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Wilm's Tumor

PRAME-specific T cell product may facilitate rapid treatment in cancer settings

Wilm's Tumor

PRAME is a cancer-testis antigen that plays a role in cancer cell proliferation and survival and is overexpressed in many human malignancies, including Wilms tumor. “Wilm’s Tumor (Nephroblastoma)” by euthman is licensed under CC BY 2.0.

Generated preferentially expressed antigen in melanoma (PRAME)-specific T cells from healthy donors can kill PRAME-expressing tumor cells in vitro, researchers at Children’s National Hospital found. Several novel epitopes, which are antigens that are recognized by the immune system, were also identified for enhanced matching, making this a potential therapeutic option for a broader patient group, according to a study published in Cytotherapy.

PRAME is a cancer-testis antigen that plays a role in cancer cell proliferation and survival and is overexpressed in many human malignancies, including melanoma, leukemia, sarcoma, renal cell cancer and Wilms tumor. PRAME also acts as a foreign substance in the body that can trigger the immune system by activating T cells, making it a good target for anticancer immunotherapy — especially for immunocompromised patients.

“The development of an effective off-the-shelf adoptive T-cell therapy for patients with relapsed or refractory cancers expressing PRAME antigen requires the identification of epitopes essential to the adaptive immune response, which are presented by major histocompatibility complex (MHC) class I and II, and are then recognized by the manufactured PRAME-specific T cell product,” said Amy Hont, M.D., oncologist for the Center for Cancer and Immunology Research at Children’s National Hospital. “We, therefore, set out to extend the repertoire of HLA-restricted PRAME peptide epitopes beyond the few already characterized and demonstrate the cytotoxic activity of PRAME-specific T cells to tumor cells known to express PRAME.”

Immunotherapy options for pediatric patients with high-risk malignancies, especially solid tumors, are few. Tumor-associated antigen-specific T cells (TAA-T) offer a therapeutic option for these patients, and Children’s National is building upon the success of the ongoing clinical trials to optimize this therapy and improve the treatment of our patients.

“These findings will also benefit patients because it better informs the pre-clinical studies of third party TAA-T to treat high-risk malignancies, so that we can move more quickly and safely to clinical trials,” said Dr. Hont.

Stanojevic et al. describes that the T-cell products killed partially HLA-matched tumors, and that this enhanced disintegration of tumor cells compared with non-specific T cells suggests an anti-tumor potential for a clinical trial evaluation to determine the safety and efficacy. Further research about the PRAME-specific T cells will help inform a treatment alternative for patients with solid tumors in the future.

The researchers generated a PRAME-specific T cell bank from healthy donor cells and demonstrated anti-tumor cytolytic activity against tumor lines partially HLA-matched to the T cells and known to express PRAME. By using epitope mapping, they identified several novel epitopes restricted to MHC class I or MHC class II to further inform HLA matching.

“Defining PRAME-specific T cells beyond HLA epitopes could be useful when developing T-cell therapies for worldwide application,” Stanojevic et al. write. “Moreover, creating off-the-shelf products has many potential advantages since such products are readily available for the treatment of patients with aggressive disease or patients for whom an autologous product cannot be manufactured.”

Additional authors from Children’s National are Maja Stanojevic, M.D., Ashley Geiger, M.S., Samuel O’Brien, Robert Ulrey, M.S., Melanie Grant, Ph.D., Anushree Datar, M.S., Ping-Hsien Lee, Ph.D., Haili Lang, M.D., Conrad R.Y. Cruz, M.D., Ph.D.,  Patrick J. Hanley, Ph.D., A. John Barrett, M.D, Michael D. Keller, M.D., and Catherine M. Bollard, M.D., M.B.Ch.B.

illustration of brain with stem cells

Innovative phase 1 trial to protect brains of infants with CHD during and after surgery

A novel phase 1 trial looking at how best to optimize brain development of babies with congenital heart disease (CHD) is currently underway at Children’s National Hospital.

Children with CHD sometimes demonstrate delay in the development of cognitive and motor skills. This can be a result of multiple factors including altered prenatal oxygen delivery, brain blood flow and genetic factors associated with surgery including exposure to cardiopulmonary bypass, also known as the heart lung machine.

