Category Archives: Cell Medicine

MORGANTOWN, W.Va. -- A new data-driven mechanistic approach that predicts cell types within tissue will help to reduce drug costs and treat diseases that were difficult to develop drugs for, according to a West Virginia University scientist.

David Klinke, professor in the Department of Chemical and Biomedical Engineering, developed and tested a mechanistic approach to predict the number and function of different cell types within a particular tissue and how they change when a malignant (cancerous) cell acquires the ability to secrete a protein.

Ultimately, we want to develop drugs that broaden the clinical benefit of immunotherapies, said Klinke, whos also an adjunct assistant professor in the WVU School of Medicine and member of the Cancer Institute.

Mechanistic models have been created by hand by experts, but there are gaps in researchers understanding of biology because 90% of research publications focus on only 20% of genes in humans.

Research from this study, published in Nature Communications, sifts through large datasets to predict how secretion of one gene product by a malignant cell influences other cell types within a tissue directly from the data. This provides a complement to the hand-created models that play important roles in drug development.

Under normal conditions, ones immune system defends against infectious disease, Klinke said. However, most cancers arise through an evolutionary process of mutation and selection. Every cell has the blueprint in its DNA to make every gene product. In that process of mutation and selection, re-expression of some of these gene products may provide malignant cells with the ability to suppress immune response.

Human tissues are made up of specialized cell types that are organized to maintain function in a changing environment. Ultimately, the functional orientation of cell types within a tissue interact to create a heterocellular network -- a network of many different cell types that interact to collectively achieve a goal. A heterocellular network is important to create and maintain tissue equilibrium.

While researchers know that tissue equilibrium is disrupted during oncogenesis, or the development of a tumor, there is no clear understanding of how genetic alterations influence the heterocellular network within human tissues.

Klinke said one of the barriers for broadening clinical benefit is that malignant cells create environments that suppress host immunity.

This new data-driven approach allows researchers to predict how a gene product secreted by a malignant cell changes the prevalence and functional orientation of other cell types within a human tissue.

Klinke said that studying how one event causes another is challenging to do in systems where it's difficult for researchers to see what is happening like within an intact human tissue.

To test their predictions, using digital cytometry and Bayesian network inference, Klinke and his team examined immunocompetent mouse models of cancer. With this approach, Klinke was able to predict how a protein secreted by malignant cells alters the heterocellular network in the context of melanoma and breast cancer.

Digital cytometry, which is the measurement of the number and characteristics of cells, and Bayesian network (a probabilistic graphical model) inference were used because there are datasets available with these models that contain sequenced homogenized (similar) tumor tissue.

We can change the expression of a gene and then see whether the prevalence and functional orientation of different cell types in the tumor changes similarly as predicted by the Bayesian network model.

Klinke said the conventional approach to predict the functional orientation of cell types is to change the expression of a secreted protein and then quantify different cell types using different experimental approaches.

For this study, Klinke used mechanistic modeling to represent the mechanisms that support the biology and predict scenarios using simulation instead of actually testing the scenario in humans.

These models are highly complicated but let me use a simple analogy, Klinke said. Say that we want to hit a target using an artillery shell and we have only one shot. Given our understanding of the laws of physics, we know that we need to know a few things about the projectile and all the forces acting on the projectile. Given this information, we can simulate with a computer that if we fire the projectile in a certain direction or angle, it will land in a certain location.

Similarly, we know a lot about the underlying biology associated with a drug, but there are also some things that we dont know, and we cant test everything in humans. Given common conversations in the media about the high price of drugs, testing new drugs in humans is expensive and the vast majority of new drugs tested dont work.

Klinke said that one of the ways that mechanistic modeling and simulation can help is by providing a way to bring all the different pieces of understanding together in the same context.

If there are key aspects missing, we run simulations to see if targeting some aspect of the biology with a drug makes sense. Mechanistic modeling and simulation have had an impact on a number of other industries, and this is now being applied to drug development.

Klinke hopes that this research can be used in other contexts like cancers or immunologic diseases.

Ultimately, we all care that when we get sick, there are treatments that can improve our health and not bankrupt us in the process. Like many other industries, the pharma industry is turning increasingly to mechanistic modeling and simulation to better prioritize potential targets and reduce the time to clinic. Collectively, this will help reduce drug costs and help treat diseases that were difficult to develop drugs for.

Citation: Data-driven learning how oncogenic gene expression locally alters heterocellular networks

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WVU researcher develops data-driven approach to help reduce drug costs and treat diseases - West Virginia University

image:Artificial heart tissue can contract against a resistance and then relax. view more

Credit: Michael Gotthardt, MDC

The contractile and elastic properties of the heart are finely tuned. This is a prerequisite for the cardiac cycle and efficient adaptation. At the MDC, Michael Gotthardt investigates the underlying molecular and biomechanical mechanisms. He is awarded with an ERC Advanced Grant for this work.

MERAS is the acronym on the recently approved project proposal. It stands for: Mechanoregulation of alternative splicing. We would like to understand how the heart responds to environmental factors and adjusts its elastic properties such that it can function at an optimal level, says Michael Gotthardt. He heads the research group Neuromuscular and Cardiovascular Cell Biology at the Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC). For his project, he now receives an Advanced Grant of 2.5 million from the European Research Council (ERC).

This ERC Advanced Grant is awarded to scientists with more than ten years of research experience who have already played a prominent role in their field. Out of the 1,735 researchers from across Europe who applied for the grants this year, 253 were successful.

The mechanical work of the heart depends on the sarcomere, the smallest contractile unit. Here, actin and myosin filaments facilitate contraction, while the giant protein titin determines the elastic properties of heart muscle cells. Different titin variants (isoforms) are expressed perfectly adapted to the mechanical needs. The researchers wish to investigate the underlying process alternative splicing in detail.

Refined regulatory feedback

Our recent analysis of sarcomeric protein composition not only identified the expected structural proteins, but also proteins that link to cell signalling, metabolism, the regulation of gene expression and alternative splicing. These are proteins you would normally expect in the nucleus but not in the sarcomere, emphasizes Michael Gotthardt. It appears that the sarcomere directly communicates with the nucleus on necessary adaptations. The unexpected feedback from sarcomere to spliceosome could explain how sarcomeres adjust to mechanical stress. This is a new hypothesis that the researchers will explore in depth.

A detailed understanding of the regulatory process could also have therapeutic relevance e.g. for people with heart failure. For most of these patients, the ventricular walls have become so rigid that the chambers are no longer able to fill sufficiently. A drug that interferes with the communication from sarcomere to spliceosome could make a stiff cardiac ventricle more compliant, resulting in more efficient filling.

A second ERC grant

This year, the ERC selection process was not solely based on the submitted proposals, but for the first time included short presentations online of course due to Covid 19. Four slides in eight minutes for a 2.5 million euro project, recounts Michael Gotthardt, who is also Professor of Experimental and translational cardiology at Charit Universittsmedizin Berlin. For the scientist, this is already the second substantial contribution from the EU following his ERC Starting Grant in 2011. It extends over a period of five years. This enables us to build up lasting collaborations and projects with extended time lines. And deep sequencing as a prerequisite to evaluate alternative splicing at scale would otherwise be prohibitively expensive.

