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Tag: Perelman School of Medicine at the University of Pennsylvania

  • First-in-human clinical trial of CAR T cell therapy with new binding mechanism shows promising early responses

    First-in-human clinical trial of CAR T cell therapy with new binding mechanism shows promising early responses

    Newswise — SAN DIEGO – Early results from a Phase I clinical trial of AT101, a new CAR T cell therapy that uses a distinct binding mechanism to target CD19, show a 100 percent complete response (CR) rate at the higher dose levels studied in the trial, according to researchers from the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center. The findings were published today in Molecular Cancer and presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 2096).

    CAR T cell therapy has revolutionized treatment for many people with blood cancers who had run out of other treatment options. While some patients experience long-term responses to CAR T cell therapy, it doesn’t work–or the cancer eventually returns–for others. The CD19 CAR T cell therapies that are currently approved all target CD19 through the same epitope (FMC63). To try and make CD19 CAR T cell therapy more effective for more patients, Marco Ruella, MD, an assistant professor of Hematology-Oncology and Scientific Director of the Lymphoma Program, and his research team, along with the Korean company AbClon Inc, co-developed a CAR T product (AT101), using cells originating from the same patient, that targets CD19 through a different epitope, located closer to the cell membrane, via a novel antibody (h1218). In preclinical studies, the team previously demonstrated that h1218-CART19 had decreased T cell exhaustion and improved control compared to FMC63-CART19.

    The Phase I first-in-human clinical trial (NCT05338931) was conducted in South Korea and enrolled 12 patients with relapsed or refractory B cell non-Hodgkin’s lymphoma (NHL). The study was designed to increase the dose level of AT101 after safety was confirmed in the first six patients. After a median follow-up of 6.5 months, all six patients who received dose level 2 or higher experienced a complete response and their cancer has not relapsed.  

    “We’ve learned that the way you design your CAR really matters. Designing a different CAR might drastically change the way the T cells work, potentially allowing that CAR T cell product to work where other CAR T cell products have failed,” Ruella said. “We were not expecting such a drastic early difference in this study. The CART19 products that are already FDA-approved are very effective, and it’s not easy to do better. While there is not a randomized trial of this product yet, the initial results seem very promising, and we look forward to moving into the planned Phase II portion of the study.”

    The drug was found to be safe, with manageable side effects, including cytokine-release syndrome in four patients and immune-cell-related neurotoxicity syndrome in three patients. One patient experienced grade 3 sepsis that resolved; the same patient later developed fatal neutropenic septic shock outside the dose-limiting toxicity time frame.

    The Phase I study enrolled patients who had not previously received any other CAR19 therapy. In the Phase II expansion, the study will also include patients who have previously received CAR19 therapy.

    Editor’s Note: The study was funded by AbClon Inc; Ruella is a paid consultant for the company and has a Sponsored Research Agreement with them.

    Yunlin Zhang, MS, a research specialist in Ruella’s lab, will present the findings in a poster session on Saturday, Dec. 9, from 5:30 to 7:30 p.m. PT in the San Diego Convention Center Halls G-H.

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    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

    The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

    The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

    Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.

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  • Third Elaine Redding Brinster Prize Awarded for Development of Sickle Cell Disease Therapy

    Third Elaine Redding Brinster Prize Awarded for Development of Sickle Cell Disease Therapy

    Newswise — PHILADELPHIA—For his work discovering the basis for hemoglobin gene switching and applying those insights to develop a therapy for sickle cell disease and other blood diseases, the Institute for Regenerative Medicine at the University of Pennsylvania awarded Stuart Orkin, MD the third Elaine Redding Brinster Prize in Science or Medicine.

    Orkin’s research advanced the understanding of how the fetal hemoglobin gene— the main oxygen carrier protein in the human fetus—is silenced in adults. He also developed a therapy that re-activates the fetal gene for adult hemoglobin gene defects, which cause red blood cell diseases.

    “Dr. Orkin has beautifully illustrated how a career of basic science investigation into the mechanisms for gene regulation can be applied, in one’s own laboratory, to a method for combating devastating human diseases. Notably, his discovery of unexpected details in how the fetal hemoglobin gene is regulated suggested insights for a therapy, for which he availed of the latest gene editing technologies to develop a specific clinical application for sickle cell disease,” said Ken Zaret, PhD, director of Penn’s Institute for Regenerative Medicine and the Joseph Leidy Professor of Cell and Developmental Biology in the Perelman School of Medicine. “We are thrilled that Dr. Orkin is the third awardee of the Elaine Redding Brinster Prize.”

    The prize, supported by an endowment from the children of Elaine Redding Brinster, is awarded annually to a researcher whose singular discovery has made a unique impact on biomedicine. Each winner receives $100,000, a commemorative medal, and an invitation to present a ceremonial lecture at the University of Pennsylvania.

    Orkin will accept the prize on March 13, 2024, as part of the day-long Ralph L. Brinster Symposium at Penn’s Philadelphia campus. The symposium will feature eminent speakers from across the biomedical sciences, including Titia de Lange, PhD, of Rockefeller University; Carla Shatz, PhD, of Stanford University; Alejandro Sànchez Alvarado, PhD, of the Stowers Institute for Medical Research; and Marianne Bronner, PhD, of the California Institute of Technology.

    “I am very honored, and humbled, by recognition with the Brinster Prize. I hope that work of my laboratory will inspire others to pursue a career of fundamental discovery for the benefit of patients,” said Orkin, the David G. Nathan Distinguished Professor of Pediatrics, Harvard Medical School, and investigator with Howard Hughes Medical Institute.

    Orkin has been honored with several prestigious awards, including the Canada Gairdner International Award, the Gruber Foundation Prize in Genetics, the King Faisal Prize in Medicine, the Kovaleno Medal of the National Academy of Sciences, and the Harrington Discovery Institute Prize for Innovation in Medicine. Orkin is also a member of the U.S. National Academy of Medicine and National Academy of Sciences.