This phase 1 trial is the first to deliver mesenchymal stromal cells from bone marrow manufactured in a lab (BM-MSC) into infants already undergoing cardiac surgery via cardiopulmonary bypass. The hypothesis is that by directly infusing the MSCs into the blood flow to the brain, more MSCs quickly and efficiently reach the subventricular zone and other areas of the brain that are prone to inflammation. The trial is open to eligible patients ages newborn to six months of age.


Learn more in this overview video.

The trial is part of a $2.5 million, three-year grant from the National Institutes of Health (NIH) led by Richard Jonas, M.D.Catherine Bollard, M.B.Ch.B., M.D., and Nobuyuki Ishibashi, M.D.. The project involves collaboration between the Prenatal Cardiology program of Children’s National Heart Institute, the Center for Cancer and Immunology Research, the Center for Neuroscience Research and the Sheikh Zayed Institute for Pediatric Surgical Innovation.

“NIH supported studies in our laboratory have shown that MSC therapy may be extremely helpful in improving brain development in animal models after cardiac surgery,” says Dr. Ishibashi. “MSC infusion can help reduce inflammation including prolonged microglia activation that can occur during surgery that involves the heart lung machine.”

Staff from the Cellular Therapy Laboratory, led by director Patrick Hanley, Ph.D., manufactured the BM-MSC at the Center for Cancer and Immunology Research, led by Dr. Bollard.

The phase 1 safety study will set the stage for a phase 2 effectiveness trial of this highly innovative MSC treatment aimed at reducing brain damage, minimizing neurodevelopmental disabilities and improving the postoperative course in children with CHD. The resulting improvement in developmental outcome and lessened behavioral impairment will be of enormous benefit to individuals with CHD.

For more information about this new treatment, contact the clinical research team: Gil Wernovsky, M.D., Shriprasad Deshpande, M.D., Maria Fortiz.

coronavirus

T-cells show promise to protect vulnerable patients from COVID-19 infection

coronavirus

Children’s National Hospital immunotherapy experts have found that T-cells taken from the blood of people who recovered from a COVID-19 infection can be successfully multiplied in the lab and maintain the ability to effectively target proteins that are key to the virus’s function.

Children’s National Hospital immunotherapy experts have found that T-cells taken from the blood of people who recovered from a COVID-19 infection can be successfully multiplied in the lab and maintain the ability to effectively target proteins that are key to the virus’s function. Their findings were published Oct. 26, 2020, in Blood.

“We found that many people who recover from COVID-19 have T-cells that recognize and target viral proteins of SARS-CoV-2, giving them immunity from the virus because those T-cells are primed to fight it,” says Michael Keller, M.D., a pediatric immunology specialist at Children’s National Hospital, who led the study. “This suggests that adoptive immunotherapy using convalescent T-cells to target these regions of the virus may be an effective way to protect vulnerable people, especially those with compromised immune systems due to cancer therapy or transplantation.”

Based on evidence from previous phase 1 clinical trials using virus-targeting T-cells “trained” to target viruses such as Epstein-Barr virus, the researchers in the Cellular Therapy Program at Children’s National hypothesized that the expanded group of COVID-19 virus-targeting T-cells could be infused into immunocompromised patients, helping them build an immune response before exposure to the virus and therefore protecting the patient from a serious or life-threatening infection.

“We know that patients who have immune deficiencies as a result of pre-existing conditions or following bone marrow or solid organ transplant are extremely vulnerable to viruses like SARS-CoV-2,” says Catherine Bollard, M.D., M.B.Ch.B., senior author of the study and director of the novel cell therapies program and the Center for Cancer and Immunology Research at Children’s National. “We’ve seen that these patients are unable to easily clear the virus on their own, and that can prevent or delay needed treatments to fight cancer or other diseases. This approach could serve as a viable option to protect or treat them, especially since their underlying conditions may make vaccines for SARS-CoV-2 unsafe or ineffective.”

The T-cells were predominantly grown from the peripheral blood of donors who were seropositive for SARS-CoV-2. The study also identified that SARS-CoV-2 directed T-cells have adapted to predominantly target specific parts of the viral proteins found on the cell membrane, revealing new ways that the immune system responds to COVID-19 infection.

Current vaccine research focuses on specific proteins found mainly on the “spikes” of the coronavirus SARS-CoV-2. The finding that T-cells are successfully targeting a membrane protein instead may add another avenue for vaccine developers to explore when creating new therapeutics to protect against the virus.