Gotthardts team works with genetic mouse models, synthetic heart tissue derived from patient cells and isolated heart muscle cells (cardiomyocytes). Single cell mechanics is precision work. For this, the cardiomyocytes first need to be isolated, secured under a special microscope and electrically stimulated. Then you can derive the active and passive forces, says Michael Gotthardt. This would provide the properties of just one single cell. However, for a convincing study, a large number of these experiments need to be conducted.

The goal: new technologies for single-cell mechanics and multi-omics

Extensive manual work is also required to understand which titin isoforms are expressed in response to stress or disease. Compared to a large piece of tissue, a single cell contains relatively few RNA molecules which means that analysis of gene expression frequently reaches the detection limit.The analysis of alternative splicing is even more difficult for giant titin isoforms with up to 100,000 bases. Here, available short reads need to be assembled like a jigsaw puzzle that misses important pieces, says Michael Gotthardt. With the ERC funding, among other things, he plans to develop technologies for single cell mechanics, -transcriptomics, -proteomics that will facilitate multi-omics approaches and enable higher rates of throughput.

The Max Delbrck Center for Molecular Medicine (MDC)

The Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC) is one of the worlds leading biomedical research institutions. Max Delbrck, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the MDCs locations in Berlin-Buch and Mitte, researchers from some 60 countries analyze the human system investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The MDC therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charit Universittsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC ), the Berlin Institute of Health (BIH) at Charit, and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the MDC today employs 1,600 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin.www.mdc-berlin.de

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ERC Advanced Grant for cardiac research at the MDC - EurekAlert

Scientists at Sinai Health and the University of Toronto say a new drug designed to block an enzyme essential for the survival of certain cancer cells shows promise in curbing tumour growth.

The preclinical findings,published this month in the journalNature, describe a new drug designed with CRISPR-Cas9 gene-editing technology in the lab ofDaniel Durocher, a senior investigator at Sinai HealthsLunenfeld-Tanenbaum Research Institute(LTRI) and a professor ofmolecular geneticsin U of Ts Temerty Faculty of Medicine.

The researchers identified genes that are essential for the viability of CCNE1 amplified cancer cells, which are characteristic of some hard-to-treat ovarian, endometrial and bladder cancers. They found the enzyme PKMYT1 is essential in CCNE1 amplified cells, but not in otherwise healthy cells. In collaboration with precision oncology companyRepare Therapeutics, the team developed a drug called RP-6306, which blocks PKMYT1 activity and effectively kills the cancer cell.

These cancer cells depend on the PKMYT1 enzyme to survive, said Durocher. Our preclinical data show enormous promise in the drug RP-6306s ability to target these types of tumours and profoundly inhibit tumour growth.

Currently, tumors with CCNE1 amplification have very few therapeutic options.David Gallo, a senior scientist at Repare Therapeutics, said theyve been able to demonstrate that RP-6306 is both potent and selective for oral use in humans.

Gynecological and other solid tumours with amplifications of CCNE1 are notoriously resistant to current standard-of-care treatments, said Gallo, co-first author on theNaturepaper. There is a dire need to find new options for these patients.

The work was a close collaboration between the Durocher lab and Repare Therapeutics. Durocher founded Repare Therapeutics in 2016 alongsideFrank Sicheri, also aLunenfeld-Tanenbaum Research Institute senior investigator who is a professor of molecular genetics andbiochemistryat U of T.

The company is built on the concept of synthetic lethality, a process that incorporates functional genomics to discover genetic vulnerabilities to specific cancer mutations.

This close collaboration between our group and Repare highlights how industry and academia can work together to discover new treatment options for cancer patients,said Durocher. Its rare that a new target is published alongside a launched clinical trial. This speaks volumes about the innovative capacity of the LTRI and its collaborators.

Repare Therapeutics has initiated Phase I clinical trials in patients with CCNE1 amplified solid tumours, with initial results expected in late 2022.

The research was funded by Repare Therapeutics and the Canadian Institutes of Health Research.

This story was originally published at Sinai Health.

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New drug shows promise slowing tumour growth in some hard-to-treat cancers - University of Toronto

Based on pivotal DESTINY-Lung01 results showing Daiichi Sankyo and AstraZenecas ENHERTU demonstrated a 54.9% tumor response rate

If approved, ENHERTU to provide patients with a much-needed targeted therapy option

TOKYO & BASKING RIDGE, N.J., April 19, 2022--(BUSINESS WIRE)--Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) have received notification of acceptance of the supplemental Biologics License Application (sBLA) of ENHERTU (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients in the U.S. with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy. The application has also been granted Priority Review.

ENHERTU is a HER2 directed antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca.

The U.S. Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is during the third quarter of the 2022 calendar year. The Priority Review follows receipt of Breakthrough Therapy Designation, granted by the FDA in May 2020 for ENHERTU in this cancer type.

Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.1 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.2 There are currently no HER2 directed therapies approved specifically for the treatment of HER2 mutant NSCLC, which occurs in approximately 2% to 4% of patients with non-squamous NSCLC.3,4

"The results of DESTINY-Lung-01 showed that ENHERTU is the first HER2 directed therapy to demonstrate a strong and robust tumor response in more than half of patients with previously treated HER2 mutant metastatic non-small cell lung cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Seeking approval in the U.S. for a third tumor type in three years further demonstrates the significant potential of ENHERTU in treating multiple HER2 targetable cancers."

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"The DESTINY-Lung01 trial confirmed the HER2 mutation as an actionable biomarker in non-small cell lung cancer," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "If approved, ENHERTU has the potential to become a new standard treatment in this patient population, offering a much-needed option for patients with HER2 mutant metastatic non-small cell lung cancer who currently have no targeted treatment options."

The sBLA is based on data from the pivotal DESTINY-Lung01 phase 2 trial published in The New England Journal of Medicine, and is supported by the phase 1 trial (DS8201-A-J101) published in Cancer Discovery.

Primary results from the HER2 mutant cohort (cohort 2) of DESTINY-Lung01 in previously-treated HER2 mutant NSCLC demonstrated a confirmed objective response rate (ORR) of 54.9% (n=50; 95% confidence interval [CI]: 44.2-65.4) in patients treated with ENHERTU (6.4 mg/kg) as assessed by independent central review (ICR). Out of a total of 91 patients, one (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed. A confirmed disease control rate (DCR) of 92.3% (95% CI: 84.8-96.9) was seen with a reduction in tumor size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for ENHERTU was 9.3 months (95% CI: 5.7-14.7). The median progression-free survival (PFS) was 8.2 months (95% CI: 6.0-11.9) and the median overall survival (OS) was 17.8 months (95% CI: 13.8-22.1).

The safety profile of the most common adverse events with ENHERTU in DESTINY-Lung01 was consistent with previous clinical trials. The most common grade 3 or higher drug-related treatment-emergent adverse events were neutropenia (18.7%), anemia (9.9%), nausea (8.8%), fatigue (6.6%), leukopenia (4.4%), diarrhea (3.3%) and vomiting (3.3%). Twenty-three patients (25%) discontinued treatment due to drug-related treatment-emergent adverse events. Overall, 26% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (75%) were low grade (grade 1 (12.5%) or grade 2 (62.5%)). Out of the total study population, four grade 3 (4.4%) and two grade 5 (2.2%) ILD or pneumonitis events were reported.