    Previous recipients of the Elaine Redding Brinster Prize include molecular biologist C. David Allis, PhD, and neurogeneticist Huda Zoghbi, MD.

    The Penn Institute for Regenerative Medicine is dedicated to researching cells and tissues with an eye toward turning the knowledge gained into new diagnostic and therapeutic techniques and tools. A member of the International Society for Stem Cell Research’s (ISSCR) Circle of Stem Cell Institute and Center Directors, the institute features faculty from five schools across the University of Pennsylvania and includes representation from Children’s Hospital of Philadelphia and the Wistar Institute.

     

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    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

    The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

    The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

    Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.

    Perelman School of Medicine at the University of Pennsylvania

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  • Real-World Data Suggests Stopping Immunotherapy after Two Years is Reasonable in Patients with Advanced Lung Cancer

    Real-World Data Suggests Stopping Immunotherapy after Two Years is Reasonable in Patients with Advanced Lung Cancer

    Newswise — CHICAGO – Over the past decade, the approval of immune checkpoint inhibitors has revolutionized treatment for patients with advanced lung cancer, helping many live longer lives and improving overall survival for the disease. However, an important question has remained unanswered: How long should a patient with advanced non-small cell lung cancer (NSCLC), who receives immunotherapy as part of their initial treatment, continue with treatment?

    A new retrospective cohort study, published today in JAMA Oncology and presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 9101) by researchers from Penn Medicine’s Abramson Cancer Center, suggests that it’s reasonable to stop immunotherapy treatment at two years as long as their cancer hasn’t progressed. The researchers found no statistically significant difference in overall survival between patients who stopped treatment at two years and those who continued treatment indefinitely.

    “We hope this data provides reassurance that stopping treatment at two years is a valid treatment strategy that does not seem to compromise overall survival,” said lead author Lova Sun, MD, an assistant professor of Hematology-Oncology at the Perelman School of Medicine at University of Pennsylvania. “In the absence of definitive prospective data about the duration of therapy – which will take years to accumulate – our goal was to use real-world observational data to provide guidance on this important clinical question.”

    The appropriate length of treatment remains an open question because pivotal clinical trials have used different treatment durations, and as therapies have been approved and become widely available, many patients have continued therapy beyond the one to two years tested in clinical trials. The longer a patient continues treatment, the higher the health care costs become – both to the patient and to the health care system – and there is ongoing risk of immune-related side effects.

    In this study, the researchers analyzed de-identified data from a national electronic health record that included patients with advanced NSCLC who were treated in both academic and community settings. Of the 1,091 patients who received an immune checkpoint inhibitor as part of their initial therapy (either alone or in combination with chemotherapy) and whose cancer had not continued to grow, only one in five stopped immunotherapy at two years and were considered the “fixed duration” group for this analysis. The vast majority who continued treatment beyond two years were considered the “indefinite duration” group.

    The team analyzed the data and found similar overall survival probabilities between the two groups: 79% for fixed duration and 81% for indefinite duration.

    “Ultimately, the field is still on the leading edge of determining the most appropriate duration for these immunotherapies that have been so effective for patients with advanced lung cancer,” said senior author Charu Aggarwal, MD, MPH, the Leslye M. Heisler Associate Professor for Lung Cancer Excellence in Hematology-Oncology at Penn. “This study provides important data that we hope will help patients feel less worried about potential risks of coming off therapy and more confident if they decide to discontinue treatment after two years.” 

    Sun will share the results in a poster session on Sunday, June 4, at 8 a.m. CT in Hall A.

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    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise. 

    The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year. 

    The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others. 

    Penn Medicine is powered by a talented and dedicated workforce of more than 47,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live. 

    Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

    Perelman School of Medicine at the University of Pennsylvania

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  • Two Penn Medicine Abramson Cancer Center Faculty Members Receive Top ASCO Awards

    Two Penn Medicine Abramson Cancer Center Faculty Members Receive Top ASCO Awards

    Newswise — PHILADELPHIA –  Two esteemed leaders from the Penn Medicine Abramson Cancer Center and Perelman School of Medicine at the University of Pennsylvania will be honored with 2023 Special Awards from the American Society for Clinical Oncology (ASCO), and Conquer Cancer, the ASCO Foundation, during the 2023 ASCO Annual Meeting, taking place June 2-6 in Chicago, Illinois.

    Angela DeMichele, MD, MSCE, the Jill and Alan Miller Endowed Professor in Breast Cancer Excellence, co-leader of the Breast Cancer Research Program in the Abramson Cancer Center, and co-director of the 2-PREVENT Breast Cancer Translational Center of Excellence, is the 2023 recipient of the Gianni Bonadonna Breast Cancer Award. Carmen E. Guerra, MD, MSCE, FACP, the Ruth C. and Raymond G. Perelman Professor of Medicine, vice chair of Diversity and Inclusion in the department of Medicine, and associate director of Diversity and Outreach for the Abramson Cancer Center, is the 2023 recipient of the ASCO Excellence in Equity Award.

    “We are delighted to see Dr. Guerra and Dr. DeMichele recognized for their impactful contributions to equity in cancer care and in breast cancer research,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center. “Through bench-to-bedside research and community outreach and engagement, their work has made a difference for cancer patients and families across our community and the country. We are so grateful to have them as part of our team.” 