“This work provides a powerful example of how both scientific advances and collaborative relationships developed in response to a particular challenge can have broad and unexpected impacts on other areas of human health,” says Brad Jones, Ph.D., an associate professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine and co-author on the study, whose lab focuses on HIV cure research. “I began working with Dr. Bollard’s team several years ago out of our shared interest in translating her T-cell therapy approaches to HIV. This put us in a position to quickly team up to help develop the approach for COVID-19.”

The Cellular Therapy Program is now seeking approval from the U.S. Food and Drug Administration for a phase 1 trial that will track safety and effectiveness of using COVID-19-specific T-cells to boost the immune response in patients with compromised immune systems, particularly for patients after bone marrow transplant.

germ cells in testicular tissues

Experimental fertility preservation provides hope for young men

germ cells in testicular tissues

Confirming the presence of germ cells in testicular tissues obtained from patients. Undifferentiated embryonic cell transcription factor 1 (UTF1) is an established marker of undifferentiated spermatogonia as well as the pan-germ cell marker DEAD-box helicase 4 (DDX4). UTF1 (green) and/or DDX4 (red) immunostaining was confirmed in 132 out of 137 patient tissues available for research, including patients who had received previous non-alkylating (B, E, H, K) or alkylating (C, F, I, L) chemotherapy treatment. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Testicular tissue samples obtained from 189 males who were facing procedures that could imperil fertility were cryopreserved at one university, proving the feasibility of centralized processing and freezing of testicular tissue obtained from academic medical centers, including Children’s National, scattered around the world.

“It’s not surprising that the University of Pittsburgh would record the highest number of samples over the eight-year period (51 patients), given its role as the central processing facility for our recruiting network of academic medical centers,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National. “Children’s National recruited the third-highest number of patients, which really speaks to the level of collaboration I have with Jeff Dome’s team and their commitment to thinking about the whole patient and longer-term issues like fertility.”

An estimated 2,000 U.S. boys and young men each year receive treatments or have cancers or blood disorders that place them at risk for infertility. While older youths who have undergone puberty can bank their sperm prior to undergoing sterilizing doses of chemotherapy or radiation, there have been scant fertility preservation options for younger boys. However, some older adolescents and young men are too sick or stressed to bank sperm. For patients with no sperm to bank or who are too sick or stressed to bank sperm, the experimental procedure of freezing testicular tissue in anticipation that future cell- or tissue-based therapies can generate sperm is the only option.

Recent research in experimental models indicates that such testicular tissue biopsies contain stem cells, blank slate cells, hinting at the potential of generating sperm from biopsied tissue.

“This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of these spermatogonia was not tested,” writes lead author Hanna Valli-Pulaski, Ph.D., research assistant professor at the University of Pittsburgh, and colleagues in a study published online May 21, 2019, in Human Reproduction.

Right now, hematologists and oncologists discuss future treatment options with patients and families, as well as possible long-term side effects, including infertility. At Children’s National, they also mention the ongoing fertility preservation study and encourage families to speak with Dr. Hsieh. He meets with families, explains the study goals – which include determining better ways to freeze and thaw tissue and separating malignant cells from normal cells – what’s known about experimental fertility preservation and what remains unknown. Roughly half of patients decide to enroll.

“This study is unique in that there is definitely a potential direct patient benefit,” Dr. Hsieh adds. “One of the reasons the study is compelling is that it presents a message of hope to the families. It’s a message of survivorship: We’re optimistic we can help your child get through this and think about long-term issues, like having their own families.”

In this phase of the study, testicular tissue was collected from centers in the U.S. and Israel from January 2011 to November 2018 and cryopreserved. Patients designated 25% of the tissue sample to be used for the research study; 75 percent remains stored in liquid nitrogen at temperatures close to absolute zero for the patient’s future use. The fertility preservation patients ranged from 5 months old to 34 years old, with an average age of 7.9 years.

Thirty-nine percent of patients had started medical treatment prior requesting fertility preservation. Sixteen percent received non-alkylating chemotherapy while 23% received alkylating chemotherapy, which directly damages the DNA of cancer cells.

The research team found that the number of undifferentiated spermatogonia per seminiferous tubule increase steadily with age until about age 11, then rise sharply.

“We recommend that all patients be counseled and referred for fertility preservation before beginning medical treatments known to cause infertility. Because the decision to participate may be delayed, it is encouraging that we were able to recover undifferentiated spermatogonia from the testes of patients already in the early stages of chemotherapy treatments,” Dr. Hsieh says.