About DESTINY-Lung01 DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU in patients with HER2 mutant (6.4 mg/kg) or HER2 overexpressing (defined as IHC3+ or IHC2+) [6.4 mg/kg and 5.4 mg/kg] unresectable and/or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by ICR. Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled approximately 180 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant NSCLC Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.1 In the U.S., lung cancer is the second most commonly diagnosed cancer, with more than 236,000 new cases expected in 2022.5 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 gene alterations (called HER2 mutations) have been identified in NSCLC as distinct molecular targets and have been reported in approximately 2% to 4% of patients with non-squamous NSCLC.3,4 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Although the role of anti-HER2 treatment is well established in breast and gastric cancers, HER2 is an emerging biomarker in NSCLC with no approved HER2 directed therapies.3,8 Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.9

About ENHERTU ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyos proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZenecas ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for ENHERTU are currently under review in Europe, Japan, U.S. and several other countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

ENHERTU also is currently under review in Europe for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. Important Safety Information for ENHERTU

Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications None.

Warnings and Precautions Interstitial Lung Disease / Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in 28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3C or a sustained temperature of 38C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% of patients.

Locally Advanced or Metastatic Gastric Cancer In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Additional Dose Modifications Thrombocytopenia For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level.

Adverse Reactions Metastatic Breast Cancer The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (20%).

Locally Advanced or Metastatic Gastric Cancer The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (75%), white blood cell count decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.

Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.

Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.

Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.

Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were 65 years and 5% were 75 years. No overall differences in efficacy were observed between patients 65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years (53%) as compared to younger patients (42%). Of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years and 14% were 75 years. No overall differences in efficacy or safety were observed between patients 65 years of age compared to younger patients.

Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose "to contribute to the enrichment of quality of life around the world." In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an "Innovative Global Healthcare Company Contributing to the Sustainable Development of Society." For more information, please visit http://www.daiichisankyo.com.

References1 WHO. Cancer Today. 2020. Accessed April 2022. 2 America Cancer Society. Lung Cancer Survival Rates. Accessed April 2022. 3 Liu S, et al. Clin Cancer Res. 2018;24(11):2594-2604. 4 Campbell JD, et al. Nat Genet. 2016 Jun;48(6):607-16. 5 American Cancer Society. Key Statistics for Lung Cancer. Accessed April 2022. 6 Pillai RN, et al. Cancer. 2017;123:4099-105. 7 Offin M, et al. Cancer. 2019;125:4380-7. 8 Zhou J, et al. Ther Adv Med Oncol. 2020;12. 9 Hechtman, J, et al. Cancer Cyto. 2019; 127 (7): 428-431.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220418005432/en/

Contacts

Media Contacts:Global: Victoria AmariDaiichi Sankyo, Inc.vamari@dsi.com +1 908 900 3010 (mobile)

US: Don MurphyDaiichi Sankyo, Inc.domurphy@dsi.com +1 917 817 2649 (mobile)

EU: Lydia WormsDaiichi Sankyo Europe GmbHlydia.worms@daiichi-sankyo.eu +49 (89) 7808751 (office)+49 176 11780861 (mobile)

Japan: Masashi KawaseDaiichi Sankyo Co., Ltd.kawase.masashi.a2@daiichisankyo.co.jp +81 3 6225 1126 (office)

Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp

See the rest here:
ENHERTU Granted Priority Review in the U.S. for Patients with Previously Treated HER2 Mutant Metastatic Non-Small Cell Lung Cancer - Yahoo Finance

Clinical update expected in second half of 2023

CAMBRIDGE, Mass. and NEW YORK, April 18, 2022 (GLOBE NEWSWIRE) -- Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of MasterKey therapies, today announced the dosing of the first patient in the Phase 1 study evaluating BDTX-1535, a MasterKey inhibitor of epidermal growth factor receptor (EGFR) for the treatment of both non-small cell lung cancer (NSCLC) and glioblastoma (GBM)derived from Black Diamonds MAP discovery engine.

The dosing of the first patient in our Phase 1 study of BDTX-1535, a next generation brain-penetrant inhibitor of oncogenic EGFR MasterKey mutations is an important step as we believe this program is uniquely positioned to address the existing unmet needs of EGFR mutant NSCLC and GBM, said David M. Epstein, Ph.D., Chief Executive Officer of Black Diamond Therapeutics. This is the second MasterKey inhibitor derived from our MAP drug discovery engine; we are incredibly excited about BDTX-1535s advancement into the clinic and we look forward to providing a clinical update in the second half of 2023.

Despite recent successes in targeting EGFR-mutated NSCLC, there is still a need for better therapeutics for patients with disease progression following first-line EGFR inhibitors, said Melissa Johnson, MD, Director of Lung Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology. We hope to assess the ability of BDTX-1535 to inhibit tumors with primary TKI-resistant EGFR mutations or those with on-target acquired resistance mutations.

NSCLC accounts for approximately 85% of lung cancer cases worldwide. About 10-20% of all lung cancer patients in North American and Europe, and up to 50% of those in Asia harbor mutations in EGFR. Intrinsic resistance EGFR mutations, of which G719X, S768I, L861Q are among the most frequent, account for 10-20% of EGFR mutations in NSCLC. The classical Exon19del and L858R mutations, which account for 80-90% of EGFR mutations in NSCLC, are well treated but resistance invariably emerges to current generation EGFR inhibitors.

"GBM is an aggressive form of brain cancer with limited treatment options, said Patrick Y. Wen, MD, Director, Center for Neuro-Oncology at Dana-Farber Cancer Institute. "A majority of GBM tumors will co-express EGFR alterations, including mutations, splice variants and amplification, making EGFR an attractive target for new therapies with CNS penetration and potency against the spectrum of co-expressed EGFR alterations.

Up to 50% of GBM tumors express one or more co-occurring oncogenic EGFR mutations that affect the extracellular region of the receptor tyrosine kinase, and consequently promote oncogenic activation. There are no precision oncology medicines approved to treat these patients. Black Diamond believes that current targeted therapies have been unsuccessful in treating GBM due to insufficiencies in (i) drug selectivity for EGFR GBM alterations versus EGFR wildtype, (ii) drug potency against the full spectrum of co-expressed EGFR alterations, and (iii) brain penetration.

About BDTX-1535BDTX-1535 is designed as an irreversible, mutant selective, brain-penetrant MasterKey inhibitor of oncogenic mutations of epidermal growth factor receptor (EGFR) expressed in glioblastoma multiforme (GBM) and intrinsic and acquired resistance EGFR mutations in non-small cell lung cancer (NSCLC). In pre-clinical studies, Black Diamond has demonstrated that oncogenic alterations of EGFR, particularly those associated with GBM, result in distinct conformations which impart unique pharmacology and drug resistance. It is estimated that approximately 50% of GBM patients harbor an oncogenic EGFR alteration that has the potential to be addressed by BDTX-1535, representing a potential patient population of greater than 60,000 patients annually across the US, EU, Japan and China. It is estimated that across the US, EU, Japan and China there are approximately 20,000 patients who are diagnosed annually with non-small cell lung cancer (NSCLC) harboring an EGFR intrinsic or acquired resistance mutation.