    Angela DeMichele, MD, MSCE, Gianni Bonadonna Breast Cancer Award

    The Gianni Bonadonna Breast Cancer Award was created to honor the profound contributions of Dr. Gianni Bonadonna, who made several pioneering contributions to the field of oncology. The award recognizes an active clinical and/or translational researcher with a distinguished record of accomplishments in advancing the field of breast cancer and with exceptional mentoring abilities. DeMichele is recognized for her instrumental role in the development of palbociclib, one of the first CDK4/6 inhibitors—a class of targeted therapy drugs used to treat certain types of HR-positive and HER2-negative breast cancer. As a physician-scientist, her research centers on the development of experimental therapeutics, investigation of prognostic and predictive biomarkers, and design of novel approaches to identify and treat minimal residual disease to prevent recurrence for breast cancer. The 2-PREVENT Breast Cancer Translational Center of Excellence that she co-directs at Abramson Cancer Center is focused on identifying and treating dormant or “sleeper” cells that may persist after initial breast cancer treatment through innovative clinical trials. She holds leadership roles in numerous national oncology groups, including ECOG-ACRIN and the I-SPY Consortium and is the chair-elect for the ASCO Scientific Program Committee.

    DeMichele’s award lecture will be available to attendees on demand for online viewing. 

    Carmen E. Guerra, MD, MSCE, FACP, Excellence in Equity Award

    The ASCO Excellence in Equity Award, endowed by the American Cancer Society, recognizes ASCO members who have made significant and measurable contributions towards increasing equity, diversity, and inclusion within the field of oncology, or increasing access to equitable care for cancer patients. Guerra is recognized for her persistent work to advance equitable access to cancer clinical trials, cancer screenings, and care. She has led the development of several cancer screening patient navigation programs, including the Flu-FIT program, an effort that began as a drive-through event during the COVID-19 pandemic, where participants could receive both a flu shot and a FIT kit for at-home testing to screen for colorectal cancer. She has also established community outreach and engagement programs to increase participation of Black patients in cancer clinical trials, which have resulted in doubling the percentage of Black participants enrolled in clinical trials at Abramson Cancer Center. As the co-chair of two ASCO-Association of Community Cancer Centers workgroups, Guerra helped create an unconscious bias training and a self-assessment on equity, diversity, and inclusion for cancer research teams.

    Guerra will participate in the Mentorship and Career Development Roundtable Discussion with ASCO’s Special Award Recipients on Sunday, June 4 at 10 a.m. CT in S103.

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    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise. 

    The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year. 

    The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others. 

    Penn Medicine is powered by a talented and dedicated workforce of more than 47,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live. 

    Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

     

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  • Penn Medicine to Open New Crisis Response Center as Part of a Unified Mental Health Care Hub at Hospital of the University of Pennsylvania – Cedar Avenue

    Penn Medicine to Open New Crisis Response Center as Part of a Unified Mental Health Care Hub at Hospital of the University of Pennsylvania – Cedar Avenue

    Newswise — PHILADELPHIA—Penn Medicine is launching a new community mental health hub at the Hospital of the University of Pennsylvania — Cedar Avenue (HUP Cedar), co-locating inpatient and outpatient psychiatric care with a new crisis response center (CRC) at the facility. The multi-year plan will put crucial psychiatric and substance use care in easy reach for West and Southwest Philadelphia residents, at a time when both mental illness and drug and alcohol dependence are surging in the city.

    The project will begin with moving inpatient psychiatric and drug and alcohol detoxification units from Penn Presbyterian Medical Center to HUP Cedar in July, followed by the opening of a new crisis response center at the facility later in the summer which is expected to provide an estimated 4,000 patient visits each year. The steps will create two comprehensive, fully integrated mental health hubs at Penn Medicine facilities in Philadelphia, offering emergency mental health services and inpatient and outpatient care at both HUP Cedar and Pennsylvania Hospital, which has operated a CRC since 1999. Together, Pennsylvania Hospital and HUP Cedar will have 73 licensed inpatient psychiatric beds and 16 beds for substance use treatment. Additional space at HUP Cedar will allow for expansion of coordinated services to further care for West and Southwest Philadelphia communities over the next five years.

    “The COVID-19 pandemic accelerated the mental health crisis across the nation. As COVID recedes, we have a moral imperative to tackle this suffering in our communities,” said Kevin B. Mahoney, chief executive officer of the University of Pennsylvania Health System (UPHS). “Providing easy access to care when people are in crisis changes – and saves – lives. We are committed to the investment and innovation needed to close the gaps in access to care and reverse the toll of mental health and substance use in Philadelphia.”

    As one of the nation’s largest cities, Philadelphia’s mental health struggles are a microcosm of broader trends: A Pew Research Center survey from late 2022 reported that 41 percent of Americans — and nearly 60 percent of young adults — have experienced high levels of psychological distress at least once since the early stages of the pandemic. At the same time, more than two-thirds of Americans live in areas without sufficient psychiatrists and other mental health professionals. In Philadelphia, more than 20 percent of the city’s residents are coping with a diagnosed depressive disorder and substance use-related deaths have climbed to record levels.

    Similar to the CRC at Pennsylvania Hospital, the HUP Cedar CRC — which will replace the CRC previously operated on the site by Mercy Philadelphia Hospital until its closure in March of 2020 — will be licensed as a crisis intervention walk-in facility and will serve as a discreet psychiatric emergency room, providing triage, evaluation, treatment and social services support for acute substance use and serious psychiatric conditions such as bipolar disorder, major depression, anxiety disorders, and schizophrenia.

    The co-location of the inpatient psychiatric units with emergency care provided through the CRC will enable a seamless transition of care for patients, eliminating the wait time and additional steps required to transfer patients to inpatient units at other facilities — a common occurrence in a city where emergency psychiatric resources remain in short supply.

    “We know that a lack of quality mental health support and crisis response services has a traumatic ripple effect across families and entire communities. When patients and families are coping with a mental health crisis, the last thing they need to think about is how to navigate a complex system,” said UPHS Chief Operating Officer Michele Volpe. “By putting all our services together, we can help keep patients safer, get them into treatment faster, and better support families as they begin to navigate supporting their loved ones during their hospitalization and recovery.”

