. It is inconvenient for patients. It's inconvenient for providers. It causes substantial anxiety.

Further, neutropenia very much hurts people. Febrile neutropenia can be a fatal event, it can delay chemotherapy, and it results in the need for drugs like pegfilgrastim that have adverse effects like bone pain. When you get to anemia, which causes fatigue, fatigue is the quality-of-life issue that perhaps we have the most trouble controlling in clinic, and for many patients, this affects them the most.

I think myelosuppression deserves a renewed focus. For years, we haven't thought that much about myelosuppression other than maybe neutropenia because we had a bit of a learned helplessness. This was the cost of business for giving cytotoxic drugs, and we started to say, "Well, of course, you get tired. Of course you get anemic." The introduction of effective drugs to protect neutrophils has changed this. Trilaciclib, which can help with the myelosuppression, now means that we can actually do something about it.

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EP. 2B: Challenges Affecting the Management of Extensive-Stage Small Cell Lung Cancer - Targeted Oncology

CARLSBAD, Calif.--(BUSINESS WIRE)--Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported today that updated interim results from a Phase 1/2a clinical study of its lead product candidate, OpRegen, an investigational retinal pigment epithelium cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (AMD), will be featured in a presentation at the 2021 American Academy of Ophthalmology (AAO) 125th Annual Meeting, to be held at the Ernest N. Morial Convention Center, New Orleans, LA (November 12 15, 2021). The presentation, OpRegen Trial: Phase 1/2a Dose Escalation Study of Human Embryonic Stem-Cell Derived Retinal Pigment Epithelium Cells Transplanted Subretinally in Patients with Advanced AMD, will be presented on November 13, 2021 at 2:38 pm EDT as part of the Gene and Cell-Based Therapies Session, by Michael S. Ip, M.D., Professor, Department of Ophthalmology at the David Geffen School of Medicine at the University of California - Los Angeles.

In addition to Dr. Ips presentation, Lineage also intends to announce updated interim results from the Phase 1/2a study next month, which will include a minimum of 12 months of follow-up in all 24 patients treated with OpRegen, including all 12 patients treated in Cohort 4, which had better baseline vision and smaller areas of GA at baseline than earlier cohorts. OpRegen is well-positioned among product candidates in development for dry AMD as the only experimental therapy that has demonstrated an ability to halt or reverse the expansion of geographic atrophy as well as restore layers of retinal tissue in three patients to date. Specifically, outer retinal layer restoration was observed via optical coherence tomography (OCT) and was evidenced by the presence of new areas of retinal pigment epithelium (RPE) monolayer with overlying ellipsoid zone, external limiting membrane, and outer nuclear layer, all of which were not present at the time of baseline assessment. These findings are suggestive of integration of the new RPE cells with functional photoreceptors in areas that previously showed no presence of any of these cells.

The American Academy of Ophthalmology is the worlds largest association of eye physicians and surgeons. The mission of the American Academy of Ophthalmology is to protect sight and empower lives by serving as an advocate for patients and the public, leading ophthalmic education, and advancing the profession of ophthalmology. For more information, please visit https://www.aao.org/ or follow the association on Twitter @aao_ophth.

About OpRegen

OpRegen is currently being evaluated in a Phase 1/2a open-label, dose escalation safety and efficacy study of a single injection of human retinal pigment epithelium cells derived from an established pluripotent cell line and transplanted subretinally in patients with advanced dry AMD with geographic atrophy (GA). The study enrolled 24 patients into 4 cohorts. The first 3 cohorts enrolled only legally blind patients with Best Corrected Visual Acuity (BCVA) of 20/200 or worse. The fourth cohort enrolled 12 better vision patients (BCVA from 20/65 to 20/250 with smaller mean areas of GA). Cohort 4 also included patients treated with a new thaw-and-inject formulation of OpRegen, which can be shipped directly to sites and used immediately upon thawing, removing the complications and logistics of having to use a dose preparation facility. The primary objective of the study is to evaluate the safety and tolerability of OpRegen as assessed by the incidence and frequency of treatment emergent adverse events. Secondary objectives are to evaluate the preliminary efficacy of OpRegen treatment by assessing the changes in ophthalmological parameters measured by various methods of primary clinical relevance. OpRegen is a registered trademark of Cell Cure Neurosciences Ltd., a majority-owned subsidiary of Lineage Cell Therapeutics, Inc.

About Age-Related Macular Degeneration

AMD is an eye disease that can blur the sharp, central vision in patients and is the leading cause of vision loss in people over the age of 60. There are two forms of AMD: dry (atrophic) AMD and wet (neovascular) AMD. Dry (atrophic) AMD is the more common of the two forms, accounting for approximately 85-90% of all cases. In atrophic AMD, parts of the macula get thinner with age and accumulations of extracellular material between Bruch's membrane and the retinal pigmented epithelium, known as drusen, increase in number and volume, leading to a progressive loss of central vision, typically in both eyes. Global sales of the two leading wet AMD therapies were in excess of $10 billion in 2019. Nearly all cases of wet AMD eventually will develop the underlying atrophic AMD if the newly formed blood vessels are treated correctly. There are currently no U.S. Food and Drug Administration, or European Medicines Agency, approved treatment options available for patients with atrophic AMD.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC2, an allogeneic dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, can, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, suggest, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the projected timing of future announcements or presentations of updated or additional data from the Phase 1/2a clinical study of OpRegen, the potential benefits of treatment with OpRegen in dry AMD patients with GA, the significance of clinical data reported to date from the ongoing Phase 1/2a study of OpRegen, including the findings of retinal tissue restoration, Lineages plans to meet with the FDA to discuss OpRegens clinical development, the potential utilization of OCT imaging to measure efficacy in a pivotal clinical trial of OpRegen for the treatment of dry AMD with GA, and the potential for Lineages investigational allogeneic cell therapies to provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the SEC and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

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OpRegen Data Update to Be Featured at 2021 American Academy of Ophthalmology Annual Meeting in Presentation by Michael S. Ip, M.D. - Business Wire