$14 Million NIH Grant

Penn Medicine has been awarded a prestigious seven-year, $14 million grant from the National Institutes of Health (NIH) to promote organ transplantation for patients with end-stage renal disease who are currently on the waitlist for a kidney transplant. The team will launch a clinical trial harnessing synthetic chimeric antigen receptor (CAR) T cells—a form of which was developed at Penn Medicine and became the first personalized cellular therapy for cancer—for use in patients for whom a compatible kidney cannot be found due to pre-existing antibodies against potential donors.

There are currently 97,000 patients on the waiting list for a kidney transplant in the United States. A major barrier to successful transplantation in some of these patients is the existence of pre-formed antibodies against potential organ donors, which arise when patients are exposed to other people’s cells or tissues such as through pregnancy, blood transfusion, or previous organ transplants. Patients who form high levels of donor-specific antibodies, termed “highly sensitized,” tend to wait longer on the transplant list and may never receive an organ.

“Engineering novel cellular immunotherapies to help improve access to kidney transplants is an exciting area of research for a unique patient population in great need of lifesaving organs,” said Ali Naji, the J. William White Professor of Surgical Research in the Perelman School of Medicine at the University of Pennsylvania and principal investigator of the study. “We’re committed to discovering an approach to help these currently transplant-ineligible end-stage renal disease patients find a path forward to an organ match.”

The NIH-funded clinical trial led by Penn will use CAR T cells, a form of immunotherapy that has proven remarkably effective as an anti-cancer treatment. Two experimental CAR T cell therapies developed at Penn will be used to deplete immune B cells and plasma cells that make donor-specific antibodies with the hope of achieving a compatible kidney match.

“CAR T cells represent a powerful and specific therapy targeting immune cells that produce antibodies that preclude successful transplantation,” said Carl H. June, the Richard W. Vague Professor in Immunotherapy in the department of pathology and laboratory medicine and director of the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy in Penn’s Abramson Cancer Center. “By combining two CAR T therapies targeting antigens that are found on B cell and plasma cells, we hope to achieve successful kidney transplantation in patients with pre-existing antibodies.”

The trial, which intends to begin enrolling patients by the end of 2022, will be offered at three sites, led by Penn and including the Massachusetts General Hospital/Harvard University and New York University Langone Health.

“Based on previous success with proving that engineered T cell immunotherapies employing synthetic CARs can induce durable remission of B cell lineage and plasma cell malignancies, we are excited for the opportunity to explore this further,” said Alfred Garfall, an assistant professor of hematology at Penn. “With the favorable safety record we observed with this combination cellular approach, there is great anticipation for what Penn’s two experimental CAR T cell therapies could do for patients with cancer, and other conditions, who might benefit from innovative immunotherapies.”

“There is a very high degree of enthusiasm for this research and the impact it can have for patients in need with a treatment approach that could change clinical practice and expand access to transplantation for those with immunologic barriers that currently make them unlikely to receive a transplant,” added Vijay Garud Bhoj, an assistant professor of pathology and laboratory medicine at Penn. “The proposed research we are looking forward to conducting is based on strong preliminary data that suggest both safety and efficacy, which is highly innovative in the field of transplantation.”

$8 Million NIH Transplantation Research Grant

A $8 million grant from the National Institutes of Health (NIH), the next stage of the THINKER project—called THINKER-NEXT—will aim to provide a comprehensive view of the risks and benefits of transplanting HCV-infected kidneys into non-infected patients. The trial will take place for five years at eight institutions, led by Peter Reese, a professor of medicine and epidemiology in the Perelman School of Medicine, and David S. Goldberg, now a professor at the University of Miami, and Douglas E. Schaubel, a professor of biostatistics at the Perelman School of Medicine.

“In the first stage of the trial, we found out that we could cure hepatitis C from the transplant patients. But now we want to know, how well do the organs function compared to others? Do the patients experience any unique complications? Are they susceptible to any other viruses?” Dr. Reese said. “Since this is a study that involves multiple centers, we hope to have enough data about the approach and its long-term implications. This information will be very important if we are to increase adoption of this practice across the country."

Penn Medicine and the seven collaborating institutions will transplant 200 kidneys from HCV-positive donors into new patients during the trial. They will determine: whether pursuing an HCV-positive kidney transplant improves patient survival; the one-year kidney function of HCV-positive kidney transplant recipients; whether the kidney transplant recipients have increased risks of cytomegalovirus infection; and if the prevalence of chronic kidney disease is similar in HCV-positive and HCV-negative kidney donors. The overarching goal is to determine the long-term clinical impact of transplanting kidneys from hepatitis C donors into HCV-negative patients with end-stage kidney disease.

Findings from the THINKER-NEXT project are urgently needed. Currently, the waiting list for a kidney transplant exceeds 94,000 people, with only 14,000 deceased donor kidneys available annually. For the elderly and some other patient groups, it is common to die waiting. Yet, hundreds of kidneys from donors infected with hepatitis C virus are discarded annually, and hundreds more kidneys are never procured because of the perception that that centers won’t accept them.

Emily Blumberg, a professor of infectious diseases; Roy Bloom, a professor of renal-electrolyte and hypertension; Stacey Prenner, an assistant professor of gastroenterology; and Peter Abt, a professor of surgery, provide expertise as co-investigators on the clinical trial.

$2 Million in CDC Grants

More than $2 million in grants from the U.S. Centers for Disease Control and Prevention (CDC) will allow a Penn Medicine team to further develop infrastructure and clinical capacity to address antimicrobial resistance and infectious diseases in Botswana. The grant will support Penn’s work, in collaboration with Children’s Hospital of Philadelphia, at multiple locations across the country through the Botswana-UPenn partnership, a 20-year collaboration between Penn’s Center for Global Health and the University of Botswana and the Botswana Ministry of Health and Wellness. While this grant primarily supports clinical work and capacity, the award also lays the groundwork to conduct more antimicrobial-resistance research in the years ahead.

Funding to Penn is part of a new $22 million, 50-plus-country, and 28-organization total investment from the CDC to tackle antimicrobial resistance, the result of virus, bacteria, and fungi changes that leave microbes tougher to kill and harder to treat in infected patients. In order to curb antimicrobial resistance, clinicians need to track resistance mutations, monitor transmission, and better control infection spread in and out of healthcare settings.

“Thanks to the Penn Center for Global Health, Penn has an extremely well-established relationship on the ground in Botswana and with the University of Botswana,” said Ebbing Lautenbach, chief of infectious diseases at Penn and co-PI of the grant. “Botswana is a key place to continue developing strategies to address antimicrobial resistance. While there is a capable cohort of experts and researchers in Botswana experienced in managing and treating various infectious diseases, there remain considerable challenges to addressing healthcare-associated infection and antibiotic resistance. As such, developing and testing infection-control interventions are vital.”

Antimicrobial resistance, particularly antibiotic resistance, continues to be a growing problem worldwide in part due to the overuse of antibiotics. More responsible antibiotic stewardship and strategies to prevent healthcare infections are just some of many interventions that can be employed to prevent further emergence of resistance.

Penn is among several organizations receiving a CDC antimicrobial-resistance grant. Other institutions receiving grants include the University of Oxford, the World Health Organization, and Johns Hopkins University.