    Staff at both CRC locations will be connected via a real-time data system providing details on bed availability in order to ensure patients can be placed as quickly as possible and that each location has the right staffing resources. Penn Presbyterian will continue to provide select outpatient psychiatric care as well treatment for substance use disorders after the transition of inpatient services to HUP Cedar.

    HUP Cedar is part of the PHMC Public Health Campus on Cedar, which opened in March 2021, transitioning the building from the former Mercy Philadelphia Hospital into a campus offering emergency and inpatient care as well as primary care and community-driven social supports.

    Penn Medicine will invest $5.76M toward the opening of the CRC at HUP Cedar as part of the mental health hub project. The CRC reopening has also received funding from the Independence Blue Cross Foundation, and the City of Philadelphia Department of Behavioral Health earmarked $4.1 million in HealthChoices reinvestment funds.

    In addition to Penn Medicine’s adult mental health services on the site, Children’s Hospital of Philadelphia plans to open an inpatient pediatric behavioral health facility, the CHOP Behavioral Health & Crisis Center, on the site, as well. The 46-bed acute inpatient psychiatric facility and 24/7 walk-in crisis center will create a safe, inclusive and restorative setting for children and adolescents.

    The second phase of the new mental health hub plan will also increase care capacity at Penn Presbyterian Medical Center (PPMC), by converting the vacated psychiatric beds to medical surgical units. Those steps will help to improve patient movement across the hospital, reducing emergency department wait times and providing additional capacity for post-surgery recovery.

    The new services at HUP Cedar are part of Penn Medicine’s wraparound commitment to bringing more mental health care support to the community across each of its mission areas. Penn Integrated Care (PIC), a program, which embeds mental health professionals in primary care practices, launched in 2018. More than 230,000 patients in 24 Penn Medicine primary clinics have access to PIC services. To date, 35,000 patients have been treated directly by PIC clinicians or connected to specialty care in the community.

    Beginning this summer, the health system will add a new path for training fellows in drug and alcohol use treatment. That program, for physicians specializing in family medicine, primary care, and emergency medicine, among other disciplines, aims to ensure that providers in multiple settings are equipped to help patients take steps toward recovery and provides a much-needed addition to the existing fellowship in Addiction Psychiatry at Penn Medicine and the Corporal Michael J. Crescenz Veterans Affairs Medical Center (CMC VAMC) in Philadelphia.

    In addition, a new consultation service provides psychiatric care to patients hospitalized for complex medical needs at the Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Penn Presbyterian Medical Center. Future plans include potential opening of a medical-psychiatric unit to ensure that patients with these complex needs are cared for in dedicated spaces.

    “Expanding our resources to care for mental health needs in Philadelphia is a core part of our mission,” said Hospital of the University of Pennsylvania CEO Regina Cunningham, PhD, RN. “No matter where people live in the city, we aspire to provide them with support in convenient settings, and work to erase both the stigmas and access problems that stand in the way of helping people get help.”

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  • Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

    Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

    Newswise — PHILADELPHIA— A new approach to the genetic engineering of cells promises significant improvements in speed, efficiency, and reduction in cellular toxicity compared to current methods. The approach could also power the development of advanced cell therapies for cancers and other diseases, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

    In the study, which appeared this week in Nature Biotechnology, researchers found that protein fragments used by some viruses to help them get into cells could also be used to get CRISPR-Cas gene editing molecules into cells and their DNA-containing nuclei with extraordinarily high efficiency and low cellular toxicity.

    The scientists expect the new technique to be particularly useful for modifying T cells and other cells from a patient’s own body to make cell therapies. One such application could be CAR T (chimeric antigen receptor T cell) therapy, which uses specially modified immune cells from a patient to treat cancer. The T cells—a type of white blood cell—are removed from the patient and reprogrammed to find and attack cancer cells when reintroduced to the bloodstream.  

    The first FDA-approved CAR T therapy was developed at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States. The therapies have revolutionized the treatment of certain B cell leukemias, lymphomas, and other blood cancers, putting many patients who otherwise had little hope into long-term remission.

    “This new approach—building on Penn Medicine’s history of cell and gene therapy innovation—has the potential to be a major enabling technology for engineered cellular therapies,” said co-senior author E. John Wherry, PhD, Richard and Barbara Schiffrin President’s Distinguished Professor and chair of Systems Pharmacology & Translational Therapeutics at Penn Medicine.

    CRISPR-Cas molecules are derived from ancient bacterial antiviral defenses, and are designed to precisely remove DNA at desired locations in a cell’s genome. Some CRISPR-Cas-based systems combine the deletion of old DNA with the insertion of new DNA for versatile genome editing. This approach can be used to replace faulty genes with corrected ones or delete or modify genes to enhance cellular function. Some systems can also add genes that confer new properties to CAR T cells such as the ability to recognize tumors or withstand the harsh tumor microenvironment that normally exhausts T cells.

    Although CRISPR-Cas systems are already widely used as standard laboratory tools for molecular biology, their use in modifying patients’ cells to make cell-based therapies has been limited—in part because CRISPR-Cas molecules can be hard to get into cells and then into cells’ DNA-containing nuclei.

    “Current methods of getting CRISPR-Cas systems into cells, which include the use of carrier viruses and electric pulses, are inefficient for cells taken directly from patients (called primary cells). These methods also typically kill many of the cells they are used on, and can even cause broad unwanted changes in gene activity,” said co-senior author Shelley L. Berger, PhD, the Daniel S. Och University Professor in Cell and Developmental Biology and Genetics and director of the Penn Epigenetics Institute.