About Black DiamondBlack Diamond Therapeutics is a precision oncology medicine company pioneering the development of novel MasterKey therapies. Black Diamond is addressing the significant unmet need for novel precision oncology therapies for patients with genetically defined cancers who have limited treatment options. Black Diamond is built upon a deep understanding of cancer genetics, onco-protein function, and drug discovery. The Companys proprietary Mutation-Allostery-Pharmacology, or MAP drug discovery engine, is designed to allow Black Diamond to analyze population-level genetic sequencing tumor data to predict and validate oncogenic mutations that promote cancer across tumor types as MasterKey mutations. Black Diamond discovers and develops selective MasterKey therapies against these families of oncogenic mutations. Black Diamond was founded by David M. Epstein, Ph.D., and Elizabeth Buck, Ph.D. For more information, please visit http://www.blackdiamondtherapeutics.com.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the Phase 1 study of BDTX-1535, including timing for future clinical updates, and the unmet need in patients with glioblastoma. Any forward-looking statements in this statement are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties set forth in the Companys 2021 annual report on Form 10-K filed with the United States Securities and Exchange Commission and its other filings filed with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

ContactsFor Investors:Julie Seidelinvestors@bdtx.com

For Media:Kathy Vincent(310) 403-8951media@bdtx.com

Originally posted here:
Black Diamond Therapeutics Announces First Patient Dosed in Phase 1 Study of BDTX-1535, a MasterKey Inhibitor of EGFR for the Treatment of...

Cancer cells can disrupt a metabolic pathway that breaks down fats and proteins to boost the levels of a byproduct called methylmalonic acid, thereby driving metastasis, according to research led by scientists at Weill Cornell Medicine. The findings open a new lead for understanding how tumors metastasize, or spread to other tissues, and hints at novel ways to block the spread of cancer by targeting the process.

The new results, published March 31 in Nature Metabolism, show that metastatic tumors suppress the activity of a key enzyme in propionate metabolism, the process by which cells digest certain fatty acids and protein components. Suppressing the enzyme increases production of methylmalonic acid (MMA). That, in turn, causes the cells to become more aggressive and invasive.

Cancer is the second leading cause of death worldwide, and metastasis drives much of that mortality. Once a tumor begins to metastasize to different tissues and organs around the body, it can quickly become difficult or impossible to treat. However, researchers have made few inroads in understanding how a tumor cell acquires the ability to metastasize.

A lot of work has been focused on primary tumor initiation and growth, or examining the metastatic tumor, but to go from the primary tumor to the metastatic tumor, that transition has not been studied very extensively, said co-senior author Dr. John Blenis, the Anna-Maria and Stephen Kellen Professor in Cancer Research, professor of pharmacology and associate director of basic science of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

To address that gap, Dr. Blenis and his colleagues have worked for several years to characterize the metabolic changes that cells undergo during the metastatic transition. That effort previously revealed that as people age, their bodies produce more serum MMA (although the source remains unknown), and that higher MMA levels drive worse cancer outcomes. Healthy cells also produce MMA, though, so in the new study Dr. Bleniss team probed the metabolites cancer-related activities more deeply.

Cancer cells themselves can hijack the pathway that makes methylmalonic acid and this forms a feed-forward cycle that drives cancer progression towards more aggressive and more metastatic forms, said co-first author Dr. Vivien Low, a postdoctoral fellow in Dr. Bleniss lab. The other co-first authors Dr. Ana Gomes and Dr. Didem Ilter, were also postdoctoral fellows in the lab at the time of the study. Dr. Gomes is now a faculty member and Dr. Ilter is a research scientist at H. Lee Moffitt Cancer Center & Research Institute.

The discovery adds to a growing body of work showing that specific products of metabolism, called oncometabolites, can drive many aspects of cancer progression and metastasis.

While the new paper focused on various models of breast cancer, Dr. Low said the team is now analyzing other types of cancer cells as well, where they expect to find similar mechanisms operating. The scientists are also searching for ways to attack the process.

Metastasis is responsible for about 80 to 90 percent of cancer-related mortality, so if we can predict when someone has the potential to develop metastatic tumors, or treat those metastatic tumors that might have this pathway up-regulated, then we might have a very effective, novel therapy, Dr. Blenis said.

Excerpt from:
Tumors Change Their Metabolism to Spread More Effectively - Weill Cornell Medicine Newsroom

- Pelareorep-CAR T combination may expand the commercial potential of CAR T cells to solid tumors

- Combining CAR T cells with pelareorep prevented antigen escape by creating CAR T cells with dual specificity through a novel mechanism

-Loading CAR T cells with pelareorep led to dramatic improvements in their persistence and anti-cancer activity as well as cures in multiple murine solid tumor models

SAN DIEGO, Calif. and CALGARY, AB, April 14, 2022 /PRNewswire/ --Oncolytics BiotechInc. (NASDAQ: ONCY) (TSX: ONC) today announced the publication of preclinical data demonstrating the synergistic anti-cancer activity of pelareorep combined with chimeric antigen receptor (CAR) T cell therapy in solid tumors. The paper, entitled "Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice," was published in Science Translational Medicine in collaboration with researchers at several prestigious institutions, including the Mayo Clinic and Duke University. A link to the paper can be found by clicking here.

"Having these results published in such a high-impact journal provides important external validation of their significance," said Thomas Heineman, M.D., Ph.D., Chief Medical Officer of Oncolytics Biotech Inc. "While CAR T cells have generated long-term cures in hematologic malignancies1, the immunosuppressive tumor microenvironments (TMEs) of solid organ cancers have thus far limited their efficacy in these indications. Pelareorep has repeatedly been shown to reverse immunosuppressive TMEs, and in the present publication pelareorep is shown to enable the effectiveness of CAR T cells in multiple murine solid tumor models. This is a powerful finding that, if translated to the clinic, could significantly improve the prognosis of patients with a variety of highly prevalent cancers by providing a novel and potentially durable treatment option. By demonstrating the ability to improve T cell perseverance, reduce antigen escape, and overcome challenging solid tumor TMEs, the inclusion of pelareorep addresses the three most challenging roadblocks to effective CAR T therapy."

Andrew de Guttadauro, President of Oncolytics Biotech U.S. and Global Head of Business Development, added, "Despite revolutionizing the treatment of certain cancers and surpassing a billion dollars in sales last year, CAR T therapies currently only serve a small subset of patients suffering from hematologic malignancies. With these latest results, we now have strong preclinical evidence that pelareorep can fully unlock the value of CAR T therapies by expanding their commercial potential to the significantly larger market of cancer patients who are battling solid tumors."