In addition to Dr. Hsieh, study co-authors include lead author, H. Valli-Pulaski, K.A. Peters, K. Gassei, S.R. Steimer, M. Sukhwani, B.P. Hermann, L. Dwomor, S. David, A.P. Fayomi, S.K. Munyoki, T. Chu, R. Chaudhry, G.M. Cannon, P.J. Fox, T.M. Jaffe, J.S. Sanfilippo, M.N. Menke and senior author, K.E. Orwig, all of University of Pittsburgh; E. Lunenfeld, M. Abofoul-Azab and M. Huleihel, Ben-Gurion University of the Negev; L.S. Sender, J. Messina and L.M. Klimpel, CHOC Children’s Hospital;  Y. Gosiengfiao, and E.E. Rowell, Ann & Robert H. Lurie Children’s Hospital of Chicago; C.F. Granberg, Mayo Clinic; P.P. Reddy, Cincinnati Children’s Hospital Medical Center; and J.I. Sandlow, Medical College of Wisconsin.

Financial support for the research covered in this post was provided by Eunice Kennedy Shriver National Institute for Child Health and Human Development under awards HD061289 and HD092084; Scaife Foundation; Richard King Mellon Foundation; University of Pittsburgh Medical Center; United States-Israel Binational Science Foundation and Kahn Foundation.

Eugene Hwang in an exam room

Clinical Trial Spotlight: Creating a super army to target CNS tumors

Eugene Hwang in an exam room

Following the noted success of CAR-T cells in treating leukemia, Eugene Hwang, M.D., and a team of physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors.

Following the noted success of CAR-T cells in treating leukemia, physicians at Children’s National are studying the efficacy of using these white blood cell “armies” to fight central nervous system (CNS) tumors. Employing a strategy of “supertraining” the cells to target and attack three tumor targets as opposed to just one, Eugene Hwang, M.D., and the team at Children’s are optimistic about using this immunotherapy technique on a patient population that hasn’t previously seen much promise for treatment or cure. The therapy is built on the backbone of T cell technology championed by Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research, which is only available at Children’s National. Hwang sees this trial as an exciting start to using T cells to recognize resistant brain cancer. “We have never before been able to pick out markers on brain cancer and use the immune system to help us attack the cancer cells. This strategy promises to help us find treatments that are better at killing cancer and lessening side effects,” he says.

This Phase 1 dose-escalation is designed to determine the safety and feasibility of rapidly generated tumor multiantigen associated specific cytotoxic T lymphocytes (TAA-T) in patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) or recurrent, progressive or refractory non-brainstem CNS malignancies. Pediatric and adult patients who have high-risk CNS tumors with known positivity for one or more Tumor Associated Antigens (TAA) (WT1, PRAME and/or surviving) will be enrolled in one of two groups: Group A includes patients with newly diagnosed DIPGs who will undergo irradiation as part of their upfront therapy and Group B includes patients with recurrent, progressive or refractory CNS tumors including medulloblastoma, non-brainstem high-grade glioma, and ependymoma, among others. TAA-T will be generated from a patient’s peripheral blood mononuclear cells (PBMCs) or by apheresis. This protocol is designed as a phase 1 dose-escalation study. Group A patients: TAA-T will be infused any time >2 weeks after completion of radiotherapy. Group B patients: TAA-T will be infused any time >2 after completing the most recent course of conventional (non-investigational) therapy for their disease AND after appropriate washout periods as detailed in eligibility criteria.

For more information about this trial, contact:

Eugene Hwang, M.D.
202-476-5046
ehwang@childrensnational.org

Click here to view Open Phase 1 and 2 Cancer Clinical Trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

Catherine Bollard and Hemant Sharma

Nationally recognized immunotherapy and pathology experts take on new leading roles at Children’s National

Catherine Bollard and Hemant Sharma

Catherine Bollard, M.D., M.B.Ch.B., has been chosen to serve as director of the Children’s Research Institute’s Center for Cancer and Immunology Research and Hemant Sharma, M.D., M.H.S., will assume the role of chief of the Division of Allergy and Immunology.

Children’s National Health System recently made several exciting leadership announcements in the allergy, immunology and laboratory medicine fields, furthering the hospital’s ongoing commitment to providing the most comprehensive, innovative care for children.