    In the study, researchers explored the use of small, virus-derived protein fragments, called peptides, to pilot CRISPR-Cas molecules more efficiently through the outer membranes of primary human cells and into their nuclei. Notably, researchers found that a fused combination of two modified peptides—one found in HIV and one in influenza viruses—could be mixed with CRISPR-Cas molecules to get them into primary human or mouse cells and their nuclei with efficiencies of up to nearly 100 percent, depending on the cell type—with almost no toxicity or gene-expression changes.

    The team demonstrated the approach, which they call PAGE (peptide-assisted genome editing), for several types of envisioned cell therapy including CAR T cell therapies.

    In addition to its potential use in cell and gene therapies, the authors note the PAGE approach could see wide application in basic scientific research. The inefficiency of standard CRISPR-Cas cell penetration methods has meant that gene-editing to create mouse models of diseases typically requires a multi-step, time-consuming process of generating transgenic mice—to introduce the gene-editing machinery into their DNA. By contrast, PAGE with its high efficiency and low toxicity might enable rapid, efficient, and straightforward gene editing in ordinary lab mice.

    “The simplicity and power of the peptide-assist concept suggests that it could potentially be adapted in the future for the delivery into primary cells of other genome-editing proteins, or even protein-based drugs,” said co-senior author Junwei Shi, PhD, an assistant professor of Cancer Biology and member of the Penn Epigenetics Institute and Abramson Family Cancer Research Institute.

    The study was a collaboration that included the laboratories of Penn co-author Rahul Kohli, MD, PhD, an associate professor of Infectious Diseases and Biochemistry and Biophysics, and co-author Gerd Blobel, MD, PhD, the Frank E. Weise III Professor of Pediatrics and co-director of the Epigenetics institute.

    This study was supported by the National Institute of Health (R01-HL119479, R01-GM138908, AI105343, AI082630, AI108545, AI155577, AI149680, U19AI082630, R35-CA263922, R01-CA258904), the Parker Institute for Cancer Immunotherapy, and institutional funds from University of Pennsylvania.

    Perelman School of Medicine at the University of Pennsylvania

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  • Penn Medicine Awarded $9.7 Million from The Warren Alpert Foundation for Genetic Counselor Continuing Education Efforts

    Penn Medicine Awarded $9.7 Million from The Warren Alpert Foundation for Genetic Counselor Continuing Education Efforts

    Newswise — PHILADELPHIA— Penn Medicine has received a $9.7 million grant from The Warren Alpert Foundation (WAF) that will fund continuing education efforts for genetic counselors, to ensure opportunities for continued training that will keep them on the leading edge of their profession interpreting genomic data and explaining its implications to patients. This grant will position genetic counselors to advance research to address the many critical questions in the implementation of genomic information into clinical practice.

    Spearheaded by genetics researchers and faculty members in the Perelman School of Medicine (PSOM) at the University of Pennsylvania, the WAF-Career Ladder Education Program for Genetic Counseling program will allow genetic counselors to continue their education and learn about new and emerging research trends. This advanced training will further inform their work helping individuals learn about specific hereditary disorders, assess risks, and make proactive decisions in areas from cancer prevention to family planning. Penn will lead these efforts, in close collaboration with four other leading institutions: Baylor College of Medicine, Northwestern University Feinberg School of Medicine, Vanderbilt University School of Medicine, and the University of Washington School of Medicine.

    According to the U.S. Bureau of Labor Statistic, the genetics counseling field is expected to see rapid growth over the next decade.  To enter the field, genetic counselors typically must complete a bachelors degree and a masters degree related to the field. However, unlike other health professions, there are currently few opportunities to formally continue and advance their training with this career. “Genetic counseling is only about 50 years old, and the world of genetics is moving at lightning speed. It can be challenging for genetic counselors to stay aware of the rapid changes in the field—especially for those based at smaller, community hospitals. It is vital for the field to keep genetic counselors on the forefront of research and education, and initiatives like this help to ensure genetic counselors are an integral part of the future of genomic medicine,” said Kathleen Valverde, PhD, LCGC, director of Penn’s Master of Science in Genetic Counseling Program.

    The grant funds the newly created WAF-Career Ladder Education Program for Genetic Counseling at Penn, which aims to drive continued education for genetic counselors through multiple pathways. This includes the creation of a state-of-the-art online continuing education unit (CEU) courses for genetic counselors. Each one-credit CEU course will contain 10 hours of instruction, lectures, activities, and assessments to provide in-depth coverage on designated topics in genomics and personalized medicine such as variant interpretation. Other initiatives include developing a certificate program with targeted area of advanced training, and pathways for the development of a post-graduate doctoral degree in genetic counseling, are being explored.

    “Genetic counselors are crucial for all aspects of genomic medicine, including molecular diagnostics, clinical genetics, and genomics research, and are essential to modern health care systems.  Creating a robust career ladder to support genetic counselors’ advanced training and professional development is critical in retaining genetic counselors in academic health systems, advancing genomics research, and implementing genomic information into clinical practice,” said Daniel Rader, MD, chair of Genetics and Chief of Translational Medicine and Human Genetics at Penn. “This commitment to the career development of genetic counselors will be transformational, not just at the five participating institutions but also nationally and globally.”

    PSOM will partner with four other institutions around the nation: Baylor College of Medicine, Northwestern University Feinberg School of Medicine, Vanderbilt University School of Medicine, and the University of Washington School of Medicine. These institutions, along with Penn, represent geographically diverse areas of the United States, and were chosen as recipients of a portion of the WAF grant money based on their clinical programs in genetics and genomics expertise, their existing genetic counseling masters programs, and their history of engaging in research. The five institutions will work together to create and offer programs and opportunities for genetic counselors to advance their skills.

    “Given the increasing complexity of career development and the expanded roles for genetic counselors, support in career development is imperative. We are excited to support the career ladder for genetic counselors and we are delighted to award Penn this grant,” said August Schiesser, WAF executive director.