Preclinical studies published in the paper evaluated the persistence and efficacy of pelareorep-loaded CAR T cells ("CAR/Pela therapy") in multiple murine solid tumor models. The effects of combining CAR/Pela therapy with a subsequent intravenous dose of pelareorep ("pelareorep boost") were also investigated. Key data and conclusions from the paper include:

Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech Inc. and co-author of the paper commented, "These exciting results are an excellent example of how we are leveraging collaborations with key opinion leaders and premier research institutions to broaden pelareorep's potential therapeutic impact. This allows us to remain primarily focused on our lead breast cancer program, which has shown how pelareorep's ability to promote tumor T cell infiltration leads to synergy with checkpoint inhibitors in the clinic. These newly published preclinical findings show pelareorep's synergistic benefits extend even beyond checkpoint inhibitors and highlight an opportunity to increase our addressable patient population. As we pursue this opportunity moving forward, we intend to utilize relationships with academic or industry partners so that we can continue to execute on our clinical and corporate objectives with efficiency."

About CAR T cells and CAR T therapy

TheCAR T process begins when blood is drawn from a patient and their T cells are separated so they can be genetically engineered to produce chimeric antigen receptors (CARs). These receptors enable the T cells to recognize and attach to a specific protein or antigen on tumor cells. Once the engineering process is complete, a laboratory can increase the number of CAR T cells into the hundreds of millions. Finally, the CAR T cells will be infused back into the patient where, ideally, the engineered cells further multiply and recognize and kill cancer cells. Historically, solid tumors have been considered beyond the reach of CAR T therapy due to their tumor microenvironment, which is detrimental to CAR T cell entry and activity, amongst other challenges.2

About Science Translational Medicine

Science Translational Medicineis the leading weekly online journal publishing translational research at the intersection of science, engineering, and medicine. The goal of Science Translational Medicine is to promote human health by providing a forum for communicating the latest research advances from biomedical, translational, and clinical researchers from all established and emerging disciplines relevant to medicine. In addition to original research, Science Translational Medicine also publishes Reviews, Editorials, Focus articles, and Viewpoints.

About Oncolytics Biotech Inc.

Oncolytics is a biotechnology company developing pelareorep, an intravenously delivered immunotherapeutic agent. This compound induces anti-cancer immune responses and promotes an inflamed tumor phenotype -- turning "cold" tumors "hot" -- through innate and adaptive immune responses to treat a variety of cancers.

Pelareorep has demonstrated synergies with immune checkpoint inhibitors and may also be synergistic with other approved oncology treatments. Oncolytics is currently conducting and planning clinical trials evaluating pelareorep in combination with checkpoint inhibitors and targeted therapies in solid and hematological malignancies as it advances towards a registration study in metastatic breast cancer. For further information, please visit:www.oncolyticsbiotech.com.

References

1. Melenhorst, J.J., Chen, G.M., Wang, M.et al.Decade-long leukaemia remissions with persistence of CD4+CAR T cells.Nature(2022). https://doi.org/10.1038/s41586-021-04390-6

2. National Cancer Institute. CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers. Updated July 31, 2019. Accessed February 18, 2021.https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended and forward-looking information under applicable Canadian securities laws (such forward-looking statements and forward-looking information are collectively referred to herein as "forward-looking statements"). Forward-looking statements contained in this press release include statements regarding Oncolytics' belief as to the potential and benefits of pelareorep as a cancer therapeutic; Oncolytics' expectations as to the purpose, design, outcomes and benefits of its current or pending clinical trials involving pelareorep; including potentially significantly improving the prognosis of patients with a variety of highly-prevalent cancers by providing them with a novel and potentially durable treatment option and the opportunity to potentially expand our addressable patient population; our intention to utilize relationships with academic or industry partners so that we can continue to execute on our clinical and corporate objectives with efficiency; our leveraging of collaborations with key opinion leaders to broaden pelareorep's potential therapeutic impact; our plans to advance towards a registration study in metastatic breast cancer; and other statements related to anticipated developments in Oncolytics' business and technologies. In any forward-looking statement in which Oncolytics expresses an expectation or belief as to future results, such expectations or beliefs are expressed in good faith and are believed to have a reasonable basis, but there can be no assurance that the statement or expectation or belief will be achieved. Such forward-looking statements involve known and unknown risks and uncertainties, which could cause Oncolytics' actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the efficacy of pelareorep as a cancer treatment, the success and timely completion of clinical studies and trials, Oncolytics' ability to successfully commercialize pelareorep, uncertainties related to the research and development of pharmaceuticals, uncertainties related to the regulatory process and general changes to the economic environment. In particular, we may be impacted by business interruptions resulting from COVID-19 coronavirus, including operating, manufacturing supply chain, clinical trial and project development delays and disruptions, labour shortages, travel and shipping disruption, and shutdowns (including as a result of government regulation and prevention measures). It is unknown whether and how Oncolytics may be affected if the COVID-19 pandemic persists for an extended period of time. We may incur expenses or delays relating to such events outside of our control, which could have a material adverse impact on our business, operating results and financial condition.Investors should consult Oncolytics' quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statements. Investors are cautioned against placing undue reliance on forward-looking statements. The Company does not undertake any obligation to update these forward-looking statements, except as required by applicable laws.

Company Contact

Jon Patton

Director of IR & Communication

+1-858-886-7813

[emailprotected]

Investor Relations for Oncolytics

Timothy McCarthy

LifeSci Advisors

+1-917-679-9282

[emailprotected]

SOURCE Oncolytics Biotech Inc.

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Oncolytics Biotech Announces Publication of Preclinical Data Demonstrating the Synergistic Anti-Cancer Activity of Pelareorep Combined with CAR T Cell...

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, announced today that Cancer Research UK recently completed patient enrollment in the ongoing Phase 1 clinical trial of VAC2, an allogeneic cancer vaccine product candidate, for the treatment of non-small cell lung cancer (NSCLC). Under the terms of an existing agreement, Cancer Research UK will complete the ongoing clinical trial and Lineage has now assumed responsibility for further clinical development of the VAC2 product candidate and any future development opportunities derived from the VAC platform.

We are pleased that Cancer Research UK has successfully completed patient enrollment in the VAC2 Phase 1 clinical study and overcame substantial challenges stemming from the COVID pandemic. We look forward to initial clinical results from this study being available later this year, stated Brian M. Culley, Lineage CEO. Clinical data previously collected by Cancer Research UK demonstrated peripheral immunogenicity in patients with NSCLC treated with VAC2, providing support to the underlying mechanism of using allogeneic dendritic cells to present tumor-associated antigens to the bodys immune system. Simultaneous with Cancer Research UK efforts to complete enrollment in the current study, the focus at Lineage has been on making improvements and modernizations to the VAC manufacturing process, an approach which we similarly employed in the development of OpRegen. We believe our focus on manufacturing will help prepare VAC2 for additional clinical trials and provide a competitive advantage for any future VAC programs which we advance, either alone or through alliances. With Cancer Research UK having completed enrollment of the current study, the team at Lineage also has begun work towards the submission of an Investigational New Drug Application for clinical testing of VAC2 in the U.S., which we anticipate submitting to the FDA later this year.

Dr. Nigel Blackburn, Director of Cancer Research UKs Centre for Drug Development, added: We are delighted to see that this innovative VAC2 program has reached such an important milestone in its development and are extremely proud to have played an important role in establishing its tolerability in lung cancer patients. We look forward to seeing Lineage advance VAC2 under their leadership in the future.