Award-winning hematologist and immunotherapist Catherine Bollard, M.D., M.B.Ch.B., currently chief of the Division of Allergy and Immunology, has been chosen to serve as director of the Children’s Research Institute’s (CRI) Center for Cancer and Immunology Research (CCIR). CCIR includes more than 50 clinicians and scientists performing groundbreaking clinical and translational research in understanding the origins of, and developing and testing novel therapies for childhood cancers and immunologic disorders. The center receives more than $10 million annually from the National Institutes of Health and other external entities. In her new role on the leadership team of CCIR, Dr. Bollard will lead the advancement and oversight of cancer and immunology research performed at Children’s National.

“All of the progress made in cellular immunotherapy here at Children’s National can be attributed to Catherine and her leadership,” says Mark L. Batshaw, M.D., chief academic officer and director of CRI. “We are confident her impact will extend even further in her new role.”

Meghan Delaney

Nationally recognized laboratory medicine expert Meghan Delaney, D.O., M.P.H., has joined Children’s National as chief of pathology and lab medicine.

Hemant Sharma, M.D., M.H.S., will assume the role of chief of the Division of Allergy and Immunology. In 2008, he joined the faculty at Children’s National and started the Food Allergy Program, which he directs today. His areas of interest include health disparities and community-based management of food allergy. He is also site principal investigator of novel clinical trials of immunotherapy for peanut allergy. He serves on the Medical Advisory Board of Food Allergy Research and Education (FARE), and was the recipient of the 2016 FARE Vision Award for his contributions to the national food allergy community. Dr. Sharma also serves as the site director of the allergy immunology fellowship program with the National Institutes of Health and has won various teaching awards.

In addition, nationally recognized laboratory medicine expert Meghan Delaney, D.O., M.P.H., has joined Children’s National as chief of pathology and lab medicine. An expert in the field of transfusion medicine, Dr. Delaney will lead efforts to unify Anatomic Pathology and Laboratory Medicine into a single division, while advancing cutting-edge practices in the lab to ensure the highest standard of quality and safety for patients. Dr. Delaney joins Children’s National from Seattle, where she held many leadership positions including serving as medical director at the Pediatric Apheresis Program at Seattle Children’s Hospital & Seattle Cancer Care Alliance, the blood bank at Seattle Children’s Hospital and the Immunohematology & Red Blood Cell Genomics Reference Laboratory at Bloodworks Northwest.

“Dr. Delaney brings extensive experience in laboratory medicine innovation and program-building, and we are confident she will make a lasting impact on our patients,” said Jeffrey Dome, M.D., Ph.D., vice president for the Center for Cancer and Blood Disorders at Children’s National. “Her leadership will bolster our commitment to providing top quality care for our patients through advancement of lab medicine research and treatments.”

Catherine Bollard named to Medicine Maker’s Annual Power List

Catherine Bollard

Children’s National Health System’s Chief of Allergy and Immunology, Catherine Bollard M.D., has been named to The Medicine Maker’s 2017 Power List, which honors the top 100 most influential people in the world of drug development. Dr. Bollard is featured as a ”Champion of Change,” a category that highlights experts striving to make the world a better place by getting medicines to those who need them the most. She joins notable scientists Frances Collins, director of the U.S. National Institutes of Health, and Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

In the Medicine Maker feature, Dr. Bollard describes the inspiration behind her dedication to cellular immunotherapy and how that led to her team’s breakthrough T-cell therapy that gives complete remissions in over 50 percent of some patient groups. Read the full piece here.

Cell therapy virtuoso: Catherine Bollard

Catherine Bollard

In the Medicine Maker piece, Cell Therapy Virtuoso, Children’s National Medical System’s Chief of Allergy and Immunology, Catherine Bollard M.D., discusses why she chose a career in medicine, the personal experience that ignited her interest in cell therapies, and her insights on the current state and future of the immunotherapy field. Highlights from the interview include:

  • On the promise of T-cell therapy: “We’ve now developed several T-cell therapies that give complete remission rates of approximately 75% and two-year progression-free survival rates ranging from 50 percent to over 90 percent depending on the patient population.”
  • Regarding the future of immunotherapy: “The field has expanded dramatically over the last 25 years. In particular, T-cell therapies for cancer have grown rapidly and now the field is expanding into other areas, such as regulatory T-cells for autoimmune disease and virus T-cells for HIV. Given what the immune system can do, the applications are almost limitless.”

Dr. Bollard was featured for her role as president of the International Society for Cellular Therapy.