    Perelman School of Medicine at the University of Pennsylvania

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  • Penn Medicine Invests in Future Nurses with ASPIRE Program at the Hospital of the University of Pennsylvania

    Penn Medicine Invests in Future Nurses with ASPIRE Program at the Hospital of the University of Pennsylvania

    Newswise — PHILADELPHIA – Penn Medicine has partnered with the Howley Foundation and La Salle University to launch the ASPIRE Program at the Hospital of the University of Pennsylvania (HUP), marking an important investment in the future of nursing. The high school and college program will support local high school students in Philadelphia with a goal of increasing diversity in health care and offering opportunities for economic mobility. The program is supported by a commitment from the Howley Foundation of up to $7.5 million.

    Each year, up to 25 outstanding high-school juniors will be selected to be ASPIRE scholars and participate in an enrichment program, lasting for the reminder of their high-school careers. The enrichment program offers mentorship and exposure to health care, the role of nurses, patient safety, and more through a series of interactive and hands-on sessions at the hospital. The first cohort of high-school students will begin with juniors in early 2023.

    Upon graduation and fulfillment of requirements, students then have the opportunity to pursue a Bachelor of Science in Nursing (BSN) at La Salle University with financial support from federal grants, a school scholarship, and a scholarship from the ASPIRE Program itself—which is funded by the Howley Foundation and Penn Medicine. During that time, they will have the opportunity to apply for paid positions at HUP where they can practice their skills and gain more relevant experience.

    “ASPIRE firmly aligns with Penn Medicine’s and HUP’s goals to offer pipeline opportunities for members of our community to continue cultivating an inclusive workforce and providing outstanding patient care,” said Colleen Mattioni, DNP, MBA, the chief nurse executive at HUP. “The ASPIRE Program will welcome a diverse pool of young people into an environment of research, innovation, and evidenced based practice, and high quality clinical care. Of course, we will benefit from participants’ enthusiasm, curiosity, and passion.”

    The first portion of the program consists of both lecture-type lessons and hands-on learning in the hospital for the high school students. Instructors are HUP nurses and hospital staff. While the students will not participate in clinical work with hospital patients, they will have opportunities to observe and assist nurses and other clinicians. At the end of this part of ASPIRE, scholars will also have a better understanding of the life of a nurse and the skills and approach required to excel at the job.

    “Those who begin nursing school may not have much experience with the field unless they’ve volunteered somewhere or perhaps they have family members who are nurses,” said Beth A. Smith, MSN, the corporate director of Nursing Professional Development at HUP. “Not only will this program attract a more diverse generation of future nurses, but will also provide a unique opportunity to see the impact nurses make while providing them with skills and giving them a strong head start in a nursing career.”

    During their college years, the ASPIRE Scholars will benefit from ongoing support and guidance through advisors who will offer guidance and support on academic and other matters effecting their education. They will also have regular check-ins with their peers and instructors from the program.

    “We are excited to see the ASPIRE Program grow over time and look forward to creating an environment where ASPIRE scholars can thrive academically and professionally,” said Smith.

    The ASPIRE Program at HUP builds upon the model established by the Howley Foundation for the Cleveland Clinic in 2017.

    “The central focus of The Howley Foundation is supporting quality educational opportunities, and the many wonderful institutions of learning in the Philadelphia region have served generations of our own family well,” said Nick Howley, chair and founder of the Foundation. “We believe these programs are the keys to creating meaningful social and economic mobility, and we are thrilled to work with Penn Medicine and La Salle whose strengths align so closely with our mission. We look forward to  seeing the ASPIRE model in Philadelphia and providing the region’s students an educational continuum that spans exposure to the nursing profession, training and mentorship, and very real opportunities for employment.”

     

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    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise.

    The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year.

    The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

    Penn Medicine is powered by a talented and dedicated workforce of more than 52,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

    Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

    Perelman School of Medicine at the University of Pennsylvania

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  • FDA Approves “Glowing Tumor” Imaging Drug to Aid Lung Cancer Surgery

    FDA Approves “Glowing Tumor” Imaging Drug to Aid Lung Cancer Surgery

    Newswise — PHILADELPHIA—The U.S. Food and Drug Administration (FDA) has approved the targeted imaging agent Cytalux (pafolacianine) for use in lung cancer surgery. This injectable diagnostic binds to cancerous tissue and glows when stimulated by near-infrared light, making it easier for surgeons to remove tumors completely while sparing healthy tissue.

    Thoracic surgeons at the Center for Precision Surgery in the Abramson Cancer Center at the University of Pennsylvania led the clinical trials evaluating the imaging agent in lung cancer, in a partnership with the Indiana-based manufacturer, On Target Laboratories. This is the second approval for Cytalux, following an approval last year for ovarian cancer surgery, also based on clinical studies in which Penn Medicine led one of the largest sites in country.   

    “The availability of this imaging agent has major implications for thoracic surgery and lung cancer patients, who make up the vast majority of thoracic surgery cases,” said Sunil Singhal, MD, the William Maul Measey Professor in Surgical Research and director of the Center for Precision Surgery at Penn Medicine. “It will allow us to do less invasive operations, find additional cancer, and more accurately detect any remaining cancer, potentially saving patients from reoperation or additional therapy.”

    More than 130,000 Americans die of lung cancer each year, making lung cancer the leading cause of cancer mortality in the country. Lung cancer mortality is high largely because it tends to be diagnosed at later stages when the tumor has begun to spread. About 20 percent of cases, or roughly 50,000 per year, are localized enough to be treated surgically, in the hope of a cure. But even with surgery there is a high chance of recurrence, which implies that standard visual and tactile inspection often fails to detect all cancerous tissue.