About VAC2

VAC2 is an allogeneic, or non-patient specific off-the-shelf, cancer vaccine product candidate designed to stimulate patient immune responses to an antigen commonly expressed in cancerous cells but not in normal adult cells. VAC2, which is produced from a pluripotent cell technology using a directed differentiation method, is comprised of a population of nonproliferating mature dendritic cells. As the most potent type of antigen presenting cell in the body, dendritic cells instruct the bodys immune system to attack and eliminate harmful pathogens and unwanted cells. Because the tumor antigen is loaded exogenously into the dendritic cells prior to administration, VAC2 is a platform technology that could be modified to carry selected antigens, including patient-specific tumor neo-antigens or viral antigens. VAC2 is currently being tested in a Phase 1 study in adult patients with NSCLC in the advanced and adjuvant settings (NCT03371485), conducted by Cancer Research UK.

About Cancer Research UKs Centre for Drug Development

Cancer Research UK has an impressive record of developing novel treatments for cancer. The Cancer Research UK Centre for Drug Development has been pioneering the development of new cancer treatments for 25 years, taking over 140 potential new anti-cancer agents into clinical trials in patients. It currently has a portfolio of 21 new anti-cancer agents in preclinical development, Phase I or early Phase II clinical trials. Six of these new agents have made it to market including temozolomide for brain cancer, abiraterone for prostate cancer and rucaparib for ovarian cancer. Two other drugs are in late development Phase III trials.

About Cancer Research UKs Commercial Partnerships Team

Cancer Research UK is the worlds leading cancer charity dedicated to saving lives through research. Cancer Research UKs specialist Commercial Partnerships Team works closely with leading international cancer scientists and their institutes to protect intellectual property arising from their research and to establish links with commercial partners. Cancer Research UKs commercial activity operates through Cancer Research Technology Ltd., a wholly owned subsidiary of Cancer Research UK. It is the legal entity which pursues drug discovery research in themed alliance partnerships and delivers varied commercial partnering arrangements.

About Cancer Research UK

For further information about Cancer Research UKs work or to find out how to support the charity, please call 0300 123 1022 or visit http://www.cancerresearchuk.org. Follow us on Twitter and Facebook.

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 four 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, which is now being developed under a worldwide collaboration with Roche and Genentech, a member of the Roche Group; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; (iii) VAC2, a 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 and (iv) ANP1, an auditory neuronal progenitor cell therapy for the potential treatment of auditory neuropathy. 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, aim, may, will, estimate, continue, anticipate, design, intend, expect, could, can, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the efficacy of using allogeneic dendritic cells to present tumor-associated antigens to the bodys immune system the collaboration and license agreement with Roche and Genentech and activities expected to occur thereunder, the broad potential for Lineages regenerative medicine platform as well as the VAC technology platform, and Lineages ability to expand the same; the projected timing of milestones of future studies, including their initiation and completion, projected manufacturing plans and improvements; the potential for Lineages investigational allogeneic cell therapies to generate clinical outcomes beyond the reach of traditional methods and 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, but not limited to, the risk that competing alternative therapies may adversely impact the commercial potential of OpRegen, which could materially adversely affect the milestone and royalty payments payable to Lineage under the collaboration and license agreement, the risk that Roche and Genentech may not be successful in completing further clinical trials for OpRegen and/or obtaining regulatory approval for OpRegen in any particular jurisdiction, the risk that Lineage might not succeed in developing products and technologies that are useful in medicine and demonstrate the requisite safety and efficacy to achieve regulatory approval in accordance with its projected timing, or at all; the risk that Lineage may not be able to manufacture sufficient clinical and, if approved, commercial quantities of its product candidates in accordance with current good manufacturing practice; the risks related to Lineages dependence on other third parties, and Lineages ability to establish and maintain its collaborations with these third parties; the risk that government-imposed bans or restrictions and religious, moral, and ethical concerns about the use of hES cells could prevent Lineage or its partners from developing and successfully marketing its stem cell product candidates; the risk that Lineages intellectual property may be insufficient to protect its products; the risk that the COVID-19 pandemic or geopolitical events may directly or indirectly cause significant delays in and substantially increase the cost of development of Lineages product candidates, as well as heighten other risks and uncertainties related to Lineages business and operations; risks and uncertainties inherent in Lineages business and other risks discussed 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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Excerpt from:
Lineage and Cancer Research UK Announce Completion of Patient Enrollment in Phase 1 Clinical Study of VAC2 for the Treatment of Non-small Cell Lung...

SAN DIEGO, April 13, 2022 (GLOBE NEWSWIRE) -- Oncternal TherapeuticsInc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced that it has deprioritized further development of ONCT-216 to reallocate resources to zilovertamab, the Companys investigational anti-ROR1 monoclonal antibody, and its Phase 3 registrational trial that the Company expects to initiate in Q3 2022. As such, the Company has discontinued enrollment in the Phase 1/2 study evaluating ONCT-216 in patients with relapsed or refractory Ewing sarcoma.

This asset prioritization allows us to further sharpen our focus on hematological malignancies and prostate cancer, while deploying our capital towards meaningful catalysts as we navigate this historically challenging pandemic, geopolitical and capital markets macroenvironment, said James Breitmeyer, MD, PhD, Oncternals President and CEO. We believe this focused approach, along with prudent cash management, will enable us to fund our operations well into the third quarter of 2023, as we continue to explore all potential sources of capital to enable us to reach our milestones.

The Company expects to initiate its global registrational Phase 3 Study ZILO-301 in the third quarter of 2022, taking into account the impact of geopolitical factors and COVID-19 related supply chain issues. The study will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo, and all patients will continue receiving oral ibrutinib. The novel ZILO-301 design is supported by encouraging data from the Companys ongoing Phase 1/2 clinical trial of zilovertamab plus ibrutinib for patients with MCL or CLL, as well as by a successful End-of-Phase-2 meeting with the U.S. Food and Drug Administration (FDA).

The Companys lead autologous ROR1-targeted CAR-T cell therapy program candidate, ONCT-808, is advancing according to plan towards an Investigational New Drug (IND) application submission expected in mid-2022, based on supportive manufacturing and preclinical data as well as a productive pre-IND meeting with the FDA earlier this year.

Finally, the Company continues to advance ONCT-534, its lead candidate in its DAARI program, and expects to initiate IND-enabling GLP toxicology studies and GMP manufacturing later this quarter. ONCT-534 has shown anti-tumor activity in preclinical studies relevant to multiple clinically important forms of resistance for patients with prostate cancer, including those involving overexpression of the androgen receptor, or expression of mutants of the androgen receptor, or splice variants such as AR-V7.

AboutZilovertamab (formerly Cirmtuzumab)Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL or chronic lymphocytic leukemia (CLL), in a collaboration with theUniversity of California San Diego(UC San Diego) School of Medicine and theCalifornia Institute for Regenerative Medicine(CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at theUC San Diego School of Medicinediscovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1 expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.

About Oncternal TherapeuticsOncternal Therapeuticsis a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies for the treatment of patients with cancers that have critical unmet medical need. Oncternal pursues drug development targeting promising, yet untapped biological pathways implicated in cancer generation or progression, focusing on hematological malignancies and prostate cancer. The clinical pipeline includeszilovertamab, an investigational monoclonal antibody designed to inhibit ROR1, a type I tyrosine kinase-like orphan receptor. Zilovertamab is being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), in investigator-initiated studies, including a Phase 1b clinical trial in combination with paclitaxel for the treatment of women with HER2-negative metastatic or locally advanced, unresectable breast cancer, in a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, in patients with relapsed/refractory CLL, and in a Phase 1b study of zilovertamab in combination with docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Oncternal is also developingONCT-808, a chimeric antigen receptor T cell (CAR-T) therapy that targets ROR1, which is currently in preclinical development as a potential treatment for hematologic cancers and solid tumors. The early-stage pipeline also includesONCT-534, a dual-action androgen receptor inhibitor (DAARI), that is in preclinical development as a potential treatment for castration resistant prostate cancer and other androgen-receptor dependent diseases. More information is available athttps://oncternal.com/.

Forward-Looking Information

Oncternal cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. In some cases, you can identify forward-looking statements by terms such as may, will, should, expect, plan, anticipate, could, intend, target, project, contemplates, believes, estimates, predicts, potential or continue or the negatives of these terms or other similar expressions. These statements are based on Oncternals current beliefs and expectations. Forward-looking statements include statements regarding Oncternals development programs, including Oncternals estimated cash and cash equivalents as of March 31, 2022, the anticipated timing for announcing additional preclinical and clinical data; timing of reaching any milestones, including IND submissions; timing for regulatory communications; Oncternals expected cash runway; and the potential that Study ZILO-301 can serve as a registrational clinical trial; and the expected initiation of clinical trials, including Study ZILO-301. Forward-looking statements are subject to risks and uncertainties inherent in Oncternals business, including risks associated with the clinical development and process for obtaining regulatory approval of Oncternals product candidates, such as potential delays in the commencement, enrollment and completion of clinical trials; we have not conducted head-to-head studies of zilovertamab in combination with ibrutinib compared to ibrutinib monotherapy and data from separate studies may not be directly comparable due to the differences in study protocols, conditions and patient populations; the risk that interim results of a clinical trial do not predict final results and that one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data, as follow-up on the outcome of any particular patient continues, and as more patient data become available; later developments with the FDA may be inconsistent with the minutes from the completed end of Phase 2 meeting, including that the proposed Study ZILO-301 that may not support registration of zilovertamab in combination with ibrutinib which is a review issue with the FDA upon submission of a BLA; and other risks described in Oncternals filings with theU.S. Securities and Exchange Commission. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, Oncternal undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Contact Information:

InvestorsRichard Vincent858-434-1113rvincent@oncternal.com

MediaCorey Davis, Ph.D. LifeSci Advisors 212-915-2577 cdavis@lifesciadvisors.com

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Oncternal Therapeutics Deprioritizes Development of ONCT-216 to Focus Resources on Phase 3 Trial for Zilovertamab in the Treatment of Mantle Cell...

Autoimmune hepatitis (AIH) is a chronic progressive inflammatory disorder commonly identified in females with a tendency to occur during the teen years and the fourth to sixth decades of life. Its distinguishing features include the presence of serum-specific autoantibodies and histopathology features of interface hepatitis [1-3]. Etiopathogenesis involves a multitude of independent factors such as human leukocyte antigen (HLA) allelic variants, infections, drugs, and the prevalence of autoimmune tautology, which cause an immunoregulatory imbalance, leading to a resultant T-cell mediated inflammation [1]. Steroids and immunosuppressants form the primary pillars of treatment, along with close monitoring of liver function tests to assess therapeutic response. The recommended duration of treatment is approximately two years, after which withdrawal can be considered. However, given the high risk of relapse, lifelong immunosuppressive therapy may be essential in most cases [3].

Natural supplements have been in use for decades in conjunction with modern medicine by mankind to treat a variety of common ailments. The rationale behind the use of such supplements is their presumed regulatory effect on the immune system, although studies conducted over the years have had mixed results [4-6]. One of the commonly used botanical supplements of interest with immunomodulatory effects is Sambucus nigra, also commonly known as elderberry, frequently used for the treatment of the common cold. The effects of elderberry on the production of pro-inflammatory cytokines such as IL-6,IL-8, and TNF have been controversial, with studies indicating a stimulatory versus inhibitory effect, leading to inconsistent interpretation [4]. We present a case of autoimmune hepatitis in a middle-aged female who was on long-term elderberry-containing supplements and developed autoimmune hepatitis. This case report aims to identify the risk factors associated with autoimmune hepatitis, debate the effects of elderberry on the immune system, and consider a causal association between the two entities.

A 60-year-old Caucasian female with a medical history of Hashimoto thyroiditis and Medullary sponge kidneys presented to the hospital with nausea, decreased appetite, abdominal pain, and bloating for two days. She was on levothyroxine, indapamide, tamsulosin, potassium citrate supplements, and an over-the-counter elderberry supplement for several years. Her vital signs were stable. Physical examination findings were remarkable for scleral icterus, generalized jaundice, and abdominal distention without tenderness.

Initial laboratory studies revealed transaminitis with elevation of AST to 1821 IU/L (13-39 IU/L), ALT >2500 IU/L (7-52 IU/L), ALP of 232 IU/L (35-104 IU/L), total bilirubin of 10.5 mg/dL (0.0-1.0 mg/dL), and direct bilirubin of 5.66 mg/dL (0.00-0.20 mg/dL) (Table 1). Abdominal imaging studies, including ultrasound and CT scans, showed mild peri hepatic inflammation and a contracted gallbladder with no obvious stones or intrahepatic dilation. The acute hepatitis panel was negative;however, she was found to have a positive antinuclear antibody (ANA) screen and SSA (RO) Ab 1.4 (<1.0) (Table 1), which raised a concern for autoimmune hepatitis.

Subsequent evaluation with a liver biopsy revealed extensive interface hepatitis, lymphohistiocytic infiltrate, eosinophils and neutrophils in the portal areas, periportal and lobular liver cell damage with piecemeal necrosis (Figure 1, 2).

Based on histological findings of the portal tract, the differential diagnoses included autoimmune hepatitis versus drug-induced hepatitis. She was instructed to stop taking natural supplements, and immunosuppressive therapy with daily Prednisone 40 mg was started for four weeks.

At a follow-up visit four weeks later, her repeat liver function tests improved to baseline. As elderberry supplements were presumed causes of hepatitis, they were not rechallenged. Prednisone therapy was tapered over two weeks, after which she was started on long-term maintenance therapy with azathioprine.