    Cytalux was designed to enhance this detection rate in surgeries where the tumor is removed. The imaging drug is infused into the patient pre-operatively, and binds to a surface protein called the folate receptor alpha (FRα), which is expressed at abnormally high levels in lung tumors and several other types of tumor. The imaging agent is designed so that, under illumination with infrared light, it will produce a glowing emission that can be detected by a special infrared camera. The camera outputs to a real-time display, enhancing the surgeon’s ability to see probable cancerous tissue. This type of technology is known as intraoperative molecular imaging.

    The randomized Phase III ELUCIDATE trial (NCT04241315), completed last year, showed that the imaging agent helped detect cancer that would have been missed by conventional techniques in more than 50 percent of patients with confirmed or suspected lung cancer. Singhal was the principal investigator of the multi-site study and presented the results at the American Association for Thoracic Surgery Annual Meeting in May 2022.

    Penn Medicine has led the field of intraoperative imaging, driving advancements to bring this imaging agent to patients. As a pioneer in the field of tumor imaging, Singhal has been working with Cytalux for nearly a decade, spearheading efforts to study it in hundreds of surgeries, in both clinical trials and exploratory studies, for ovarian and lung cancer. The Center for Precision Surgery and its affiliated Penn Medicine researchers have also developed several other innovative technologies for imaging brain, breast, head and neck, and urinary tract cancers.

    “Today’s approval gives thoracic surgeons a new tool to accurately detect and remove cancer tissue, while sparing healthy lung tissue,” Singhal said. “With intraoperative molecular imaging, our ultimate goal is to improve patient care through more precise surgery.” 

    Editor’s Note: Funding for Cytalux clinical studies conducted at Penn and the Center for Precision Surgery was provided by On Target Laboratories.

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    Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise.

    The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year.

    The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

    Penn Medicine is powered by a talented and dedicated workforce of more than 52,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

    Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

    Perelman School of Medicine at the University of Pennsylvania

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  • Novel Drug Shows Early Promise in Treating Multiple Myeloma

    Novel Drug Shows Early Promise in Treating Multiple Myeloma

    Newswise — NEW ORLEANS –  A first-of-its-kind drug known as modakafusp alfa has shown early potential in combating multiple myeloma, a form of bone marrow cancer, in a study presented by researchers from the University of Pennsylvania’s Abramson Cancer Center at the 2022 American Society of Hematology (ASH) Annual Meeting (Abstract 565). 

    Patients in the Phase I/II multicenter trial (NCT03215030) receiving 1.5 milligrams of modakafusp every four weeks, 43 percent saw a partial response, or a decrease in their cancer by over 50 percent. Patients enrolled in the study had received at least three prior lines of treatment and had their disease relapsed or stopped responding following the previous therapy. 

    “We are excited by these findings and continue to be optimistic about the potential this treatment holds for patients with multiple myeloma,” said presenting author Dan Vogl, MD, an expert in blood cancers, medical director of the Clinical Research Unit at Penn Medicine’s Abramson Cancer Center, and an associate professor of Hematology-Oncology at the Perelman School of Medicine of the University of Pennsylvania. “We have been working with this new medication at Penn since we gave it to the first patient ever to receive it five years ago. We now see that a substantial number of patients benefit from modakafusp as a single agent, including patients whose myeloma has become resistant to other treatments, which is really impressive.” 

    Modakafusp (developed by Takeda Pharmaceuticals) is fusion protein that targets interferon (a pro-inflammatory hormone that is also used for treating viral infections and other cancers) to cells that have CD38, a surface marker present on myeloma cells and a variety of immune cells. 

    According to the American Cancer Society, about 12,640 deaths from multiple myeloma are expected to occur in the U.S. in 2022. The cancer is uncommon, affecting less than 1 percent of the population. Myeloma is currently not curable, and despite advances in treatment, all patients see their cancers relapse after initial treatment and other early lines of therapy. In this trial, modakafusp made a positive difference in people for whom drugs aimed at the same target, including well-established monoclonal antibodies like daratumumab and isatuximab, were no longer effective. 

    Preliminary results from the study were presented during the 2021 ASH Annual Meeting. The final safety and efficacy results presented this year confirm the drug has a manageable side effects and produces strong anti-myeloma responses. 

    “Modakafusp has a truly novel mechanism of action, delivering a hormonal signal directly to target cells that simultaneously is toxic to cancer cells while stimulating an immune response. We saw responses in patients whose cancer did not respond to or who experienced a relapse after receiving the anti-CD38 antibody drugs that are currently on the market,” Vogl said. “We also saw responses in patients whose myeloma had developed resistance to all currently available effective therapies.” 

    Most patients (87 percent) on the study experienced treatment-related adverse events, as expected for this heavily pre-treated population. The most common side effects among study participants included neutropenia, or a decrease in white blood cells and thrombocytopenia, or low blood platelet count; and about one third of patients had mild reactions after infusion of the medication. 

    Vogl and his colleagues are now enrolling patients in a randomized phase II study, which is designed to identify the optimal dose of modakafusp and provide more information about its effectiveness in people with myeloma. 

    The study was sponsored by Takeda Pharmaceuticals. 

    Editor’s note: Vogl has received consulting fees from Takeda.

     

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    Perelman School of Medicine at the University of Pennsylvania

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  • Penn Medicine Researchers Present Advance in Re-Treatment with CAR T Therapy

    Penn Medicine Researchers Present Advance in Re-Treatment with CAR T Therapy

    Newswise — NEW ORLEANS –  Researchers from the University of Pennsylvania’s Abramson Cancer Center presented preliminary results of an ongoing Phase I clinical trial demonstrating successful re-treatment with CAR T cell therapy for patients whose cancers relapsed after previous CAR T therapy at the 2022 American Society of Hematology (ASH) Annual Meeting (Abstract 2016).

    CAR T therapies have revolutionized blood cancer treatment over the last decade, providing hope for patients who have run out of conventional treatment options, but patients whose cancers return or stop responding to CAR T therapy have limited options for further treatment.

    The first-in-human study (NCT04684563) evaluated a novel fourth-generation CAR T therapy in patients with non-Hodgkin lymphoma (NHL) who had previously received CAR T therapy that failed to stop their cancer. The study is the first clinical trial in the United States with anti-CD19 CAR T cells secreting interleukin 18 (IL 18). The early results show this combination approach is safe and did not result in new or increased side effects compared to other commercially available CAR T therapies. 

    Senior author and CAR T pioneer Carl June, MD, led the preclinical research that demonstrated IL18 could enhance CAR T activity. “We designed an ‘armored’ CAR that secretes IL18 and tested it in mice, where we found it to have potent antitumor efficacy in our preclinical studies,” said June, who is the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of the Center for Cellular Immunotherapies at Penn’s Abramson Cancer Center.

    Among the first seven patients who received huCART19-IL18 – including those who previously did not respond to or relapsed following treatment with commercial CAR T cell therapies – all responded to the therapy (four patients had a complete response and three patients had a partial response). None of the four patients whose cancers completely responded to treatment at month three have seen their disease return, and all patients are alive at a median follow-up of eight months.

    “Patients whose cancers don’t respond or become refractory to CAR T therapy tend to have poor outcomes, so we are very motivated to find new options for them,” said lead author Jakub Svoboda, MD, an associate professor of Hematology-Oncology at Penn. “Although these are preliminary results, it’s encouraging to see how well these patients have done.  Our team at Penn is very excited about this ongoing project and these early results continue to motivate us.”

    The study enrolled patients with CD19+ relapsed/refractory NHL or chronic lymphocytic leukemia (CLL), who had received at least two lines of therapy, including CAR T therapy. The study is continuing to increase the dose of huCART19-IL18 and will enroll patients one at a time until the appropriate dose is determined.

    Toxicities related to huCART19-IL18 were temporary and similar to those which have been observed with other CAR T products. Cytokine release syndrome occurred in four patients and neurotoxicity occurred in two patients. No grade four adverse events or study-related deaths have occurred.

    Notably, with a three-day manufacturing time, huCART19-IL18 can be ready to administer more quickly than CAR T products with the typical manufacturing time of nine to 14 days, which is especially important for patients with aggressive, fast-growing disease. A previous, preclinical study found the shortened manufacturing time also may enhance the potency of the T cells.

    Svoboda will present the abstract in a poster session on Saturday, Dec. 10 from 5:30 to 7:30 p.m. CT in Hall D.   

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    Perelman School of Medicine at the University of Pennsylvania

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  • Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness

    Gene Therapy Rapidly Improves Night Vision in Adults with Congenital Blindness

    Newswise — PHILADELPHIA—Adults with a genetic form of childhood-onset blindness experienced striking recoveries of night vision within days of receiving an experimental gene therapy, according to researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

    The patients had Leber Congenital Amaurosis (LCA), a congenital blindness caused by mutations in the gene GUCY2D. The researchers, whose findings are reported in the journal iScience, delivered AAV gene therapy, which carries the DNA of the healthy version of the gene, into the retina of one eye for each of the patients in accordance with the clinical trial protocol. Within days of being treated, each patient showed large increases, in the treated eye, of visual functions mediated by rod-type photoreceptor cells. Rod cells are extremely sensitive to light and account for most of the human capacity for low-light vision.

    “These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness,” said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology at Penn.

    LCA is one of the most common congenital blindness conditions, affecting roughly one in 40,000 newborns. The degree of vision loss can vary from one LCA patient to another but all such patients have severe visual disability from the earliest months of life. There are more than two dozen genes whose dysfunction can cause LCA.

    Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the “phototransduction cascade”—the process that converts light to neuronal signals. Prior imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, especially in rod-rich areas, hinting that rod-based phototransduction could work again if functional GUCY2D were present. Early results with low doses of the gene therapy, reported last year, were consistent with this idea.

    The researchers used higher doses of the gene therapy in two patients, a 19- year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits. In daylight, the patients had some, albeit greatly impaired, visual function, but at night they were effectively blind, with light sensitivity on the order of 10,000 to 100,000 times less than normal.

    The researchers administered the therapy to just one eye in each patient, so the treated eye could be compared to the untreated eye to gauge treatment effects. The retinal surgery was performed by Allen C. Ho, MD, a professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests revealed that, in both patients, the treated eyes became thousands of times more light-sensitive in low-light conditions, substantially correcting the original visual deficits. The researchers used, in all, nine complementary methods to measure the patients’ light sensitivity and functional vision. These included a test of room navigation skills in low-light conditions and a test of involuntary pupil responses to light. The tests consistently showed major improvements in rod-based, low-light vision, and the patients also noted functional improvements in their everyday lives, such as “can [now] make out objects and people in the dark.”

    “Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy,” said study co-author Artur V. Cideciyan, PhD, a research professor of Ophthalmology at Penn.

    To the researchers, the results confirm that GUCY2D gene therapy to restores rod-based photoreceptor functions—and suggest that GUCY2D–LCA patients with more severe rod-based dysfunction are likely to benefit most dramatically from the therapy. The practical message is that there should be an emphasis on rod vision measurements at screening of LCA candidates and in monitoring them throughout a treatment trial.

    The findings, the researchers said, also underscore the remarkable fact that in some patients with severe congenital vision loss, the retinal cell networks that mediate vision remain largely alive and intact, and need only the resupply of a missing protein to start working again, more or less immediately.

    The ongoing clinical trial is registered at clinicaltrials.gov as trial NCT03920007.

    Support for the research was provided by Atsena Therapeutics, Inc., the developer of the GUCY2D gene therapy; the National Institutes of Health (R01 EY11522); and by a CURE Formula grant from the Pennsylvania Department of Health.

    Perelman School of Medicine at the University of Pennsylvania

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