Autoimmune hepatitis is a chronic inflammatory liver disease depicted by a combination of elevated liver enzymes, the presence of specific serum autoantibodies and histological features of interface hepatitis, infiltration of lobules with lymphocytes, and plasma cells [3]. AIH is further classified into two types depending on the presence of autoantibodies: type 1 is positive for ANAand/or anti-smooth muscle antibodies (SMA), while type 2 is positive for liver-kidney-microsomal-type-1 (LKM-1) antibodies [2,3].While studies have shown that it affects all ages, ethnicities, and genders, it has a bimodal distribution with peaks in the teens and the fourth to the sixth decadeof life, with a female preponderance [1-3]. Literature suggests that the presence of one autoimmune disorder can increase the risk of an individual developing other autoimmune disorders [7]. One such commonly studied association with AIH is the presence of autoimmune thyroiditis [8,9]. In a case-control study, it was found that 30% of patients with AIH have concurrent extrahepatic autoimmune manifestations, out of which 51.4% were found to be diagnosed with autoimmune thyroid disease [9]. Another similar study revealed that autoimmune thyroid disease was the most common concurrent extrahepatic autoimmune disease with an 18% prevalence in those with autoimmune hepatitis [8]. On the other hand, in another cohort study, autoimmune hepatitis was found in 8.69% of patients with Hashimoto thyroiditis [10]. Uncertainty lies within the issue of whether autoimmune thyroid disorder is a risk factor or a cause of autoimmune liver disease, or vice versa, warranting further exploration.

The mechanism behind the development of autoimmune hepatitis is still not completely clear. A complex interplay between genetic predisposition, molecular mimicry, and effector-regulatory immunity is thought to be involved in the pathogenesis of autoimmune hepatitis. The presentation of an autoantigenic peptide to nave CD4 T-helper cells (Th0) causes the secretion of proinflammatory cytokines like IL-12, IL-6, and TGF-B which leads to the development of Th1, Th2, and Th17 cells [11]. Th1 cells produce IL-2 and IFN-y, which activate cytotoxic T lymphocytes (CD8), thereby inducing the expression of HLA class I and II molecules on hepatocytes with further stimulation of macrophages. Th2 cells secrete IL-4, IL-10, and IL-14, leading to the maturation of B cells and plasma cells that produce autoantibodies [11]. Regulatory T cells (Treg) derived from Th0 cells are responsible for restricting hepatocellular injury by Th1, Th17, macrophages, complement, and natural killer cells [8,12]. Th17 cells produce cytokines that suppress Treg cells, thus amplifying liver damage along with the cascading effects of Th1 and Th2 cells, leading to the formation of characteristic lymphocytic and plasma cell infiltrates termed interface hepatitis [8].

As per another study, SPW 2, a neutral polysaccharide derived from Sambucus leaves, induced the secretion of IL-beta, IL-6, and TNF-alpha and increased the mRNA expression level of IL-6 and TNF-alpha in macrophages in vitro [6].

Sambucus species, commonly known as elderberry, is a traditional dietary supplement used to treat minor health conditions, particularly influenza [5]. While there are insufficient data to substantiate the effectiveness of elderberry, some studies have displayed its immunomodulatory effects. In a study done by Barak et al., Sambucol (elderberry) extract led to the production of inflammatory cytokines including IL-1 beta, TNF-alpha, IL-6, and IL-8 (2-45 fold) as compared to lipopolysaccharide, a known monocyte activator (3.6-10.7 fold) in vitro, thereby concluding that Sambucol extract activates the immune system by increasing inflammatory cytokine production [5]. Another comparable study revealed similar in vitro effects of Sambucus as well as its ability to stimulate the mRNA expression of inducible Nitric oxide synthase in macrophages, supporting the notion of elderberrys potential regulatory effects on the immune system [6]. Considering the aforementioned discussion, it is worth debating whether elderberry may be contributing to the amplification of the cytokine production in vivo, inciting autoimmunity in genetically predisposed individuals - parallel to the development of autoimmune hepatitis in our patient with a history of a known autoimmune condition (Hashimoto's thyroiditis) on long-term elderberry supplements.

In addition to playing a vital role in the diagnosis, the purpose of a liver biopsy in AIH is to determine the prognosis, severity of the disease, and therapeutic response. The characteristic histological features of AIH are depicted by the presence of interface hepatitis or piecemeal necrosis, which is the inflammation of hepatocytes at the junction of the portal tract and hepatic parenchyma consisting of lymphocytes and plasma cells [13]. However, there exists approximately 25% overlap between AIH and acute viral hepatitis, with the degree of plasmacytosis being the discriminating factor, although 33% of patients with AIH do not exhibit plasma cells in the portal tract, and thus diagnosis should be made in the context of a clinical and serological background [13]. The presence of eosinophils seen in Figure 1can correspond to a differential diagnosis of drug-induced hepatitis, although these findings can also be seen with AIH, making it difficult to differentiate between the two and establish a clear diagnosis. At the same time, our patient had a negative hepatitis serology, which helped in making the distinction.Another entity that is relevant to our case is a drug-induced liver injury with autoimmune features, which is a syndrome where one develops biochemical and histological features of autoimmune hepatitis after the ingestion of a drug or a herbal product [14,15]. It has a shorter incubation period with a gradual improvement observed after the inciting drug is stopped and can recur if it is re-introduced, whereas idiopathic AIH requires long-term immunosuppression [14,15]. In addition to the presence of a pre-existing autoimmune condition (Hashimotos thyroiditis) in our patient, there is a possibility that elderberry supplements could have initiated a self-propagating autoimmune process that could have caused the liver injury.

The cornerstone of treatment in AIH lies in limiting inflammation and preventing the progression to end-stage liver disease [11]. Debilitating symptoms like arthralgia and fatigue accompanied by hepatic inflammation, serum AST elevation 10-fold upper normal limit or AST elevation 5-fold upper normal limit concurrent with -globulin level 2-fold upper normal limit, and histological findings of bridging necrosis are absolute indications for treatment [16]. Treatment regimens include prednisone alone or in conjunction with azathioprine, which is continued until normalization of transaminases and IgG is achieved and is further maintained depending on the individuals response and tolerance to therapy [2,11,16]. Considering the possibility of drug-induced hepatitis, our patient was instructed to stop the elderberry supplement and not to reuse it again. In addition, she was given immunosuppressive therapy to treat the significant hepatic inflammation as evidenced by severely elevated transaminases and liver biopsy. A four-week course of prednisone resulted in the resolution of symptoms and normalization of liver function tests. She was started on azathioprine maintenance therapy with a plan to potentially discontinue it after sustained remission for 18 months. Follow-up over time regarding the development of flare-ups, should they arise, will shed light on the subject of autoimmune hepatitis triggered by elderberry, as opposed to elderberry-induced hepatic injury. This could aid in recognizing the significance of using elderberry judiciously in patients with a history or predisposition to autoimmune disorders.

Exposure to elderberry could be responsible for either the initiation or progression of autoimmune liver disease in the setting of genetic predisposition and molecular mimicry. Therefore, obtaining a meticulous history pertaining to medications is warranted, with an emphasis on over-the-counter supplements. A combination of serum-specific antibodies and distinct histological features in the liver biopsy can aid in formulating a diagnosis, while an initial course of steroids along with indefinite immunosuppressive therapy is essential to control inflammation as well as avert relapses.

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A Plausible Association Between the Use of Elderberry and Autoimmune Hepatitis - Cureus